Change in apparent and true absorption and retention of dietary zinc with age in rats

Two groups of 16 rats each were fed the same diet with 12.9 ppm Zn. Nine days after each animal was injected with⁶⁵Zn for assessing fecal zinc of endogenous origin, zinc intake and excretion were determined for a six-day period at the age of about five (group I) and nine (II) weeks. At mean growth rates of 5.1 and 5.2 g/day, food consumption per gram of gain was 2.01 g in group I vs 2.86 g in II. Overall, zinc retention amounted to 21 vs 25 μg Zn/g of gain. Apparent absorption averaged 92 vs 74% of Zn intake (132 vs 189 μg/day), while true absorption averaged 98 vs 92%. It was concluded that endogenous fecal zinc excretion was limited to the indispensable loss (F _em) in group I (7 μg/day), while it exceeded this minimum loss in group II (33 μg/day). True retention, which reflected total zinc utilization (true absorption times metabolic efficiency), was derived from apparent absorption plusF _em (11 μg/day for group II according to the greater metabolic body size of the rats). It averaged 98% of Zn intake in group I vs 80% in group II. The mean metabolic efficiency was 100% vs 87%. The conclusion was that these marked differences between age groups in utilizing the dietary zinc reflected the efficient homeostatic adjustments in absorption and endogenous excretion of zinc to the respective zinc supply status.     

Antibody suppression by zinc and nickel

Rats were treated with zinc chloride and with nickel acetate 2 weeks prior to immunization withE. coli bacteriophageT-1; antibody titers to bacteriophageT-1 were reduced 500–2600-fold in metal-treated rats compared to titers found in untreated control animals. Examination of the effect of metal treatment on lymphocyte blastogenesis revealed a significant reduction in the number of blast cells in the spleens of metal-treated rats.     

Increased absorption of zinc from alimentary tract in primary arterial hypertension

Zinc absorption from the alimentary tract, as revealed by serum zinc concentration, was studied in a group of 10 patients (age 37.7±5.1 yr) with moderate and severe untreated primary arterial hypertension before and after a 30-d treatment with perindopril 4 mg/d. Blood pressure was 177.33±16.24/111.33±15.26 mm Hg before and 143.41±17.34/91.29±12.54 mm Hg after treatment (p<0.05/p<0.05). Nine persons (age 37±6.2 yr) with normal blood pressure (121.33±9.9/78±5.23 mm Hg) were the control group. Blood samples were taken from the ulnar vein at 8.00 am (0 h), before taking zinc orally (one tablet of Zincas (zinc aspartate), containing 5 mg Zn²⁺) and at 1, 3, and 6 h after the dose. Serum zinc concentration in control and hypertensive group (before treatment) were initially 15.47±6.26 versus 15.99±5.65 (NS), 19.37±6.40 versus 20.83±4.48 (NS) after 1 h, 17.91±4.76 versus 31.32±10.49 (p<0.003) after 3 h, and 15.32±5.47 versus 17.87±6.56 (NS) after 6 h. Maximal increase of Zn was 4.77±2.10 versus 17.53±4.13, respectively (p<0.001). In the hypertensive group, serum Zn before and after perindopril treatment was initially 15.98±5.65 versus 14.81±3.11 (NS), 20.83±4.48 versus 18.17±2.50 (NS) after 1 h, 31.32±10.49 versus 22.94±5.80 (NS) after 3 h, 17.53±4.13 (p<0.001) after 6 h. Maximal increase of Zn before treatment was 17.53±4.13 versus 9.17±4.67 (p<0.017) after treatment. The following conclusions were reached: (1) In patients with primary arterial hypertension, an increased zinc absorption from alimentary tract was found; (2) A 30-d perindopril treatment 4 mg/d orally decreased zinc absorption in these patients.     

Zinc content in lymphocytes and the activity of zinc ion efflux from lymphocytes in primary arterial hypertension

Clinical observations and experimental data show that zinc (Zn) plays a role in regulating arterial blood pressure and in arterial hypertension etiopathogenesis. To determine the direction of changes in Zn metabolism in primary arterial hypertension, Zn absorption from the alimentary tract, Zn levels in blood serum, its content in lymphocytes, Zn efflux rate constants from lymphocytes, and urinary Zn excretion in patients with hypertension and in healthy subjects were studied. In this article, Zn levels in blood serum, its content in lymphocytes, and Zn efflux rate constants from lymphocytes are presented. In primary arterial hypertension, on the basis of this study, decreasing Zn levels in blood serum and its decreasing content in lymphocytes were found. The Zn efflux rate constants from lymphocytes increased at the initial stage of hypertension (mild arterial hypertension) and decreased in the late stage of the hypertension disease (severe arterial hypertension). Taking into consideration all of the directions of changes and the fact that Zn can be a factor that increases arterial blood pressure, the changes in Zn distribution can be regarded as having, to a certain extent, a protective character leading to weakening of the pressor reaction, assuming a genetic existence of relative or absolute Zn excess in the body. The changes of Zn distribution can lead, after some time, to Zn deficiency and the resulting metabolic changes (e.g., carbohydrate intolerance).     

Determination of standard zinc values in the intact tissues of mice by ICP spectrometry

The most commonly encountered difficulties for the quantitative measurement of zinc in biological samples are the limited sample amount, total and effective digestion of connective and fatty residues, and low zinc concentrations. These problems often lead to the determination of lower zinc values than actually present, so that the sample preparation, digestion, and analytical procedure deserve careful attention. In this short communication, a new method for microwave tissue disintegration is described. The authors have obtained consistent and reproducible results with tissue samples of 0.5 g or less.     

The science and engineering of stem cell-derived organoids-examples from hepatic,biliary, and pancreatic tissues

The field of organoid engineering promises to revolutionize medicine with wide-ranging applications of scientific, engineering, and clinical interest, including precision and personalized medicine, gene editing, drug development, disease modelling, cellular therapy, and human development. Organoids are a three-dimensional (3D) miniature representation of a target organ, are initiated with stem/progenitor cells, and are extremely promising tools with which to model organ function. The biological basis for organoids is that they foster stem cell self-renewal, differentiation, and self-organization, recapitulating 3D tissue structure or function better than two-dimensional (2D) systems. In this review, we first discuss the importance of epithelial organs and the general properties of epithelial cells to provide a context and rationale for organoids of the liver, pancreas, and gall bladder. Next, we develop a general framework to understand self-organization, tissue hierarchy, and organoid cultivation. For each of these areas, we provide a historical context, and review a wide range of both biological and mathematical perspectives that enhance understanding of organoids. Next, we review existing techniques and progress in hepatobiliary and pancreatic organoid engineering. To do this, we review organoids from primary tissues, cell lines, and stem cells, and introduce engineering studies when applicable. We discuss non-invasive assessment of organoids, which can reveal the underlying biological mechanisms and enable improved assays for growth, metabolism, and function. Applications of organoids in cell therapy are also discussed. Taken together, we establish a broad scientific foundation for organoids and provide an in-depth review of hepatic, biliary and pancreatic organoids.     

Effect of zinc on cadmium influx and toxicity in cultured CHO cells

Addition of zinc lowers the toxicity level of cadmium in cultured CHO cells. Cell survival and protein synthesis were used to measure the cellular toxicity of cadmium.¹⁰⁹Cd was used to measure cadmium uptake by the cells. The results suggest that these class IIB transition metals, zinc and cadmium, share a common transport mechanism. Thus, the antagonism appears to involve a reduction in the influx of cadmium due to the presence of zinc.     

Lead increases urinary zinc excretion in rats

The major purpose of this study was to determine whether acute or chronic Pb exposure would increase urinary excretion of zinc in the rat. Four groups of unanesthetized rats were given 0, 0.03, 0.3, or 3 mg Pb (as acetate) kg intravenously, and urinary excretion of zinc, sodium, and potassium was monitored for 6 h. Only at the highest dose was urinary Zn excretion significantly elevated; there were no significant changes in sodium and potassium excretion at any dose. Two other groups of rats were studied for 9 weeks in metabolism cages before and during administration of either 500 ppm Pb (as acetate) or equimolar Na acetate in the drinking water. Two days after Pb treatment and continuing through day 35, Zn excretion was elevated in the Pb-exposed animals; beyond this day, zinc excretion became similar in the two groups. The difference in Zn excretion was not the result of lower water intake by the Pb-treated animals. At sacrifice (70 days after starting Pb exposure), Pb-exposed animals had lower Zn content of the plasma and testis, but there was no difference in kidney Zn. Plasma renin activity was significantly higher in Pb-exposed animals. We conclude that chronic Pb exposure in rats can result in some degree of decreased tissue zinc, which is, at least in part, secondary to increased urinary losses of zinc.     

The zinc transporter Slc39a5 controls glucose sensing and insulin secretion in pancreatic β-cells via Sirt1- and Pgc-1α-mediated regulation of Glut2

Zinc levels are high in pancreatic β-cells, and zinc is involved in the synthesis, processing and secretion of insulin in these cells. However, precisely how cellular zinc homeostasis is regulated in pancreatic β-cells is poorly understood. By screening the expression of 14 Slc39a metal importer family member genes, we found that the zinc transporter Slc39a5 is significantly downregulated in pancreatic β-cells in diabetic db/db mice, obese ob/ob mice and high-fat diet-fed mice. Moreover,β-cell-specific Slc39a5 knockout mice have impaired insulin secretion. In addition, Slc39a5-deficient pancreatic islets have reduced glucose tolerance accompanied by reduced expression of Pgc-1α and its downstream target gene Glut2. The down-regulation of Glut2 in Slc39a5-deficient islets was rescued using agonists of Sirt1, Pgc-1α and Ppar-γ. At the mechanistic level, we found that Slc39a5-mediated zinc influx induces Glut2 expression via Sirt1-mediated Pgc-1α activation. These findings suggest that Slc39a5 may serve as a possible therapeutic target for diabetes-related conditions.     

Comparative studies of zinc metabolism in cultured chinese hamster cells with differing metallothionein-induction capacities

Previous work in our laboratory led to the isolation of a cadmium (Cd)-resistant variant (Cd^r2C10) of the line CHO Chinese Hamster cell having a 10-fold greater resistance to the cytotoxic action of Cd²⁺ compared with the CHO cell. This resistance was attributed to an increased capacity of the Cd²⁺-resistant Cd^r2C10 subline to induce synthesis of the Cd²⁺- and Zn²⁺-binding protein(s), metallothionein(s) (MT). Evidence that Cd²⁺ behaves as an analog of the essential trace metal, Zn²⁺, especially as an inducer of MT synthesis, suggested that the Cd^r and CHO cell types could be employed to investigate cellular Zn²⁺ metabolism. In the present study, measurements were made to compare CHO and Cd^r cell types for (a) growth as a function of the level of ZnCl₂ added to the culture medium, (b) uptake and subcellular distribution of Zn²⁺, and (c) capacity to induce MT synthesis. The results of these measurements indicated that (a) both CHO and Cd^r cell types grew normally (T _d≊16–18 h) during exposures to Zn²⁺ at levels up to 100 μM added to the growth medium, but displayed abrupt growth inhibition at higher Zn²⁺ levels, (b) Cd^r cells incorporate fourfold more Zn²⁺ during a 24-h exposure to the maximal subtoxic level of Zn²⁺ and (c) the CHO cell lacks the capacity to induce MT synethesis while the Cd^r cell is proficient in this response during exposure to the maximal subtoxic Zn²⁺ level. These findings suggest that (a) the CHO and Cd^r cell systems will be useful in further studies of cellular Zn²⁺ metabolism, especially in comparisons of Zn²⁺ metabolism in the presence and absence of induction of the Zn²⁺-sequestering MT and (b) a relationship exists between cellular capacity to induce MT synthesis and capacity for cellular Zn²⁺ uptake.     

Cardiac copper,magnesium, and zinc in recent and old myocardial infarction

X-ray fluorescence spectrometry and atomic absorption spectrometry were used in a quantitative study of zinc, copper, and magnesium in 71 postmortal human hearts. Samples were obtained from individuals who had demonstrated no previous clinical or subsequent pathological findings of myocardial infarction and from victims of a recent or an old infarction. A significant difference (p<0.001) in the elemental levels was observed between the noninfarct and the recent infarct groups. The noninfarct group had higher cardiac levels of all three elements. However, the difference in elemental concentrations between the noninfarct and the old-infarct groups was not significant. Cardiac levels of zinc (p<0.001) and copper (p<0.01) were significantly greater in the old-infarct group than in the recent-infarct group. Magnesium levels were higher in the recent-and-old-infarct group than in the recent infarct group (p<0.01). It is possible that the elements are redistributed during myocardial infarction, and that uptake of these elements (from the serum pool) by the heart may be important in maintaining myocardial integrity and function.     

Effects of dietary zinc levels on the activities of enzymes, weights of organs, and the concentrations of zinc and copper in growing rats

Zinc (Zn) is an essential nutrient that is required in humans and animals for many physiological functions, including immune and antioxidant function, growth, and reproduction. The present study was performed to investigate the effects of three Zn levels, including Zn adequate (35.94 mg/kg, as a control), Zn deficiency (3.15 mg/kg), and Zn overload (347.50 mg/kg) in growing male rats for 6 wk. This allowed for evaluation of the effects that these Zn levels might have on body weight, organ weight, enzymes activities, and tissues concentrations of Zn and Cu. The results showed that Zn deficiency has negative effects on growth, organ weight, and biological parameters such as alkaline phosphatase (ALP) and Cu−Zn superoxide dismutase (Cu−Zn SOD) activities, whereas Zn overload played an effective role in promoting growth, improving the developments of organs and enhancing immune system. Hepatic metallothionein (MT) concentration showed an identical increase tendency in rats fed both Zn-deficient and Zn-overload diets. The actual mechanism of reduction of Cu concentration of jejunum in rats fed a Zn-overload diet might involve the modulation or inhibition of a Cu transporter protein by Zn and not by the induction of MT.     

Biological function of metallothionein. VI. Metabolic interaction of cadmium and zinc in rats

The accumulation and depletion of cadmium in liver and kidney metallothionein (MT) and the effects of dietary zinc deficiency on cadmium metabolism were studied in rats. The accumulation of cadmium in liver MT started to plateau after 80 days, but there was a linear accumulation of this element in kidney MT over the entire 300-day experiment. Cadmium in MT fractions was depleted very slowly when rats were changed to a diet without cadmium. The accumulation of cadmium in MT also caused zinc to accumulate in this protein, even in rats fed zinc-deficient diets. However, the reverse situation was found not to be true; zinc did not cause cadmium to accumulate in MT. Dietary zinc deficiency limited the binding of injected¹⁰⁹Cd to MT of liver, but not of kidneys or testes. However, zinc-deficient rats fed cadmium in their diets metabolized cadmium similarly to zinc-supplemented rats, suggesting that zinc deficiency does not limit the ability of cadmium to stimulate MT synthesis.     

Effect of dietary fenugreek seeds on biliary proteins that influence nucleation of cholesterol crystals in bile

Formation of cholesterol gallstones in gallbladder is controlled by procrystallising and anticrystallising factors present in bile. Dietary fenugreek seed has been recently observed to possess anti-lithogenic potential in experimental mice. In the current animal study, we evaluated the effect of dietary fenugreek on the compositional changes in the bile, particularly its effect on glycoproteins, low-molecular-weight (LMW) and high-molecular-weight (HMW) proteins, cholesterol nucleation time and cholesterol crystal growth. Groups of Wistar rats were fed for 10 weeks with diets: (1) basal control (C), (2) C + fenugreek (12%), (3) high cholesterol diet (HCD) and (4) HCD + fenugreek (12%). Feeding of HCD containing 0.5% cholesterol for 10 weeks rendered the bile lithogenic. Incorporation of fenugreek into HCD decreased the cholesterol content (70.5%), total protein (58.3%), glycoprotein (27.5%), lipid peroxides (13.6%) and cholesterol saturation index (from 1.98 to 0.75) in bile, increased the bile flow rate (19.5%), prolonged the cholesterol nucleation time and reduced the vesicular form of cholesterol (65%), which was accompanied with an increase in smaller vesicular form (94%). There was an increase in biliary phospholipid (33%) and total bile acid (49%) contents in the HCD + fenugreek group as compared with the HCD group. Electrophoretic separation of biliary LMW proteins showed the presence of a high concentration of 28-kDa protein, which might be responsible for the prolongation of cholesterol nucleation time in the fenugreek-fed groups. These findings indicate that the beneficial anti-lithogenic effect of dietary fenugreek, which primarily is due to reduction in the cholesterol content in bile, was additionally affected through a modulation of the nucleating and anti-nucleating proteins, which, in turn, affect cholesterol crystallisation.     

Speciation and bioavailability of zinc in amended sediments

Abstract

The speciation and bioavailability of zinc (Zn) in smelter-contaminated sediments were investigated as a function of phosphate (apatite) and organic amendment loading rate. Zinc species identified in preamendment sediment were zinc hydroxide-like phases, sphalerite, and zinc sorbed to an iron oxide via X-ray adsorption near edge structure (XANES) spectroscopy. Four months after adding the amendments to the contaminated sediment, hopeite, a Zn phosphate mineral, was identified indicating phosphate was binding and sequestering available Zn and Zn pore water concentrations were decreased at levels of 90% or more. Laboratory experiments indicate organic amendments exhibit a limited effect and may hinder sequestration of pore water Zn when mixed with apatite. The acute toxicity of the sediment Zn was evaluated with Hyalella azteca, and bioaccumulation of Zn with Lumbriculus variegates. The survivability of H. azteca increased as a function of phosphate (apatite) loading rate. In contaminated sediment without apatite, no specimens of H. azteca survived. The bioaccumulation of Zn in L. variegates also followed a trend of decreased bioaccumulation with increased phosphate loading in the contaminated sediment. The research supports an association between Zn speciation and bioavailability.     

Tissue zinc dynamics during the immune reaction in mice

Owing to the importance of zinc for the functioning of the immune system, the role of endogenous Zn, located both in lymphoid and nonlymphoid organs, was investigated during the standard humoral and cellular types of immune response. For this purpose, the dynamics of hepatic, thymic, splenic, and renal Zn content was determined in mice sensitized with (a) sheep red blood cells and (b) semiallogeneic lymphocytes during the local host vs graft reaction (HVGR). The data obtained by ion-coupled plasma spectrometry revealed that the humoral type of immunity is characterized by a significant increase of Zn concentration in the liver and in the thymus. Simultaneously, linear regression analysis showed that the generation of plaque-forming cells in the individual mouse was highly positively correlated with Zn concentration in the liver (r = 0.897), and spleen (r = 0.833), and negatively with Zn concentration in the thymus (r = -0.624). Similar relationships between the intensity of local immune reaction and tissue Zn levels were found in local HVGR at the fifth day in the liver and spleen (r = 0.861 andr = 0.695, respectively), at the seventh day in the thymus (r = -0.797), and at the tenth day in the liver (r = -0.859). The data emphasize the necessity of Zn for the development of normal immune response and point to the existence of a Zndependent hepato-thymic axis during the humoral and cellular types of immune reactivity.     

Cadmium,copper, and zinc levels in the rice and rice field soil of Houston,Texas

Fifty-one pairs of hulled rice samples and the soil from which each rice sample was grown were analyzed for heavy metals in August, 1979, in order to estimate the background contamination of cadmium (Cd), copper (Cu), and zinc (Zn) in rice grown in the Houston, Texas area. Both samples were divided into three groups by soil types and colors. The cadmium concentration in Texas rice was only one-half to one-quarter lower than that of Asian rice. However, the levels of Cu and Zn in rice in Texas were similar to those reported. Soil heavy metals were lower than ever reported, but these values were consistent with the geochemical characteristics of the Texas Houston area. No particular relationship was found between the three metals in rice and the metals in soil where the sampled rice was grown.     

Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers

This phase I clinical trial (NCT01935843) is to evaluate the safety, feasibility, and activity of chimeric antigen receptor-engineered T cell (CART) immunotherapy targeting human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancers (BTCs) and pancreatic cancers (PCs). Eligible patients with HER2-positive (>50%) BTCs and PCs were enrolled in the trial. Well cultured CART-HER2 cells were infused following the conditioning treatment composed of nabpaclitaxel (100–200 mg/m²) and cyclophosphamide (15–35 mg/kg). CAR transgene copy number in the peripheral blood was serially measured to monitor the expansion and persistence of CART-HER2 cells in vivo. Eleven enrolled patients received 1 to 2-cycle CARTHER2 cell infusion (median CAR⁺ T cell 2.1 × 10⁶/kg). The conditioning treatment resulted in mild-to-moderate fatigue, nausea/vomiting, myalgia/arthralgia, and lymphopenia. Except one grade-3 acute febrile syndrome and one abnormal elevation of transaminase (>9 ULN), adverse events related to the infusion of CART-HER2 cells were mild-to-moderate. Post-infusion toxicities included one case of reversible severe upper gastrointestinal hemorrhage which occurred in a patient with gastric antrum invaded by metastasis 11 days after the CART-HER2 cell infusion, and 2 cases of grade 1–2 delayed fever, accompanied by the release of C-reactive protein and interleukin-6. All patients were evaluable for assessment of clinical response, among which 1 obtained a 4.5-months partial response and 5 achieved stable disease. The median progression free survival was 4.8 months (range, 1.5–8.3 months). Finally, data from this study demonstrated the safety and feasibility of CART-HER2 immunotherapy, and showed encouraging signals of clinical activity.     

Development of the islets, exocrine pancreas, and related ducts in the Nile tilapia, Oreochromis niloticus (Pisces: Cichlidae)

Pancreatic development and the relationship of the islets with the pancreatic, hepatic, and bile ducts were studied in the Nile tilapia, Oreochromis niloticus, from hatching to the onset of maturity at 7 months. The number of islets formed during development was counted, using either serial sections or dithizone staining of isolated islets. There was a general increase in islet number with both age and size. Tilapia housed in individual tanks grew more quickly and had more islets than siblings of the same age left in crowded conditions. The pancreas is a compact organ in early development, and at 1 day posthatch (dph) a single principal islet, positive for all hormones tested (insulin, SST-14, SST-28, glucagon, and PYY), is partially surrounded by exocrine pancreas. However, the exocrine pancreas becomes more disseminated in older fish, following blood vessels along the mesenteries and entering the liver to form a hepatopancreas. The epithelium of the pancreatic duct system from the intercalated ducts to the main duct entering the duodenum was positive for glucagon and SST-14 in 8 and 16 dph tilapia. Individual insulin-immunopositive cells were found in one specimen. At this early stage in development, therefore, the pancreatic duct epithelial cells appear to be pluripotent and may give rise to the small islets found near the pancreatic ducts in 16-37 dph tilapia. Glucagon, SST-14, and some PPY-positive enteroendocrine cells were present in the intestine of the 8 dph larva and in the first part of the intestine of the 16 dph juvenile. Glucagon and SST-14-positive inclusions were found in the apical cytoplasm of the mid-gut epithelium of the 16 dph tilapia. These hormones may have been absorbed from the gut lumen, since they are produced in both the pancreatic ducts and the enteroendocrine cells. At least three hepatic ducts join the cystic duct to form the bile duct, which runs alongside the pancreatic duct to the duodenum.