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The Role of Zinc in Growth and Cell Proliferation
Abstract
The inhibition of growth is a cardinal symptom of zinc deficiency. In animals fed a zinc-inadequate diet, both food intake and growth are reduced within 4–5 d. Despite the concomitant reduction in food intake and growth, reduced energy intake is not the limiting factor in growth, because force-feeding a zinc-inadequate diet to animals fails to maintain growth. Hence, food intake and growth appear to be regulated by zinc through independent, although well coordinated, mechanisms. Despite the long-term study of zinc metabolism, the first limiting role of zinc in cell proliferation remains undefined. Zinc participates in the regulation of cell proliferation in several ways; it is essential to enzyme systems that influence cell division and proliferation. Removing zinc from the extracellular milieu results in decreased activity of deoxythymidine kinase and reduced levels of adenosine(5′)tetraphosphate(5′)-adenosine. Hence, zinc may directly regulate DNA synthesis through these systems. Zinc also influences hormonal regulation of cell division. Specifically, the pituitary growth hormone (GH)–insulin-like growth factor-I (IGF-I) axis is responsive to zinc status. Both increased and decreased circulating concentrations of GH have been observed in zinc deficiency, although circulating IGF-I concentrations are consistently decreased. However, growth failure is not reversed by maintaining either GH or IGF-I levels through exogenous administration, which suggests the defect occurs in hormone signaling. Zinc appears to be essential for IGF-I induction of cell proliferation; the site of regulation is postreceptor binding. Overall, the evidence suggests that reduced zinc availability affects membrane signaling systems and intracellular second messengers that coordinate cell proliferation in response to IGF-I.
... Growth factors, cytokines, and hormones are primary inducers of cell proliferation [3,35,37]. These molecules activate MAPK, PI3K/AKT, and PKC signaling, all involved in cell growth and proliferation [20,[37][38][39][40]. The phosphorylation reactions of the MAPK cascade, activated by growth factors (e.g., IGF-1 and IGF-2), culminate in the nuclear translocation of extracellular signal-regulated kinases (ERK) and the activation of transcription factors that control key cell cycle events. ...
... Zinc deficiency was shown to reduce IGF-1 levels both in humans and rats [41,42]. Accordingly, in murine fibroblasts, increases in extracellular Zn improved the affinity of IGF-1 and IGF-2 to the IGF receptor and enhanced protein tyrosine phosphorylation and MAPK signaling, leading to cell proliferation [39,43]. On the other hand, Zn chelation abolished MAPK activity in rat fibroblasts, which was reversed by Zn addition [44]. ...
... The secretion of growth hormone (GH) from the pituitary gland also decreases in low-Zn conditions, as observed by low GH expression in the rat liver under Zn depletion [46]. Since GH stimulates liver synthesis and the secretion of IGF-1, this decrease correlates with the low levels of IGF-1 observed in Zn deficiency and the consequent decrease in cell proliferation [39]. Regulation of cyclin D1 expression, together with CDK4/6, is also of great relevance. ...
The trace element zinc (Zn) displays a wide range of biological functions. Zn ions control intercellular communication and intracellular events that maintain normal physiological processes. These effects are achieved through the modulation of several Zn-dependent proteins, including transcription factors and enzymes of key cell signaling pathways, namely those involved in proliferation, apoptosis, and antioxidant defenses. Efficient homeostatic systems carefully regulate intracellular Zn concentrations. However, perturbed Zn homeostasis has been implicated in the pathogenesis of several chronic human diseases, such as cancer, diabetes, depression, Wilson’s disease, Alzheimer’s disease, and other age-related diseases. This review focuses on Zn’s roles in cell proliferation, survival/death, and DNA repair mechanisms, outlines some biological Zn targets, and addresses the therapeutic potential of Zn supplementation in some human diseases.
... Zinc is an essential trace element that serves important structural, enzymatic, and regulatory functions in the tissues and cells of the mammalian body [1][2][3][4]. As the second-most abundant transition metal after iron, its prevalence is a reflection of its widespread functions, which include regulating cell proliferation and differentiation [1,[5][6][7], cell apoptosis [8,9], gene expression and transcription factors [10][11][12], and stabilizing enzyme structures [13]. In addition to its role in basic cellular functioning, the maintenance of zinc homeostasis in the central nervous system also proves vital, the dysregulation of which has been implicated in a wide array of neurological disorders, including neurodevelopmental disorders such as autism spectrum disorder [14][15][16][17], mood disorders such as depression and anxiety [18,19], and neurodegenerative diseases such as Alzheimer's and Parkinson's disease [20][21][22]. ...
... Thus, compared to the ZnT3 KO mice that only have vesicular zinc in the brain eliminated, the bioavailability of zinc throughout the entire body is restricted, which could affect a greater number and variety of proliferation-related pathways [73]. Accordingly, these effects in multiple different pathways can impair normative cellular functioning, resulting in decreased cell proliferation and survival of cells [7,37]. Thus, the systemic loss of zinc may have greater consequences on cell proliferation at P6 than the loss of vesicular zinc, given the more global effects of the former. ...
In the brain, vesicular zinc, which refers to a subset of zinc that is sequestered into synaptic vesicles by zinc transporter 3 (ZnT3), has extensive effects on neuronal signalling and modulation. Vesicular zinc-focused research has mainly been directed to its role in the hippocampus, particularly in adult neurogenesis. However, whether vesicular zinc is involved in modulating neurogenesis during the early postnatal period has been less studied. As a first step to understanding this, we used ZnT3 knockout (KO) mice, which lack ZnT3 and, thus, vesicular zinc, to evaluate cell proliferation at three different age points spanning postnatal development (P6, P14, and P28). The survival and the neuronal phenotype of these cells was also assessed in adulthood. We found that male ZnT3 KO mice exhibited lower rates of cell proliferation at P14, but a greater number of these cells survived to adulthood. Additionally, significantly more cells labelled on P6 survived to adulthood in male and female ZnT3 KO mice. We also found sex-dependent differences, whereby male mice showed higher levels of cell proliferation at P28, as well as higher levels of cell survival for P14-labelled cells, compared to female mice. However, female mice showed greater percentages of neuronal differentiation for P14-labelled cells. Finally, we found significant effects of age of BrdU injections on cell proliferation, survival, and neuronal differentiation. Collectively, our results suggest that the loss of vesicular zinc affects normal proliferation and survival of cells born at different age points during postnatal development and highlight prominent sex- and age-dependent differences. Our findings provide the foundation for future studies to further probe the role of vesicular zinc in the modulation of developmental neurogenesis.
... Zinc plays a critical role in growth and development; it is cofactor for enzymes that control cell division and proliferation. Zinc deficiency impairs the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and protein which has implications on the FFM [21]. Iron is also another important cofactor in the synthesis of amino acids and its deficiency has an effect on metabolism of glucose, lipid biosynthesis and amino acid biosynthesis. ...
... The body composition changes in the present study were attributed to the consumption of the AIVs and these corroborated findings of similar studies done earlier [3,18,19,20,22,23,24,27,28]. Increase in FFM implies growth of soft tissue as a result of increased cell division due to the nutrients supplied by the AILVs consumed [21]. ...
... Particularly, zinc oxide nanoparticles (ZnO-NPs) have gained interest by their effective microbicidal properties against wide pathogen microorganisms, including some antibiotic resistant-bacteria (18,19). Moreover, Zn is an essential trace element in human beings (20), involved in essential cellular processes such as DNA synthesis, enzyme activity, and cell division (21,22). It has been reported that Zn has an essential effect on bone formation and mineralization, stimulating osteoblast cells proliferation (23,24) and increasing the expression of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 A c c e p t e d M a n u s c r i p t 6 osteoblast gene markers and calcium deposition in human bone marrow-derived mesenchymal stem cells (BM-MSC) (25,26). ...
... These results suggest the potential of the PCL-G-1Zn membranes, mainly PCL-G45-1Zn, for generating a favorable cellular microenvironment to promote bone regeneration (78,81). This cellular behavior can be attributed to the presence of ZnO-NPs; zinc is one of the most abundant trace elements in the human body, and plays an essential role in the proper function of many macromolecules and enzymes (20)(21)(22). Our study and other studies have shown that Zn ions at certain concentrations and under some environmental conditions can lead to osteogenic differentiation of stem cells (25,26). ...
Periodontitis is a highly prevalent infectious disease that causes the progressive destruction of the periodontal supporting tissues. If left untreated, it can lead to tooth loss impairing oral function, aesthetics, and the patient's overall quality of life. Guided and Bone Tissue Regeneration (GTR/BTR) are surgical therapies based on the placement of a membrane that prevents epithelial growth into the defect, allowing the periodontal/bone cells (including stem cells) to regenerate or restore the affected tissues. The success of these therapies is commonly affected by the local bacterial colonization of the membrane area and its fast biodegradation, causing postoperative infections and a premature rupture of the membrane limiting the regeneration process. This study presents the antibacterial and osteogenic differentiation properties of polycaprolactone-gelatin (PCL-G) electrospun membranes modified with ZnO nanoparticles (ZnO-NPs). The membranes´ chemical composition, surface roughness, biodegradation, water wettability, and mechanical properties under simulated physiological conditions, were analyzed by the close relationship with their biological properties. The PCL-G membranes modified with 1, 3, and 6 wt.% of ZnO-NPs showed a significant reduction in the planktonic and biofilm formation of four clinically relevant bacteria; A. actinomycetemcomitans serotype b, P. gingivalis, E. coli, and S. epidermidis. Additionally, the membranes presented appropriate mechanical properties and biodegradation rates to be potentially used in clinical treatments. Notably, the membranes modified with the lowest concentration of ZnO-NPs (1 wt.%) stimulated the production of osteoblast markers and calcium deposits in human bone marrow-derived mesenchymal stem cells (BM-MSC) and were biocompatible to human osteoblasts cells (hFOB). These results suggest that the PCL-G membranes with 1 wt.% of ZnO-NPs are high-potential candidates for GTR/BTR treatments, as they were the most effective in terms of better antibacterial effectiveness at a lower NPs-concentration while creating a favorable cellular microenvironment for bone growth.
... More than 300 enzymes require zinc to function properly, and zinc is therefore involved in regulating various cellular processes, including cell division and DNA synthesis [9]. Zinc is thought to interact with 10% of the human proteome, and it is essential for processes such as cell division and protein synthesis [10,11]. More than 99% of intracellular zinc binds to proteins, and although there is growing evidence that interchangeable zinc ions act as second messengers capable of transducing extracellular stimuli into intracellular signaling events, the specific mechanisms remain uncertain [12]. ...
Spinal cord injury (SCI) is accompanied by loss of Zn²⁺, which is an important cause of glutamate excitotoxicity and death of local neurons as well as transplanted stem cells. Dental pulp stem cells (DPSCs) have the potential for neural differentiation and play an immunomodulatory role in the microenvironment, making them an ideal cell source for the repair of central nerve injury, including SCI. The zeolitic imidazolate framework 8 (ZIF-8) is usually used as a drug and gene delivery carrier, which can release Zn²⁺ sustainedly in acidic environment. However, the roles of ZIF-8 on neural differentiation of DPSCs and the effect of combined treatment on SCI have not been explored. ZIF-8-introduced DPSCs were loaded into gelatin methacryloyl (GelMA) hydrogel and in situ injected into the injured site of SCI rats. Under the effect of ZIF-8, axon number and axon length of DPSCs-differentiated neuro-like cells were significantly increased. In addition, ZIF-8 protected transplanted DPSCs from apoptosis in the damaged microenvironment. ZIF-8 promotes neural differentiation and angiogenesis of DPSCs by activating the Mitogen-activated protein kinase (MAPK) signaling pathway, which is a promising transport nanomaterial for nerve repair.
... Deficiencia de zinc: el zinc es indispensable en diversos procesos biológicos básicos relacionados con la expresión de genes, el crecimiento y la diferenciación celular (49); su deficiencia deprime el sistema inmune, ocasiona retardo del crecimiento (24,50), atrofia del timo, linfopenia, deterioro de la función de los linfocitos B, reducción de la actividad quimiotáctica de los neutrófilos, disminución de las concentraciones de interferón y del número de linfocitos T ayudadores CD4+ (51). Las alteraciones en la inmunidad celular y humoral asociadas con la deficiencia de zinc, podrían incrementar la susceptibilidad a la malaria por P. falciparum (52), como lo reveló un estudio de Shankar referenciado por Caulfield (53), en el que la deficiencia moderada de zinc aumentó en 40% la mortalidad por malaria en roedores infectados con P. yoelii. ...
Antecedentes: la malaria, la desnutrición y la inseguridad alimentaria, son problemas de salud pública en Colombia, que deben estudiarse integradamente. Objetivo: describir la relación entre morbimortalidad por malaria con desnutrición proteico-calórica, anemia y deficiencia de vitamina A y de zinc en los niños e inseguridad alimentaria en sus hogares, al igual que el efecto de los suplementos poblacionales de retinol, hierro y zinc sobre morbimortalidad por malaria. Metodología: se consultaron Medline y otras bases biográficas. Resultados: la desnutrición proteico-calórica y las deficiencias de vitamina A y zinc, aumentan la morbimortalidad por malaria. Los estudios sobre los efectos de los suplementos poblacionales de micronutrientes en niños sobre morbimortalidad por malaria por P. falciparum muestran: los de vitamina A, sugieren efecto protector, los de zinc no tienen resultados concluyentes frente a la malaria pero otros beneficios y los de hierro, tienen efecto perjudicial. Los estudios sobre los efectos de tales suplementos sobre la morbimortalidad por malaria por P. vivax son incipientes y en el caso del hierro, parecen estar influenciados por la edad de los niños y si se usan solos o combinados con zinc. La malaria coexiste con la inseguridad alimentaria en el hogar y la prevención de esta última contribuye a reducir la desnutrición infantil y posiblemente la morbimortalidad por malaria. Conclusión: reducir la inseguridad alimentaria disminuirá la desnutrición infantil y las deficiencias de micronutrientes, así contribuirá a reducir la morbi-mortalidad por malaria. En zonas endémicas para P. falciparum, los suplementos poblacionales de vitamina A tienen resultados promisorios: los efectos de los suplementos de zinc no son claros aún y los de hierro son perjudiciales.
... Thus, zinc activates oxidation enzymes and has a dual effect -it supports osteoblastogenesis, inhibits osteoclastogenesis, and strengthens osteogenesis due to the stimulation of collagen synthesis and the increase in the activity of the bone isoenzyme of alkaline phosphatase. At the same time, Zn reduces the toxic effects of other metals, particularly cadmium (Macdonald, 2000;Hadley et al., 2010;Qi et al., 2020;O'Connor et al., 2020). ...
Bone defects that occur with fragment fractures lead to an increase in the number of postoperative complications. Therefore, to restore the structure and function of the bone, there is a need for bone replacement, in particular doped calcium-phosphate ceramics. The purpose of the work is the biochemical assessment of acute-phase and endothelial reactions and immune complex formation during bone replacement with germanium-doped calcium-phosphate ceramics of bone fragment fractures in dogs. Dogs with fragment fractures of long tubular bones and plate osteosynthesis were included in the study. In the experimental group (n = 10), bone defects were replaced with germanium-doped calcium-phosphate ceramics (HА/β-TCP/l-Gе-700), in the control group (n = 10) – unalloyed (HА/β-TCP-700). Blood samples were taken after the injury and on the 3rd, 7th, 14th, 30th, and 60th days after osteosynthesis. Partial recovery of limb function in the experimental group was faster by 1.3 times (P < 0.001) and full by 1.2 times (P < 0.01) compared to the control. On the 60th day, in experimental animals, the defect was filled with a regenerate of high X-ray density without a periosteal reaction, while in the control animals, the bone regenerate did not have sufficient density with a significant periosteal reaction. In both groups, total protein and albumin content varied within the normal range. The activity of protein C on the 3rd day in the experimental group was 1.3 times higher (Р ˂ 0.001), and on the 7th day, it was twice as high (P ˂ 0.001) compared to the control group with normalization by the 14th day. The concentration of ceruloplasmin from the 7th day in the control animals was 1.1 times higher (Р ˂ 0.001) than in the experimental animals, with normalization in the latter by the 60th day. The level of small molecular circulating immune complexes (CIC) after the injury increased by 1.1 times (Р ˂ 0.001) and reached a peak in the control and experimental groups on the 14th day, with an increase in indicators by 2.1 and 1.4 times (Р ˂ 0.001), respectively, with normalization in the experimental group on the 60th day. The level of nitric oxide (NO) in the control group increased from the 7th to the 60th day, with a peak on the 30th day, and in the experimental group – from the 3rd to the 30th, with a peak on the seventh day. Osteoreplacement of fragment fractures of long tubular bones in dogs with calcium-phosphate ceramics doped with germanium is accompanied by a moderate level of the acute phase reaction and immune complex formation, an increase in the endothelial reaction and the anticoagulant potential of the blood, which contributes to a decrease in the intensity of the inflammatory-resorptive stage of reparative osteogenesis and an increase in its proliferative phase, which, respectively, accelerates the consolidation of fractures.
... Overall, Zn supports the quality and density of bone, which can indirectly contribute to optimal growth and height attainment (Hie et al., 2011;Molenda & Kolmas, 2023;Park et al., 2018Park et al., , 2013Seo et al., 2010). It also plays an important role in growth hormone production, DNA transcription-translation, and cell division (Hamza et al., 2012;Ho & Ames, 2002;MacDonald, 2000;Song et al., 2009). The relationship of Zn with IGF-I, height, and weight in our study suggests the abovementioned mechanisms. ...
Objectives:
Copper (Cu) and zinc (Zn) are important trace elements for the growth and development of children. In Wilson disease (WD), impaired Cu metabolism may affect growth. This study was conducted to evaluate the height and weight of children with neurological WD and correlate these with serum Cu, Zn, and insulin-like growth factor-I (IGF-I).
Methods:
This prospective cohort study was conducted in a tertiary care teaching institute. Children with neurologic WD were included. The height, weight, and body-mass index of each child were measured and categorized according to the revised national growth chart. Serum Cu, Zn, calcium, alkaline phosphatase, albumin, thyroid-stimulating hormone, and urinary-Cu were measured. Serum IGF-1 was measured by enzyme-linked immunosorbent assay. The relationship between height and weight with trace elements and IGF was analyzed using parametric or non-parametric tests.
Results:
There were 52 children (5-18 years) with neurologic WD. Thirty-six (69.2%) children had normal height, 12 (23.1%) were tall, and 4 (7.7%) were stunted. Forty-six (88.5%) children had normal weight and six (11.5%) children were underweight. IGF-1 correlated with height, weight, duration of treatment, and serum Zn level. About 15.4% of children had stunting and/or wasting, which was associated with low levels of serum IGF-I, Zn, and calcium.
Conclusions:
Stunting and/or wasting occurs in 15.4% of children with neurologic WD and is associated with reduced serum IGF-I, Zn, and calcium concentration. Adjunctive Zn and calcium treatment may help in achieving normal growth.
... Recent studies have found that caloric restriction reduces in the number of OSNs after OE injury (Iwamura et al. 2019), and long-term caloric restriction induces dorsal zone-specific reduction in the number of OSNs (Tuerdi et al. 2018). However, it is difficult for severely Zn-deficient mice to avoid reduced food intake and weight loss because Zn deficiency causes gastrointestinal disturbances (Skrovanek et al. 2014), depression (Tassabehji et al. 2008), and decreased growth hormone levels (MacDonald 2000). Moreover, because gastrointestinal tract dysfunction induced by Zn deficiency causes impaired absorption of nutrients, it is impossible to eliminate the effects of different level of caloric intakes, even if the amounts of food are the same. ...
The olfactory epithelium can regenerate after damage; however, the regeneration process is affected by various factors, such as viral infections, head trauma, and medications. Zinc is an essential trace element that has important roles in organ development, growth, and maturation. Zinc also helps regulate neurotransmission in the brain; nevertheless, its relationship with olfactory epithelium regeneration remains unclear. Therefore, we used a severe zinc deficiency mouse model to investigate the effects of zinc deficiency on olfactory epithelium regeneration. Male wild-type C57BL/6 mice were divided into zinc-deficient and control diet groups at the age of 4 weeks, and methimazole was administered at the age of 8 weeks to induce severe olfactory epithelium damage. We evaluated the olfactory epithelium before and 7, 14, and 28 d after methimazole administration by histologically analyzing paraffin sections. RNA sequencing was also performed at the age of 8 weeks before methimazole administration to examine changes in gene expression caused by zinc deficiency. In the zinc-deficient group, the regenerated olfactory epithelium thickness was decreased at all time points, and the numbers of Ki-67-positive, GAP43-positive, and olfactory marker protein-positive cells (i.e., proliferating cells, immature olfactory neurons, and mature olfactory neurons, respectively) failed to increase at some time points. Additionally, RNA sequencing revealed several changes in gene expression, such as a decrease in the expression of extracellular matrix-related genes and an increase in that of inflammatory response-related genes, in the zinc-deficient group. Therefore, zinc deficiency delays olfactory epithelium regeneration after damage in mice.
... many cellular processes. In addition, there are more than 200 enzymes that need zinc as a cofactor in order to carry out metabolic processes 11 . It was found that there is an antimicrobial efficacy of glass based on phosphate saturated with zinc in the treatment of urinary tract infections 12 . ...
Bioactive glass (BG) was prepared by sol–gel method following the composition 60-(x\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$x$$\end{document}) SiO2.34CaO.6P2O5, where x = 10 (FeO, CuO, ZnO or GeO). Samples were then studied with FTIR. Biological activities of the studied samples were processed with antibacterial test. Model molecules for different glass compositions were built and calculated with density functional theory at B3LYP/6-31 g(d) level. Some important parameters such as total dipole moment (TDM), HOMO/LUMO band gap energy (ΔE), and molecular electrostatic potential beside infrared spectra were calculated. Modeling data indicated that P4O10 vibrational characteristics are enhanced by the addition of SiO2.CaO due to electron rush resonating along whole crystal. FTIR results confirmed that the addition of ZnO to P4O10.SiO2.CaO significantly impacted the vibrational characteristics, unlike the other alternatives CuO, FeO and GeO that caused a smaller change in spectral indexing. The obtained values of TDM and ΔE indicated that P4O10.SiO2.CaO doped with ZnO is the most reactive composition. All the prepared BG composites showed antibacterial activity against three different pathogenic bacterial strains, with ZnO-doped BG demonstrating the highest antibacterial activity, confirming the molecular modeling calculations.
... Zinc is an essential trace element that is proposed to interact with >10% of the human proteome (Andreini et al., 2006). It is essential for processes including cell division (MacDonald, 2000) and protein synthesis (Kimball et al., 1995). The human body contains approximately 2-3 g of zinc. ...
Increasing evidence suggests that Zn²⁺ acts as a second messenger capable of transducing extracellular stimuli into intracellular signaling events. The importance of Zn²⁺ as a signaling molecule in cardiovascular functioning is gaining traction. In the heart, Zn²⁺ plays important roles in excitation–contraction (EC) coupling, excitation–transcription coupling, and cardiac ventricular morphogenesis. Zn²⁺ homeostasis in cardiac tissue is tightly regulated through the action of a combination of transporters, buffers, and sensors. Zn²⁺ mishandling is a common feature of various cardiovascular diseases. However, the precise mechanisms controlling the intracellular distribution of Zn²⁺ and its variations during normal cardiac function and during pathological conditions are not fully understood. In this review, we consider the major pathways by which the concentration of intracellular Zn²⁺ is regulated in the heart, the role of Zn²⁺ in EC coupling, and discuss how Zn²⁺ dyshomeostasis resulting from altered expression levels and efficacy of Zn²⁺ regulatory proteins are key drivers in the progression of cardiac dysfunction.
... Zinc is essential for growth, immunity, and tissue repair [27]. Zinc deficiency is often presented in IBD patients [28,29], and zinc deficiency plays a role in Fig. 4 Representative micrographs of histopathological changes. ...
Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, are chronic relapsing inflammatory gastrointestinal tract diseases of uncertain origin, which are frequently associated with zinc deficiency. Animal models have a considerable value in elucidating the process of IBD. In this study, 50 male C57BL/6 J mice were randomly assigned to five groups: control group (Con), 2,4,6-trinitrobenzenesulfonic acid (TNBS) group, and three zinc supplementation groups, namely 160 ppm group, 400 ppm group, and 1000 ppm group. The results showed that supplementation of dietary zinc with zinc oxide could effectively relieve the severity of ulcerative colitis induced by TNBS in mice. We demonstrate that the protective mechanism involves the immunomodulation of dietary zinc by increasing CD3⁺, CD3⁺CD8⁺, and Th2 cells, suppressing Th1 and Th17 cells, and decreasing the production of serum IL-1β and IL-18. The dietary zinc oxide seems to be able to suppress the NF-κB/NLRP3 signaling pathway by downregulating the mRNA and protein expression of NIK, IKK, NF-κB, and NLRP3. The results suggest that dietary supplementation of zinc oxide may protect against colitis, and proper daily zinc supplementation may reduce the risk of IBD.
... Zinc is needed for biological processes (for example, DNA and RNA synthesis) that are important for epigenetic mechanism. [37] Also, inadequate maternal intake of zinc might increase risk for gestational hypertension, preeclampsia, preterm delivery, low birth weight for gestational age, and congenital anomalies. [10] Our data showed that approximately 66% of participants met recommendations for zinc, which is similar to a prior study of pregnant women. ...
... ZnO NPs have been subjugated as drug transporters, thereby reducing side and off-target effects and amplifying synergistic effects (Vigneshwaran et al. 2006, Hanley 2008, Mishra 2017. Zinc (Zn) is essential for cell division, skeletal development, and immune system functioning (MacDonald 2000;Rink 2000). Furthermore, Zn has similar mechanical properties to mammalian bone and is a capable biomaterial for loading scaffolds. ...
Mesenchymal stem cells with tissue repair capacity involve in regenerative medicine. MSCs can promote bone repair when employed with nano scaffolds/particles. Here, the MTT and Acridine Orange assay enabled the cytotoxic concentration of Zinc oxide nanoparticles and Polyurethane evaluation. Following culturing adipose tissue-derived MSCs, ADSCs' proliferation, growth, and osteogenic differentiation in the presence of PU with and without ZnO NPs is tracked by a series of biological assays, including Alkaline Phosphatase activity, Calcium deposition, alizarin red staining, RT-PCR, scanning electron microscope, and immunohistochemistry. The results showed boosted osteogenic differentiation of ADSCs in the presence of 1% PU scaffold and ZnO NPS and can thus apply as a new bone tissue engineering matrix. The expression level of Osteonectin, Osteocalcin, and Col1 increased in PU-ZnO 1% on the 7th and 14th days. There was an increase in the Runx2 gene expression on the 7th day of differentiation in PU-ZnO 1%, while it decreased on day 14th. In conclusion, Polyurethane nano scaffolds supported the MSCs’ growth and rapid osteogenic differentiation. The PU-ZnO helps not only with cellular adhesion and proliferation but also with osteogenic differentiation.
... The similarity in final BW of birds subjected to feed restriction regimes is dependent on gut metabolic capacity during the compensatory growth period, and this might be supported by added OZ to diet. Zinc is important nutrient for the functioning of many enzymes (carbonic anhydrase, dehydrogenase, peptidase, phosphatase) and participates in many other enzymatic activities which involved in metabolic processes in the body [47] and therefore it is very necessary for proteins, lipids and carbohydrates metabolism [48]. Zinc is also a powerful antioxidant, which might reduce the oxidative stress status of birds exposed to starvation and the antioxidant supplemented diets are crucial element in lowering the economic cost in poultry production as well [49]. ...
This study was conducted to evaluate the effect of two feed restriction methods with or without powders of peppermint leaves (PL) and organic zinc (OZ) added to diet from 2 to 3 weeks of age followed by compensatory growth stage from 4 to 5 weeks of age on growth performance and economic cost of broilers rearing. The research was included 024 broiler chicks Ross 308 distributed randomly into 7 groups (n=60 chicks per group) with 3 replications each. 1st group (control) was ad libitum feeding (G1), 2nd (G2), 3rd (G3) and 4th (G4) groups were quantitative feed restriction (40%) of control without any dietary additives, or with 1% PL or 50 mg OZ / kg of diet, respectively, whereas 5th (G5), 6th (G6) and 7th (G7) groups were temporal feed restriction (12 hours/day) only or with 1% PL or 50 mg OZ/ kg of diet, respectively. The obtained results revealed there was significant low (p>0.01) in feed intake for all feed restricted groups at 2-3 weeks and for G2, G3 and G4 at 1-5 weeks compared to G1. Similar final body weights to G1 were achieved by G3,G4,G5 and G7 whereas G2, G4, G6 and G7 had similar body weight gain to G1 at 1-5 weeks. It was there an improvement (p>0.01) in feed conversion ratio for all groups at 2-3 weeks and for G2, G3, G4 and G6 at 1-5 weeks compared to G1. Low (p>0.05) total mortality was registered for G3, G5, G6 and G7. High (p>0.01) protein or energy efficiency ratios was in favor of G2, G3, G4 and G7 at 2-3 weeks and an increase (p>0.05) for G3 and G4 at 1-5 weeks compared to G1. High values (p>0.05) of production efficiency factor for all groups except for G5 compared to G1. In comparison to G1, there was high (p>0.01) carcass yield without giblets for G2, G4 and G6 and high (p>0.01) carcass yield with giblets for G3 only. All feed restricted groups reduced the total expenses cost with increase in net revenue and economic efficiency of project. In conclusion, it was improved performance and lowering in economic cost of birds rearing exposed to feed restriction especially in groups potentiated by added PL and OZ in diet therefore, we recommend to follow these regimes in poultry nutrition protocols to support the sustainable development perspectives in poultry industry sector as one of the important agricultural part of a global food system.
... This makes sense since these two elements (zinc and copper) are of great importance to cells and are closely related. These two elements have known essential functions such as: maintaining the integrity of the cell membrane; cell proliferation and growth; having antioxidant properties, by participating in the structure of the antioxidant enzyme superoxide dismutase (SOD), guaranteeing defense against reactive oxygen species (ROS) and consequently also maintaining the integrity of the DNA; being involved in gene expression, apoptosis, among other processes [40][41][42][43][44][45][46][47][48][49]. Due to such functions and their importance, the level of these elements and their transport are tightly regulated [2]. ...
Background
Essential elements have functions in tumor progression by promoting protumoral cellular processes, such as proliferation, and migration, among others. Obtaining an understanding of how these elements relate to tumor progression processes is of great importance for research. Elemental profile studies in distant tissues, which can be modulated by tumor cells to promote metastasis, have not been sufficiently investigated. The main goal of this study is to evaluate multielemental distribution during tumor progression, focusing on tumor tissue and distant tissues that may be affected.
Methods
Tumor progression in vivo was simulated by inoculating C57BL/6 mice with Lewis Lung Carcinoma (LLC) cells. Samples of the primary tumor and distant tissues were collected during 5 weeks of tumor progression for the control and experimental (tumor-bearing) groups. The biological samples were analyzed using the synchrotron radiation X-Ray fluorescence technique. Data on the concentration of P, S, K, Ca, Mn, Fe, Cu, and Zn in the samples were obtained and statistically analyzed to evaluate the distribution of the elements during tumor progression in the primary tumor as well as distant tissues.
Results
It was possible to observe significant changes in the concentrations’ distribution of P, S, K, Ca, Mn, Fe, and Cu in distant tissues caused by the presence of tumor cells. It was also possible to detect a greater similarity between tumor tissue (which has the lung as tissue of origin) and a tissue of non-origin, such as the liver, which is an unprecedented result. Moreover, changes in the distributions of concentrations were detected and studied over time for the different tissues analyzed, such as primary tumor, liver and lung, in Control and Tumor groups.
Conclusions
Among other results, this paper could explore the modulation of distant tissues caused by the presence of a primary tumor. This could be achieved by the evaluation of several elements of known biological importance allowing the study of different biological processes involved in cancer. The role of essential elements as modulators of the tumor microenvironment is a relevant aspect of tumor progression and this work is a contribution to the field of tumoral metallomics.
... Specifically, the pituitary growth hormone (GH)-insulin-like growth factor-I axis is responsive to zinc status. Decreased GH concentrations have been observed in zinc deficiency, suggesting that zinc deficiency results in growth inhibition in animals [22]. Zinc is a component of multiple enzyme systems that control DNA synthesis, normal growth, reproduction, and wound healing [10]. ...
Background and aim:
Eimeria tenella is a causative agent of avian cecal coccidiosis resulting in bleeding, diarrhea, weight loss, high morbidity, and mortality in chickens. Zinc supplementation increases body weight gain, reduces mortality, and improves some immune response parameters of broilers infected with E. tenella. This study aimed to investigate the effects of zinc hydroxychloride (ZnOHCl) supplementation and ZnOHCl combined with an anticoccidial drug on E. tenella infection in broiler chickens.
Materials and methods:
Forty one-day-old broilers were randomly divided into five groups, the study was replicated twice and had four chickens per replicate. Group 1 was an uninfected and unmedicated control group, and Group 2 was an infected but unmedicated control group. Group 3 was infected and treated with 120 mg/kg ZnOHCl, Group 4 was infected and medicated with 7 mg/kg toltrazuril (TOL), and Group 5 was infected and treated with 120 mg/kg ZnOHCl and 7 mg/kg TOL. Body weight gain, feed intake, and feed conversion ratio were monitored on days 15, 21, and 28. Oocyst shedding, hematological data, and lesion scores were analyzed on 7 days post-infection.
Results:
The average weight gain, feed intake, and packed cell volume of chickens treated with ZnOHCl and TOL were significantly higher than those of the infected and unmedicated controls (p ≤ 0.05). Lesion scores, oocyst output, and lymphocytes of the chickens treated with ZnOHCl and TOL were significantly lower than those of the infected and unmedicated controls (p ≤ 0.05).
Conclusion:
This study demonstrated that zinc supplementation alone reduced only oocyst output. However, growth performance, lesion scores, and oocyst output were affected by the combination of ZnOHCl and TOL supplementation. This suggests that ZnOHCl supplementation combined with an anticoccidial drug can improve growth performance and lessen the severity of E. tenella infection.
... In contrast, other CNS regions including the cerebellum and spinal cord contain low concentrations of zinc [87]. Adequate concentrations of zinc are critical under physiological conditions, as zinc is essential for cell division and DNA synthesis, as well as to establish memory function [88,89]. However, in the case of brain diseases such as hypoglycemia, head trauma, epilepsy, and ischemic stroke, it was found that excessively released zinc from synaptic vesicles is translocated and accumulated in the post-synaptic neurons of the hippocampal pyramidal layer and dentate gyrus, as visualized by N-(6-methyl-8quinolye)-para-tolurnesulfonamide [90]. ...
Maintaining the correct ionic gradient from extracellular to intracellular space via several membrane-bound transporters is critical for maintaining overall cellular homeostasis. One of these transporters is the transient receptor potential (TRP) channel family that consists of six putative transmembrane segments systemically expressed in mammalian tissues. Upon the activation of TRP channels by brain disease, several cations are translocated through TRP channels. Brain disease, especially ischemic stroke, epilepsy, and traumatic brain injury, triggers the dysregulation of ionic gradients and promotes the excessive release of neuro-transmitters and zinc. The divalent metal cation zinc is highly distributed in the brain and is specifically located in the pre-synaptic vesicles as free ions, usually existing in cytoplasm bound with metallothionein. Although adequate zinc is essential for regulating diverse physiological functions, the brain-disease-induced excessive release and translocation of zinc causes cell damage, including oxidative stress, apoptotic cascades, and disturbances in energy metabolism. Therefore, the regulation of zinc homeostasis following brain disease is critical for the prevention of brain damage. In this review, we summarize recent experimental research findings regarding how TRP channels (mainly TRPC and TRPM) and zinc are regulated in animal brain-disease models of global cerebral ischemia, epilepsy, and traumatic brain injury. The blockade of zinc translocation via the inhibition of TRPC and TRPM channels using known channel antagonists, was shown to be neuroprotective in brain disease. The regulation of both zinc and TRP channels may serve as targets for treating and preventing neuronal death.
... Finally, zinc deficiency itself may be a component of impaired cellular proliferation, not just in the brain but in all cells. Zinc is needed for DNA synthesis, enzymatic function, and cell cycle progression, [155][156][157] and zinc deficiency causes cell cycle arrest [116,144]. Intestinal ZIP4 loss of function leads to a near 50% reduction in intestinal stem cell division within four days [44]. ...
Zinc is a tightly regulated trace mineral element playing critical roles in growth, immunity, neurodevelopment, and synaptic and hormonal signaling. Although severe dietary zinc deficiency is relatively uncommon in the United States, dietary zinc deficiency is a substantial public health concern in low- and middle-income countries. Zinc status may be a key determinant of neurodevelopmental processes. Indeed, limited cohort studies have shown that serum zinc is lower in people diagnosed with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and depression. These observations have sparked multiple studies investigating the mechanisms underlying zinc status and neurodevelopmental outcomes. Animal models of perinatal and adult dietary zinc restriction yield distinct behavioral phenotypes reminiscent of features of ASD, ADHD, and depression, including increased anxiety and immobility, repetitive behaviors, and altered social behaviors. At the cellular and molecular level, zinc has demonstrated roles in neurogenesis, regulation of cellular redox status, transcription factor trafficking, synaptogenesis, and the regulation of synaptic architecture via the Shank family of scaffolding proteins. Although mechanistic questions remain, the current evidence suggests that zinc status is important for adequate neuronal development and may be a yet overlooked factor in the pathogenesis of several psychiatric conditions. This review aims to summarize current knowledge of the role of zinc in the neurophysiology of the perinatal period, the many cellular targets of zinc in the developing brain, and the potential consequences of alterations in zinc homeostasis in early life.
... More than 200 enzymes require zinc ion as a functional component, and these enzymes affect most major metabolic processes. It plays an essential role in enhancing immune function, protein and DNA synthesis, wound healing, and cell signaling and division [24]. However, zinc ion is often mistaken for zinc, which is used as a conductive material to promote electron transfer between anaerobic bacteria and archaea [5,25,26]. ...
To overcome major limiting factors of microbial processes in anaerobic digestion (AD), metal and metal ions have been extensively studied. However, there is confusion about the effects of metals and metal ions on biomethane productivity in previous research. In this study, Zn and Zn2+ were selected as representatives of metals and metal ions, respectively, to investigate the effects on biomethane productivity. After the metals and metal ions at different concentrations were added to the batch AD experiments under the same mesophilic conditions, a Zn dose of 1 g/L and a Zn2+ dose of 4 mg/L were found to cause the highest biomethane production, respectively. The results indicate that metal (Zn) and metal ion (Zn2+) have different mechanisms to improve AD performance. There may be two possible explanations. To act as conductive materials in interspecies electron transfer (IET), relatively high doses of metals (e.g., 1 g/L of Zn, 10 g/L of Fe) are needed to bridge the electron transfer from syntrophic bacteria to methanogenic archaea in the AD process. As essential mineral nutrients, the AD system requires relatively low doses of metal ions (e.g., 4 mg/L of Zn2+, 5 mg/L of Fe2+) to supplement the component of various enzymes that catalyze anaerobic reactions and transformations. This research will provide clear insight for selecting appropriate amounts of metals or metal ions to enhance biomethane productivity for industrial AD processes.
... The elucidation of these points is of great relevance, since it may, for instance, help with the development and implementation of possible preventive measures, such as specific inhibitors with anticipated reduction, or the prevention of such undesirable, therapy-related consequences. Zinc (Zn) is an essential micronutrient implicated in numerous biological processes within human cells, tissues, and organs [14]. The total Zn content of the human body is estimated to be in the range of grams, however, several tissues/cells are known to be extra rich in Zn, including the prostate, the skin, bones, and muscles [15]. ...
(1) the mechanisms and outcomes of doxorubicin (DOX)-dependent toxicity upon changed intracellular zinc (Zn) concentrations in the cardiomyocytes obtained from human-induced pluripotent stem cells (hiPCS-CMs) were investigated; (2) cells exposed to the DOX were pretreated or cotreated with zinc pyrythione (ZnPyr) and various cellular endpoints and mechanisms were analyzed via cytometric methods; (3) both DOX concentrations (0.3 and 1 µM) induced a concentration-dependent loss of viability, an activation of autophagy, cell death, and the appearance of senescence. These phenotypes were preceded by an oxidative burst, DNA damage, and a loss of mitochondrial and lysosomal integrity. Furthermore, in DOX-treated cells, proinflammatory and stress kinase signaling (in particular, JNK and ERK) were upregulated upon the loss of free intracellular Zn pools. Increased free Zn concentrations proved to have both inhibitory and stimulatory effects on the investigated DOX-related molecular mechanisms, as well as on signaling pathways on the resulting cell fates; and (4) free intracellular Zn pools, their status, and their elevation might have, in a specific context, a pleiotropic impact upon DOX-dependent cardiotoxicity.
... Zinc plays an important role as a cofactor of more than 300 enzymes including alcohol dehydrogenase, alkaline phosphatase (ALP), angiotensin converting enzyme, carbonic anhydrase, collagenase, lactate dehydrogenase (LDH), and DNA and RNA polymerases (Table 1). Therefore, zinc is involved in the regulation of alcohol metabolism, bone metabolism, blood pressure control, cellular energy production, and nucleic acid synthesis [2][3][4][5]. Zinc also plays significant roles in the regulation of immune functions, genital functions, glucose metabolism, cognitive performance, and the structural maintenance of proteins, which are called zinc finger proteins including tumor necrosis factor (TNF)-α-induced protein 3 (TNFAIP3, also known as A20), nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and peroxisome proliferator-activated receptors (PPARs) [4,[6][7][8]. In addition, zinc is essential in the active site of superoxide dismutase (SOD), an important antioxidant enzyme that catalyzes the dismutation of superoxide (O − ) [9,10]. ...
The trace element zinc is essential for diverse physiological processes in humans. Zinc deficiency can impair growth, skin reproduction, immune function, maintenance of taste, glucose metabolism, and neurological function. Patients with chronic kidney disease (CKD) are susceptible to zinc deficiency, which is associated with erythropoiesis-stimulating agent (ESA) hypo-responsive anemia, nutritional problems, and cardiovascular diseases as well as non-specific symptoms such as dermatitis, prolonged wound healing, taste disturbance, appetite loss, or cognitive decline. Thus, zinc supplementation may be useful for the treatment of its deficiency, although it often causes copper deficiency, which is characterized by several severe disorders including cytopenia and myelopathy. In this review article, we mainly discuss the significant roles of zinc and the association between zinc deficiency and the pathogenesis of complications in patients with CKD.
... Zinc has important physiological functions in processes such as protein synthesis, signal transduction, and cell proliferation [7,8]. Under normal conditions, released zinc ionotropically and metabotropically modulates postsynaptic receptors [9,10]. ...
Glutathione (GSH) is necessary for maintaining physiological antioxidant function, which is responsible for maintaining free radicals derived from reactive oxygen species at low levels and is associated with improved cognitive performance after brain injury. GSH is produced by the linkage of tripeptides that consist of glutamic acid, cysteine, and glycine. The adequate supplementation of GSH has neuroprotective effects in several brain injuries such as cerebral ischemia, hypoglycemia, and traumatic brain injury. Brain injuries produce an excess of reactive oxygen species through complex biochemical cascades, which exacerbates primary neuronal damage. GSH concentrations are known to be closely correlated with the activities of certain genes such as excitatory amino acid carrier 1 (EAAC1), glutamate transporter-associated protein 3–18 (Gtrap3-18), and zinc transporter 3 (ZnT3). Following brain-injury-induced oxidative stress, EAAC1 function is negatively impacted, which then reduces cysteine absorption and impairs neuronal GSH synthesis. In these circumstances, vesicular zinc is also released into the synaptic cleft and then translocated into postsynaptic neurons. The excessive influx of zinc inhibits glutathione reductase, which inhibits GSH’s antioxidant functions in neurons, resulting in neuronal damage and ultimately in the impairment of cognitive function. Therefore, in this review, we explore the overall relationship between zinc and GSH in terms of oxidative stress and neuronal cell death. Furthermore, we seek to understand how the modulation of zinc can rescue brain-insult-induced neuronal death after ischemia, hypoglycemia, and traumatic brain injury.
... Vitamin D contributes to normal cell division, and influences the action of many genes that regulate the proliferation, differentiation and apoptosis of cells [135]. Magnesium serves as a regulator of many physiological functions including the maintenance of cellular membrane stability [37], while zinc is also required for normal cell division [136]. ...
... Fe Cu Zn participating in the structure of the antioxidant enzyme superoxide dismutase (SOD), guaranteeing defense against reactive oxygen species (ROS) and consequently also maintaining the integrity of the DNA; being involved in gene expression, apoptosis, among other processes [35,36,37,38,39,40,41,42,43,44]. Due to such functions and their importance, the level of these elements and their transport are tightly regulated [2]. ...
Background: Knowing how cancer develops, progresses, and spreads (metastasis) is required to mobilize the development of new ways to prevent, detect, diagnose and treat cancer. Essential elements present functions in tumor progression, promoting proliferation, migration, among other protumoral cellular processes. Understanding how those elements are related to the processes of tumor progression is of great relevance for research. The study of the elemental profile in distant tissues, which can be modulated by tumor cells to promote metastasis, has not been sufficiently investigated. Therefore, the main objective of this study is to evaluate the distribution of medium to heavy elements during tumor progression, focusing on the tumor tissue and distant tissues that could be affected.
Results: With this work, it was possible to observe significant changes in the concentrations’ distribution of P, S, K, Ca, Mn, Fe and Cu in distant tissues caused by the presence of tumor cells. It was also possible to detect a greater similarity between tumor tissue (which has the lung as tissue of origin) and a tissue of non-origin, such as the liver, which is an unprecedented result. Moreover, changes in the distributions of concentrations were detected and studied over time for the different tissues analyzed, such as primary tumor, liver and lung, in Control and Tumor groups. Finally, the importance of elements for biological processes of normal cells, as well as tumor cells during tumor progression was also discussed.
Conclusions: This work presents as contributions the study of the elemental profile in tumor and distant tissues. Furthermore, this work evaluates several elements of known biological importance (P, S, K, Ca, Mn, Fe, Cu, and Zn) allowing the study of different biological processes involved in cancer.
... Interestingly, in another study of vitamin B12 and/or folic acid supplementation in 9 year old children, we reported differential DNA methylation of genes associated with G2/M checkpoint regulation. 45 The MMN supplementation also included vitamins A and D, and zinc which are known to affect gene expression in specific tissues [46][47][48] and may have contributed to some of DEGs in the B12þMMN group. A review has summarised the recent exciting understanding of the role of core cellular metabolites (ATP, S-adenosyl methionine, acetyl-CoA, NAD/NADP, and α-ketoglutarate) in the nuclear compartment to influence the epigenome; all these metabolites are likely to be influenced in our intervention. ...
In The Pune Maternal Nutrition Study, vitamin B12 deficiency was seen in 65% of pregnant women, folate deficiency was rare. Maternal total homocysteine concentrations were inversely associated with offspring birthweight, and low vitamin B12 and high folate concentrations predicted higher offspring adiposity and insulin resistance. These findings guided a nested pre-conceptional randomised controlled trial 'Pune Rural Intervention in Young Adolescents'. The interventions included: (1) vitamin B12+multi-micronutrients as per the United Nations International Multiple Micronutrient Antenatal Preparation, and proteins (B12+MMN), (2) vitamin B12 (B12 alone), and (3) placebo. Intervention improved maternal pre-conceptional and in-pregnancy micronutrient nutrition. Gene expression analysis in cord blood mononuclear cells in 88 pregnancies revealed 75 differentially expressed genes between the B12+MMN and placebo groups. The enriched biological processes included G2/M phase transition, chromosome segregation, and nuclear division. Enriched pathways included, mitotic spindle checkpoint and DNA damage response while enriched human phenotypes were sloping forehead and decreased head circumference. Fructose-bisphosphatase 2 (FBP2) and Cell Division Cycle Associated 2 (CDCA2) genes were under-expressed in the B12 alone group. The latter, involved in chromosome segregation was under-expressed in both intervention groups. Based on the role of B-complex vitamins in the synthesis of nucleotides and S-adenosyl methionine, and the roles of vitamins A and D on gene expression, we propose that the multi-micronutrient intervention epigenetically affected cell cycle dynamics. Neonates in the B12+MMN group had the highest ponderal index. Follow-up studies will reveal if the intervention and the altered biological processes influence offspring diabesity.
... Zinc is one of the nine essential trace elements in humans, and is involved in the function of over 300 types of enzymes, cytokines, hormones, etc. It regulates the activation and signal transduction mechanisms involved in intracellular metabolism and cell response in nutrient metabolism and in the central nervous, immune, endocrine, digestive, and circulatory systems [5,6]. ...
Objectives:
Zinc deficiency (Zn < 60 μg/dL) is known to play an important role for vascular calcification. However, little data is available regarding the association between zinc deficiency and aorta stiffness in dialysis patients. Thus, we studied the relationship between zinc deficiency and aorta stiffness in non-diabetic hemodialysis (HD) patients.
Methods:
Of 150 patients receiving maintenance HD at our hospital, we included 79 non-diabetic HD patients (age: 70±11 years, 49 men) after excluding 71 diabetic HD patients. Zinc deficiency was defined as Zn <60 μg/dL during pre-HD blood sampling. The association between zinc deficiency and aorta stiffness was analyzed. Aorta stiffness was evaluated as brachial-ankle pulse wave velocity (baPWV). Other surrogate markers for cardiovascular complications were also measured.
Results:
The zinc deficiency group (ZD group) included 45 patients (57.0%). Compared to the zinc non-deficiency group (ZND group), patients with ZD group were significantly older, higher levels of CRP and hypoalbuminemia. Moreover, they had significantly higher levels of baPWV, and lower levels of ankle-brachial pressure index (ABI) (p<0.05). After adjusting for hypoalbuminemia, and CRP, multivariate analysis showed that age and zinc level were independent predictors of baPWV.
Conclusion:
The study suggested that zinc deficiency may be an independent risk factor for aorta stiffness, even after adjusting for malnutrition and inflammation.
There has been a global increase in the older population in recent decades and, as age advances, complex metabolic and epigenetic changes occur in the organism, and these may trigger some health complications commonly found among this population. Additionally, several changes occur in older people that can reduce the dietary intake or the process of nutrient absorption. In this way, tissues with high nutrient requirements are more affected. Hematopoiesis is the process of formation, development, and maturation of blood cells and is a process with a high turnover. This high demand makes the integrity of the hematopoietic process susceptible to various factors that impair physiological function, such as aging and micronutrient bioavailability. Among these micronutrients, Zinc is considered an important micronutrient, playing diverse roles across various tissues and cell types. Some of the alterations in hematopoiesis that appear as a consequence of aging and due to insufficient micronutrient intake are well described in the literature; however, not much is known about how zinc deficiency contributes towards the development of diseases seen in aging. Considering the importance of zinc to act on several biological processes, this narrative review discusses several studies related to the physiological requirements, deficiency, or excess of zinc, including studies in experimental models and humans, and aimed to shed light on the relationship between zinc and the regulation of hematopoietic tissue, exploring possible links between this mineral with common disorders that appear during aging.
Zinc (Zn) malnutrition is a serious public health issue across the world and is mostly caused by inadequate dietary intake of micronutrients—particularly Zn. Its deficiency in humans might be resolved by improving their bioavailability in food items consumed at large for instance cereals, pulses etc. Mungbean, being an utmost important pulse crop grown worldwide, would play a significant role to ameliorate Zn deficiency amongst vegetarian population of the world. Besides this, Zn application also helps to enhance mungbean productivity and livelihood of farmers. Keeping this in view, the current study was conducted during 2021 and 2022 in randomised complete block design (RCBD) with four replications and the effect of soil and/or foliar application of Zn at flower initiation and/or pod formation on grain yield and Zn accumulation in mungbean grains were assessed. On the basis of 2-year pooled mean data, soil application of ZnSO4 at 20 kg ha-1 + its foliar spray (0.5%) at flower initiation and pod formation resulted in significantly higher grain yield (1043 kg ha-1), grain Zn concentration (44.3 mg zinc kg-1), grain protein content (26.5%) and net returns (646.9 US $ ha-1) followed by soil application of ZnSO4 (20 kg ha-1) + foliar application (0.5%) at flower initiation alone. Therefore, it can be concluded that soil application of ZnSO4 (20 kg ha-1) + its foliar spray (0.5%) at flower initiation and pod formation has ample scope in improving productivity and profitability of mungbean along with improved grain Zn concentration for ameliorating Zn malnutrition in the form of hidden hunger in the burgeoning population.
Zinc (Zn) is an essential trace element that has physiological and nutritional functions. However, excessive use of Zn can lead to waste of resources. In this study, we compared the effects of inorganic (ZnSO4) and organic Zn glycine chelate (Zn-Gly) on the growth performance, intestinal morphology, immune function, barrier integrity, and gut microbiome of Cherry Valley ducks. We randomly divided 180 1-day-old male meat ducks into three groups, each with six replicates of 10 birds: basal diet group (CON), basal diet with 70 mg Zn/kg from ZnSO4 (ZnSO4 group), and basal diet with 70 mg Zn/kg from Zn-Gly (Zn-Gly group). After 14 and 35 days of feeding, birds in the Zn groups had significantly increased body weight and average daily gain, decreased intestinal permeability indicator D-Lactate, improved intestinal morphology and barrier function-related tight junction protein levels, and upregulated mucin 2 and secretory immunoglobulin A levels compared to the control (P < 0.05). Additionally, compared to the ZnSO4 group, we found that supplementation with Zn-Gly at 70 mg/kg Zn resulted in the significant increase of body weight at 35 days, 1-35 day average daily gain and average daily feed intake, villus height at 14 and 35 days, secretory immunoglobulin A and immunoglobulin G at 14 days, and mucin 2 mRNA level at 14 days (P < 0.05). Compared with the control group, dietary Zn had a significant effect on the gene expression of metallothionein at 14 and 35 days (P < 0.05). 16S rRNA sequencing showed that Zn significantly increased alpha diversity (P < 0.05), whereas no differences in beta diversity were observed among groups (P > 0.05). Dietary Zn significantly altered the cecal microbiota composition by increasing the abundances of Firmicutes, Blautia, Lactobacillus, Prevotellaceae NK3B31, and [Ruminococcus] torques group and reducing that of Bacteroides (P < 0.05). Spearman correlation analysis revealed that the changes in microbiota were highly correlated (P < 0.05) with growth performance, intestinal morphology, and immune function-related parameters. Taken together, our data show that, under the condition of adding 70 mg/kg Zn, supplementation with Zn-Gly promoted growth performance by regulating intestinal morphology, immune function, barrier integrity and gut microbiota of Cherry Valley ducks compared with the use of ZnSO4 in feed.
Lipopolysaccharide (LPS) is an endotoxin derived from the cell wall of Gram-negative bacteria. LPS exposure during early gestation is associated with adverse effects on the placenta as well as on developmental outcomes, including embryonic resorption, fetal death, congenital teratogenesis, and fetal growth retardation. This work aimed to explore the adverse effects of LPS injected at an early stage of gestation on the gonads of pregnant rats and the ovaries of their pups and the role of zinc nanoparticles (Zn-NPs) against these adverse effects. Twenty-four pregnant rats were used in this study. They were divided at gestation day 4 into four groups (n = 6): control, Zn-NPs (20 mg/kg orally from gestation day E14 till the end of weaning), LPS (50 µg/kg at gestation days E7 and E9), and LPS + Zn-NPs group. The body weight and placenta weight were recorded at gestational day 16. At postnatal day 21 (weaning), the mothers rats and their offspring were sacrificed and immediately dissected to remove the ovaries and uteri from the mothers and the ovaries from their offspring for subsequent biochemical, histological, and immunohistochemical investigations. The obtained results revealed that LPS exposure during early gestation caused severe histopathological alterations in the placenta, uterus, and ovaries of mothers, as well as in the ovaries of their pups. Also, the uterine and ovarian sections displayed a positive reaction for caspase-3 antibody and a negative reaction for Bcl-2 antibody, which reflects the apoptotic effect of LPS. Additionally, remarkable reductions in the levels of antioxidants (superoxide dismutase and catalase) and significant increases in malondialdehyde (MDA) levels were recorded in the serum of LPS-treated mothers and in the ovarian tissues of their offspring. Further biochemical analysis of the ovarian tissues from LPS-maternally treated offspring showed a significant increase in the levels of caspase-3, TNF-α, and TGF-β1, but a significant decrease in the level of IGF-1. On the other hand, treatment of mothers with Zn-NPs from day 14 of gestation until the weaning day (21st day postnatal) successfully ameliorated most of the deleterious histopathological, immunohistochemical, and biochemical changes induced by LPS.
Graphical abstract
Acute pancreatitis (AP) often leads to a high incidence of cardiac injury, posing significant challenges in the treatment of severe AP and contributing to increased mortality rates. Mesenchymal stem cells (MSCs) release bioactive molecules that participate in various inflammatory diseases. Similarly, extracellular vesicles (EVs) secreted by MSCs have garnered extensive attention due to their comparable anti-inflammatory effects to MSCs and their potential to avoid risks associated with cell transplantation. Recently, the therapeutic potential of MSCs-EVs in various inflammatory diseases, including sepsis and AP, has gained increasing recognition. Although preclinical research on the utilization of MSCs-EVs in AP-induced cardiac injury is limited, several studies have demonstrated the positive effects of MSCs-EVs in regulating inflammation and immunity in sepsis-induced cardiac injury and cardiovascular diseases. Furthermore, clinical studies have been conducted on the therapeutic application of MSCs-EVs for some other diseases, wherein the contents of these EVs could be deliberately modified through prior modulation of MSCs. Consequently, we hypothesize that MSCs-EVs hold promise as a potential therapy for AP-induced cardiac injury. This paper aims to discuss this topic. However, additional research is essential to comprehensively elucidate the underlying mechanisms of MSCs-EVs in treating AP-induced cardiac injury, as well as to ascertain their safety and efficacy.
Background: Methadone maintenance treatment (MMT) is associated with immunity dysfunction, increased inflammation, oxidative stress, and DNA damage. Zinc has various effects, including antioxidant and anti-inflammatory effects. In addition, zinc-finger proteins act as transcription factors regulating the expression of genes. In this study, we investigated the effect of Zinc supplement on the metabolic, and oxidative stress profiles, and expression of IL-10, NRF2, and PPARγ genes in heroin patients under MMT.
Methods: Randomized double-blind placebo-controlled clinical trial was carried out on 60 patients under MMT to receive 30 mg/day Zinc supplement (n=30) or placebo (n=30). Fasting blood samples were collected at the baseline and 12 weeks after intervention to quantify related markers, including metabolic, oxidative stress, and gene expression.
Results: At the end of the intervention, Zinc levels was significantly elevated in the intervention group in comparison with the placebo group (p=0.03). In addition, consuming Zink significantly changed the levels of HDL (p=0.04), insulin (p=0.01) and HOMA-IR (p=0.01). As well as the concentration of NO (p=0.02), GSH (p=0.01), TAC (p=0.04) were statistically significant between two groups. Taking Zink upregulated NRF2 gene expression (p< 0.05) in peripheral blood mononuclear cells of patients under MMT.
Conclusion: Results of this study indicated that, Zinc supplement can be recommended as an adjunct to MMT which may have beneficial effects on metabolic profile, oxidative stress, and gene expression and decrease methadone side effects.
Zinc (Zn) plays a critical role in the growth of livestock, which depends on cell proliferation. In addition to modifying the growth associated with its effects on food intake, mitogenic hormones, signal transduction and gene transcription, Zn also regulates body weight gain through mediating cell proliferation. Zn deficiency in animals leads to growth inhibition, along with an arrest of cell cycle progression at G0/G1 and S phase due to depression in the expression of cyclin D/E and DNA synthesis. Therefore, in the present study, the interplay between Zn and cell proliferation and implications for the growth of livestock were reviewed, in which Zn regulates cell proliferation in several ways, especially cell cycle progression at the G0/G1 phase DNA synthesis and mitosis. During the cell cycle, the Zn transporters and major Zn binding proteins such as metallothioneins are altered with the requirements of cellular Zn level and nuclear translocation of Zn. In addition, calcium signaling, MAPK pathway and PI3K/Akt cascades are also involved in the process of Zn-interfering cell proliferation. The evidence collected over the last decade highlights the necessity of Zn for normal cell proliferation, which suggests Zn supplementation should be considered for the growth and health of poultry.
Zinc oxide (ZnO) has been applied for many years in the production of pigs to reduce
the number of diarrhoea in weaned piglets. In June 2022, the European Union banned the use of zinc oxide (ZnO) in pig feed. According to scientific reports, the may reason was the accumulation of this microelement in the environment of pig production. It has been shown that frequent application of ZnO can lead to increased antibiotic resistance in pathogenic swine microflora. The main alternatives to ZnO are probiotics, prebiotics, organic acids, essential oils, and liquid feeding systems. Alternatives to ZnO can be successfully used in pig production to reduce the number of diarrhoea among piglets during the postweaning period. Additional reports indicated that bacteriophage supplementation has a positive effect on the health of pigs. The article provides an overview of current ZnO substitutes that can be used in pig farming
Fe and Zn ions are essential enzymatic cofactors across all domains of life. Fe is an electron donor/acceptor in redox enzymes, while Zn is typically a structural element or catalytic component in hydrolases. Interestingly, the presence of Zn in oxidoreductases and Fe in hydrolases challenge this apparent functional dichotomy. In hydrolases, Fe either substitutes for Zn or specifically catalyzes certain reactions. On the other hand, Zn can replace divalent Fe and substitute for more complex Fe assemblies, known as FeS clusters. Although many zinc-binding proteins interchangeably harbor Zn and FeS clusters, these cofactors are only sometimes functional proxies.
Zinc is an essential micronutrient required for all domains of life. Cells maintain zinc homeostasis using a network of transporters, buffers, and transcription factors. Zinc is required for mammalian cell proliferation, and zinc homeostasis is remodeled during the cell cycle, but whether labile zinc changes in naturally cycling cells has not been established. We use genetically encoded fluorescent reporters, long-term time-lapse imaging, and computational tools to track labile zinc over the cell cycle in response to changes in growth media zinc and knockdown of the zinc-regulatory transcription factor MTF-1. Cells experience a pulse of labile zinc in early G1, whose magnitude varies with zinc in growth media. Knockdown of MTF-1 increases labile zinc and the zinc pulse. Our results suggest that cells need a minimum zinc pulse to proliferate and that if labile zinc levels are too high, cells pause proliferation until labile cellular zinc is lowered.
Background and aims:
To evaluate the effects of a high-fat diet during post-weaning growth on intermediate metabolism and retroperitoneal adipose tissue, in adult male rats exposed to adequate or deficient zinc intake during prenatal and postnatal life.
Methods and results:
Female Wistar rats were fed low- or control-zinc diets from pregnancy to offspring weaning. Male offspring born from control mothers were fed either control or high-fat, control-zinc diets for 60 days. Male offspring born from zinc deficient mothers were fed either low-zinc or high-fat, low-zinc diets for 60 days. At 74 days of life, oral glucose tolerance test was performed. In 81-day-old offspring, blood pressure, lipid profile, plasmatic lipid peroxidation and serum adiponectin level were determined. In retroperitoneal adipose tissue, we evaluated oxidative stress, morphology and adipocytokines mRNA expression. Low-zinc diet induced adipocytes hypertrophy, increased oxidative stress, and decreased adiponectin mRNA expression in adipose tissue. Low-zinc diet increased systolic blood pressure, triglyceridemia, plasmatic lipid peroxidation and glycemia at 3 h after glucose overload. Animals fed high-fat or high-fat, low-zinc diets showed adipocytes hypertrophy, decreased adiponectin mRNA expression, and increased leptin mRNA expression and oxidative stress in adipose tissue. They also exhibited decreased serum adiponectin levels, increased triglyceridemia, plasmatic lipid peroxidation and area under the oral glucose tolerance curve. High-fat, low-zinc diet induced greater alterations in adipocyte hypertrophy, leptin mRNA expression and glucose tolerance test than high-fat diet.
Conclusion:
Zinc deficiency since early stages of intrauterine life could increase susceptibility to metabolic alterations induced by high-fat diets during postnatal life.
The aim of this study was to study the effect of zinc oxide-chitosan nanoparticles (Zn-CNPs) on growth performance, plasma constituents, carcass indices, and immune function in rabbit diets. Eighty weaned V-line males rabbits at 5 weeks of age were divided into four dietary groups of control diet; 50 Zn-CNPs; 75 Zn-CNPs;100 Zn-CNPs. Supplementation of Zn-CNPs did not affect final live body weight and average daily weight gain. 100 ppm Zn-CNPs recorded (p < 0.05) higher digestibility of DM, OM, CP, EE, and NFE. Dietary groups of 75 and 100 ppm were higher (p < 0.05) in DCP, TDN (%), and DE (kcal/kg). Zn-CNPs supplementation was higher (p < 0.05) in hot carcass and spleen weights %. The addition of Zn-CNPs in diets promoted dressing%. Significant increases (p < 0.05) in plasma total protein and albumin levels for 75 and 100 Zn-CNPs. Zn-CNPs decreased (p < 0.05) glucose, total cholesterol, LDL concentrations and increased (p < 0.05) plasma zinc levels, IgG, IgM. Plasma HDL level increased (p < 0.05) with 75 and 100 ppm Zn-CNPs. In conclusion, Zn-CNPs supplementations can use safely as a zinc source in rabbits diets without any detrimental effects on growth performance, plasma constituents, and carcass indices. Moreover, 50, 75, and 100 ppm Zn-CNPs enhanced the immune functions.
We evaluated the effects of prenatal and postnatal dietary zinc (Zn) deficiency or supplementation on mammary gland morphology and on acute response to 7,12-dimethylbenzanthracene (DMBA) in pubertal female rats. On gestational day 10 (GD 10), rat dams were allocated randomly into three experimental groups of 10: a Zn-adequate diet group (ZnA) fed 35 mg Zn/kg chow, a Zn-deficient diet group (ZnD) fed 3 mg ZN/kg chow and a Zn-supplemented diet group (ZnS) fed 180 mg Zn/kg chow. After weaning, female offspring were fed the same diet as their dams until postnatal day 53 (PND 53). All animals received a single 50 mg/kg dose of DMBA on PND 51 and were euthanized on PND 53. Female ZnD offspring exhibited significantly less weight gain compared to the ZnA group and reduced mammary gland development compared to the ZnD and ZnA groups. By PND 53, the Ki-67 labeling index in mammary gland epithelial cells was significantly greater for the ZnS group than for the ZnA and ZnD groups. Apoptosis and ER-α indices did not differ among groups. The ZnD group exhibited significantly increased lipid hydroperoxide (LOOH) levels and decreased catalase and glutathione peroxidase (GSH-Px) activity compared to the ZnA and ZnS groups. The ZnS group exhibited significantly reduced superoxide dismutase (SOD) activity compared to the ZnA and ZnS groups. We observed atypical ductal hyperplasia in the mammary gland of female ZnS group offspring compared to the ZnA and ZnD groups and decreased expression of the Api5 and Ercc1 genes related to apoptosis inhibition and DNA damage repair, respectively. Both the Zn-deficient and Zn-supplemented diet exerted adverse effects on offspring mammary gland morphology and acute response to DMBA.
Zinc is an essential micronutrient that is involved in several metabolic processes, especially children’s growth and development. Although many previous studies have evaluated the zinc nutritional status of children, there are very few reports on children aged 6–18 years old. Furthermore, there are few reports on children’s zinc nutrition status based on the Chinese population. According to WHO data, the prevalence of zinc deficiency in Asian countries is rather high and has resulted in high child mortality. In this study, we aimed to comprehensively assess zinc nutritional status and the prevalence of zinc deficiency among children aged 6–18 years in China based on nationally representative cross-sectional data. Subgroup comparisons were made under possible influencing factors. The potential risk factors of zinc deficiency were also discussed. A total of 64,850 children, equally male and female, were recruited from 150 monitoring sites in 31 provinces through stratified random sampling from China National Nutrition and Health Survey of Children and Lactating Mothers (CNNHS 2016–2017). Median and interquartile intervals were used to represent the overall zinc concentration levels and different subgroups. A Chi-square test was used to compare serum zinc levels and the prevalence of zinc deficiency in children under different group variables. In order to study the influencing factors of zinc deficiency, multiple logistic regression was utilized. It was found that the median concentration of serum Zn was 88.39 μg/dL and the prevalence of Zn deficiency was 9.62%. The possible influence factors for Zn deficiency were sex, anemia, nutritional status, city type and income. By conducting a subgroup analysis of the factors, it was found that males; those with anemia, stunting and low income; and children living in rural areas have a higher risk of Zn deficiency. This study offers a comprehensive analysis of Zn nutritional status among Chinese children, which provides reliable data for policy formulation to improve the zinc nutrition status of children.
Background:
Zinc deficiency is prevalent in low- and middle-income countries, and is considered a significant risk factor for morbidity, mortality, and linear growth failure. The effectiveness of preventive zinc supplementation in reducing prevalence of zinc deficiency needs to be assessed.
Objectives:
To assess the effects of zinc supplementation for preventing mortality and morbidity, and for promoting growth, in children aged 6 months to 12 years.
Search methods:
A previous version of this review was published in 2014. In this update, we searched CENTRAL, MEDLINE, Embase, five other databases, and one trials register up to February 2022, together with reference checking and contact with study authors to identify additional studies.
Selection criteria:
Randomized controlled trials (RCTs) of preventive zinc supplementation in children aged 6 months to 12 years compared with no intervention, a placebo, or a waiting list control. We excluded hospitalized children and children with chronic diseases or conditions. We excluded food fortification or intake, sprinkles, and therapeutic interventions.
Data collection and analysis:
Two review authors screened studies, extracted data, and assessed the risk of bias. We contacted study authors for missing information and used GRADE to assess the certainty of evidence. The primary outcomes of this review were all-cause mortality; and cause-specific mortality, due to all-cause diarrhea, lower respiratory tract infection (LRTI, including pneumonia), and malaria. We also collected information on a number of secondary outcomes, such as those related to diarrhea and LRTI morbidity, growth outcomes and serum levels of micronutrients, and adverse events.
Main results:
We included 16 new studies in this review, resulting in a total of 96 RCTs with 219,584 eligible participants. The included studies were conducted in 34 countries; 87 of them in low- or middle-income countries. Most of the children included in this review were under five years of age. The intervention was delivered most commonly in the form of syrup as zinc sulfate, and the most common dose was between 10 mg and 15 mg daily. The median duration of follow-up was 26 weeks. We did not consider that the evidence for the key analyses of morbidity and mortality outcomes was affected by risk of bias. High-certainty evidence showed little to no difference in all-cause mortality with preventive zinc supplementation compared to no zinc (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.84 to 1.03; 16 studies, 17 comparisons, 143,474 participants). Moderate-certainty evidence showed that preventive zinc supplementation compared to no zinc likely results in little to no difference in mortality due to all-cause diarrhea (RR 0.95, 95% CI 0.69 to 1.31; 4 studies, 132,321 participants); but probably reduces mortality due to LRTI (RR 0.86, 95% CI 0.64 to 1.15; 3 studies, 132,063 participants) and mortality due to malaria (RR 0.90, 95% CI 0.77 to 1.06; 2 studies, 42,818 participants); however, the confidence intervals around the summary estimates for these outcomes were wide, and we could not rule out a possibility of increased risk of mortality. Preventive zinc supplementation likely reduces the incidence of all-cause diarrhea (RR 0.91, 95% CI 0.90 to 0.93; 39 studies, 19,468 participants; moderate-certainty evidence) but results in little to no difference in morbidity due to LRTI (RR 1.01, 95% CI 0.95 to 1.08; 19 studies, 10,555 participants; high-certainty evidence) compared to no zinc. There was moderate-certainty evidence that preventive zinc supplementation likely leads to a slight increase in height (standardized mean difference (SMD) 0.12, 95% CI 0.09 to 0.14; 74 studies, 20,720 participants). Zinc supplementation was associated with an increase in the number of participants with at least one vomiting episode (RR 1.29, 95% CI 1.14 to 1.46; 5 studies, 35,192 participants; high-certainty evidence). We report a number of other outcomes, including the effect of zinc supplementation on weight and serum markers such as zinc, hemoglobin, iron, copper, etc. We also performed a number of subgroup analyses and there was a consistent finding for a number of outcomes that co-supplementation of zinc with iron decreased the beneficial effect of zinc.
Authors' conclusions:
Even though we included 16 new studies in this update, the overall conclusions of the review remain unchanged. Zinc supplementation might help prevent episodes of diarrhea and improve growth slightly, particularly in children aged 6 months to 12 years of age. The benefits of preventive zinc supplementation may outweigh the harms in regions where the risk of zinc deficiency is relatively high.
Zinc ion (Zn) is an essential nutrition element and it is important to understand its regulation and distribution among different cellular organelles. Here, subcellular trafficking of Zn in rabbitfish fin cells was investigated through bioimaging, and the results showed that the toxicity and bioaccumulation of Zn were both dose- and time-dependent. Cytotoxicity of Zn only occurred when the Zn concentration reached 200-250 μM after 3 h of exposure when the cellular quota of Zn:P reached a threshold level around 0.7. Remarkably, the cells were able to maintain homeostasis at a low Zn exposure concentration or within the first 4-h exposure. Zn homeostasis was mainly regulated by the lysosomes which stored Zn within the short exposure period, during which the number and size of lysosomes as well as the lysozyme activity increased in response to incoming Zn. However, with increasing Zn concentration beyond a threshold concentration (> 200 μM) and an exposure time > 3 h, homeostasis was disrupted, leading to an Zn spillover to cytoplasm and other cellular organelles. At the same time, cell viability decreased due to the Zn damage on mitochondria which caused morphological changes (smaller and rounder dots) and over production of reactive oxygen species, indicating the dysfunction of mitochondria. By further purifying the cellular organelles, cell viability was found to be consistent with the mitochondrial Zn amount. This study suggested that the amount of mitochondrial Zn was an excellent predictor of Zn toxicity on fish cells.
This experiment was conducted in field of sheep breeding, College of Agriculture and Forestry / University
of Mosul. Twenty Awassi lambs were used in this experiment and was similar in age and weight at the
beginning of experiment. This experiment was lasted for 90 days and was preceded by a two-week
acclimatization period. This study included randomly distributing their lambs into four treatments. The first
treatment (control) without dose. While the second treatment of lambs were dosing by zinc (30 mg zinc /
head) for three times per week. The third treatment were given vitamin E (20 mg of vitamin E / head) for
three times a week. As for fourth treatment the lambs were doses a mixture of zinc and vitamin E per
three times a week. The results of the current study indicated that there was a significant effect of doses
of zinc or vitamin E, or both on average weights of proportions of the main and secondary carcasses and
separated fats among treatments. The results indicated that there were significant differences between
the groups treated with zinc and vitamin E and interaction between them compared to the control
treatment.As for physical inventory of components of three-ribs region (9-10-11) the results of the current
experiment showed that there was a significant effect of dossing with zinc and vitamin E or mixture
between them on the proportions of muscle and fats,rates of moisture content, percentage of crude
protein and a highly significant effect (P≤ 0.01)) in proportion of ether extract in favor of the experimental
treatments over the control treatment when compared to the control treatment that was not treated with
zinc and vitamin E.The results indicates that dosing of Awassi lambs with zinc ,vitamin E or their mixture
which led to a significant improvement in rates of weights percentages of main and secondary carcasses,
and significant increase in percentages of muscle tissue sedimentation and crude protein and significant
decrease in percentages of fats and ether extract in favor of the groups of lambs treated with zinc ,
vitamin E or a mixture together compared to the control group.
Keywords: zinc, vitamin E, carcass cuts, meat quality, separated fats.
A nutrição é uma característica inerente à vida. A aquisição de matéria-prima
proveniente do meio ambiente é considerado fator imprescindível para a existência
dos mais variados seres, dos unicelulares, mais simples, aos pluricelulares, mais
complexos. Assim o fenômeno da vida e o da nutrição são, reciprocamente, codependentes.
Os elementos essenciais e a energia necessários para manter as atividades mais
primordiais do organismo vivo estão presentes nos alimentos. Estes devem atender
às demandas dos tecidos vivos tais como de crescimento, manutenção, restauração e trabalho. Nos alimentos encontram-se os nutrientes, seus constituintes químicos mais simples, tais como carboidratos, lipídios e proteínas (macronutrientes
– fornecedores de energia metabólica); sais minerais e vitaminas (micronutrientes
– elementos reguladores); e também a água. Todos estes, em conjunto, apresentam
relevante papel nos mais diversos eventos biológicos como regulação das reações
orgânicas, síntese de moléculas, crescimento, desenvolvimento e reparo de tecidos,
entre outros.
O sistema nervoso exerce a função integradora e de comando sobre os outros
sistemas fisiológicos, favorecendo o dinamismo homeostático que o nosso organismo necessita para estar vivo. Assim o sistema nervoso é originado, desenvolve-se, passa pelo processo de maturação, pode modificar-se com a capacidade de reorganizar-se ao longo da vida, envelhece, degenera e morre. Essa capacidade de modificar-se, tanto morfologicamente como funcionalmente, é conhecida como plasticidade e proporciona ao organismo a adaptação ao meio em que vive. Alguns fatores externos, como a nutrição, influenciam diretamente os processos de desenvolvimento e são vitais para guiar toda a organização, estrutura, função e metabolismo do sistema nervoso.
No decorrer do capítulo iremos correlacionar os processos de formação, desenvolvimento e crescimento, que envolvem os aspectos morfofuncionais das células neurais com nutrição adequada, utilização de nutrientes, durante os períodos pré e pós-natal, infância, adolescência e envelhecimento do sistema nervoso. Ressaltaremos as alterações da nutrição inadequada na fase precoce da vida, a qual pode interferir na plasticidade neural, modificando características fenotípicas do sistema nervoso maduro.
No decorrer da evolução da humanidade, observamos mudanças no comportamento de ingestão dos alimentos. Antes, havia um maior consumo de alimentos naturais, ricos em nutrientes. Contudo, atualmente, após a evolução industrial, houve uma mudança no padrão de vida das pessoas e, associada a isso, verifica-se também uma alteração nos hábitos alimentares. Hoje em dia, as pessoas ingerem muito mais alimentos processados, pobres em nutrientes, rápidos e de fácil ingestão. Nas fases iniciais da vida, durante o período crítico do desenvolvimento, muitas crianças consomem predominantemente alimentos tipo fast food. Dessa forma, podem comprometer o seu desenvolvimento craniofacial e, por conseguinte, funções básicas para o comportamento alimentar, como a mastigação e a deglutição. Tais atos motores são funções vitais para o ser humano, e agem de forma sincrônica, haja vista que a mastigação prepara o alimento para a deglutição. Tanto a mastigação como a deglutição são de extrema importância para a nutrição, já que controlam, direta ou indiretamente, os mecanismos de apetite e saciedade. Ademais, as características dos alimentos, a exemplo da textura, do sabor e do odor, podem interferir na dinâmica das supracitadas funções motoras, podendo interferir no tempo de trânsito dos alimentos, controlando, assim, o tamanho e a duração das refeições. Portanto, no decorrer deste capítulo, abordaremos os conceitos e o processamento básico do alimento durante a mastigação e a deglutição, além de como ocorre o seu desenvolvimento e como se processa durante o envelhecimento. Ressaltaremos também a importância das mencionadas funções motoras para a nutrição, abordando a influência das características dos alimentos sobre tais funções motoras. E, por último, destacaremos o efeito da manipulação nutricional, sobretudo da desnutrição, sobre a mastigação e a deglutição.
The action of insulin-like growth factor II (IGF-II) on calcium influx was studied in BALB/c 3T3 cells. IGF-II did not affect calcium influx rate in either quiescent or platelet-derived growth factor-treated “competent” cells. In contrast, IGF-II induced an approximately 2-fold sustained increase in calcium influx rate in competent cells briefly primed with epidermal growth factor (“primed competent” cells). The IGF-II-stimulated calcium influx was dependent on extracellular calcium and was inhibited by lanthanum, cobalt, and tetramethlin but not by nitrendipine. The IGF-II-stimulated [3H]thymidine incorporation was also dependent on extracellular calcium and was inhibited by cobalt and tetramethlin. A pharmacological stimulation of calcium influx by BAYK8644 resulted in an increase in [3H]thymidine incorporation in primed competent cells but not in either quiescent or competent cells. Pretreatment of primed competent cells with pertussis toxin completely abolished subsequent action of IGF-II on both calcium influx and [3H]thymidine incorporation. Inhibitory actions of pertussis toxin correlated well with toxin-induced ADP-ribosylation of a 41-kDa protein. The binding of 125I-IGF-II to membrane fraction was inhibited by guanosine 5'-O-(thiotriphosphate), and this inhibition was reversed by pretreatment of the cell with pertussis toxin. These results suggest that IGF-II stimulates calcium influx in primed competent BALB/c 3T3 cells by a mechanism involving G protein and that calcium influx may be a message of IGF-II action on cell proliferation.
Serum pituitary levels of growth hormone (GH), thyrotropin (TSH), prolactin (PRL), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured in sexually mature (adult) and sexually immature (juvenile) male rats who had been deprived of dietary zinc for 15 and 7 weeks, respectively. When compared to pair-fed control rats receiving a zinc supplemented diet, both the adult and juvenile zinc deficient rats had significantly lower body weights, tail lengths and ventral prostate weights. The testes of the sexually immature rats were also smaller than those of the pair-fed animals. In sexually mature, zinc deficient rats serum concentrations of GH and testosterone were significantly lower and serum LH levels significantly higher than in ad libitum fed control rats. Pituitary and hypothalamic levels of other hormones did not differ from values recorded in control animals. In sexually immature zinc deficient rats serum concentrations of GH were also significantly depressed; pituitary content and concentration of LH and pituitary and serum levels of FSH were significantly increased over control values. No discernible effects of zinc deficiency upon hyplthalamic content of LH-releasing hormone or serum concentrations of PRL or TSH were recorded in juvenile rats. Zinc deficiency has minimal effects upon the hypothalamic-pituitary axis of sexually mature rats. In sexually immature males, zinc deprivation leads to impairment of gonadal growth and increased synthesis and/or secretion of the pituitary gonadotropins.
X-ray absorption spectroscopy is ideally suited for the investigation of the electronic structure and the local environment (approximately 5 A) of specific atoms in biomolecules. While the edge region provides information about the valence state of the absorbing atom, the chemical identity of neighboring atoms, and the coordination geometry, the extended x-ray absorption fine structure region contains information about the number and average distance of neighboring atoms and their relative disorder. The development of sensitive detection methods has allowed studies using near physiological concentrations (as low as approximately 100 microM). RNA polymerase from Escherichia coli contains two zinc atoms: one tightly bound in the beta' subunit, the subunit that participates in template binding, and the other loosely bound in the beta subunit, the subunit that participates in substrate binding. X-ray absorption studies of these zinc sites in the native protein and of the zinc site in the beta' subunit after removal of the zinc in the beta subunit site by p-(hydroxymercuri)benzenesulfonate (Giedroc, D. P., and Coleman, J. E. (1986) Biochemistry 25, 4969-4978) indicate that both zinc sites have octahedral coordination. The zinc in the beta' subunit site has four sulfur ligands at an average distance of 2.36 +/- 0.02 A and two oxygen (or nitrogen) ligands at an average distance of 2.23 +/- 0.02 A. The beta subunit zinc site has five sulfur ligands at an average distance of 2.38 +/- 0.01 A and one histidine nitrogen ligand at 2.14 +/- 0.02 A. These results are in general agreement with earlier biochemical and spectroscopic studies.
Nutritional deficiencies of magnesium or zinc lead to a progressive and often marked growth retardation. We have evaluated the effect of Mg and Zn deficiency on growth, serum insulin-like growth factor-1 (s-IGF-1), growth hormone (s-GH) and insulin (s-insulin) in young rats. In 3-week-old rats maintained on Mg-deficient fodder for 12 d the weight gain was reduced by about 34%, compared with pair-fed controls. This was accompanied by a 44% reduction in s-IGF-1, while s-insulin showed no decrease. After 3 weeks on Mg-deficient fodder, growth had ceased while serum Mg (s-Mg) and s-IGF-1 were reduced by 76 and 60% respectively. Following repletion with Mg, s-Mg was completely normalized in 1 week, and s-IGF-1 reached control level after 2 weeks. Growth rate increased, but the rats had failed to catch up fully in weight after 3.5 weeks. Absolute and relative pair-feeding were compared during a Mg repletion experiment. Absolute pair-fed animals were given the same absolute amount of fodder as the Mg-deficient rats had consumed the day before. Relative pair-fed animals were given the same amount of fodder, on a body-weight basis, consumed in the Mg-deficient group the day before. In a repletion experiment the two methods did not differ significantly from each other with respect to body-weight, muscle weight, tibia length and s-IGF-1, although there was a tendency towards higher levels in the relative pair-fed group. The peak in s-GH after growth hormone-releasing factor 40 (GRF 40) was 336 (SE 63) micrograms/l in 5-week-old rats that had been Mg depleted for 14 d, whereas age-matched control animals showed a peak of 363 (SE 54) micrograms/l (not significant). In 3-week-old rats maintained on Zn-deficient fodder for 14 d weight gain was reduced by 83% compared with pair-fed controls. Serum Zn (s-Zn) and s-IGF-1 were reduced by 80 and 69% respectively, while s-insulin was reduced by 66%. The Zn-deficient animals showed a more pronounced growth inhibition than that seen during Mg deficiency and after 17 d on Zn-deficient fodder s-IGF-1 was reduced by 83%. Following repletion with Zn, s-Zn was normalized and s-IGF-1 had increased by 194% (P less than 0.05) after 3 d. s-IGF-1, however, was not normalized until after 2.5 weeks of repletion.(ABSTRACT TRUNCATED AT 400 WORDS)
The action of insulin-like growth factor II (IGF-II) on calcium influx was studied in BALB/c 3T3 cells. IGF-II did not affect calcium influx rate in either quiescent or platelet-derived growth factor-treated "competent" cells. In contrast, IGF-II induced an approximately 2-fold sustained increase in calcium influx rate in competent cells briefly primed with epidermal growth factor ("primed competent" cells). The IGF-II-stimulated calcium influx was dependent on extracellular calcium and was inhibited by lanthanum, cobalt, and tetramethlin but not by nitrendipine. The IGF-II-stimulated [3H]thymidine incorporation was also dependent on extracellular calcium and was inhibited by cobalt and tetramethlin. A pharmacological stimulation of calcium influx by BAYK8644 resulted in an increase in [3H]thymidine incorporation in primed competent cells but not in either quiescent or competent cells. Pretreatment of primed competent cells with pertussis toxin completely abolished subsequent action of IGF-II on both calcium influx and [3H]thymidine incorporation. Inhibitory actions of pertussis toxin correlated well with toxin-induced ADP-ribosylation of a 41-kDa protein. The binding of 125I-IGF-II to membrane fraction was inhibited by guanosine 5'-O-(thiotriphosphate), and this inhibition was reversed by pretreatment of the cell with pertussis toxin. These results suggest that IGF-II stimulates calcium influx in primed competent BALB/c 3T3 cells by a mechanism involving G protein and that calcium influx may be a message of IGF-II action on cell proliferation.
When G0-arrested BALB/c 3T3 cells were treated sequentially with platelet-derived growth factor and epidermal growth factor, cells became responsive to insulin-like growth factor-I (IGF-I). In these primed competent cells, 1 nM IGF-I elicited an approximately 3-fold increase in the calcium influx rate. IGF-I-induced calcium influx was relatively slow in onset and continued for at least 2 h in the presence of IGF-I. When a single Ca2+ channel current was studied by the patch-clamp technique using the cell-attached mode, inward currents with unitary conductance of 19 pS were observed in the presence of 1 nM IGF-I in the patch pipette. IGF-I-sensitive inward current was independent of membrane potential and was activated by a high concentration of insulin. Accordingly, 1 nM IGF-I caused a gradual increase in cytoplasmic free calcium concentration measured by fura2. The action of IGF-I on calcium influx was dependent on extracellular calcium, and IGF-I did not stimulate calcium influx when extracellular calcium concentration was reduced to 10 microM. Both cobalt and tetramethrin blocked the action of IGF-I on calcium influx without affecting the binding of 125I-IGF-I. In primed competent cells, IGF-I-stimulated [3H]thymidine incorporation was dependent on extracellular calcium and was attenuated by cobalt and tetramethrin. When cell-bound 125I-IGF-I was cross-linked by use of disuccinimidyl suberate, a 130-kDa protein was radiolabeled. Affinity labeling of the 130-kDa protein, presumably the alpha-subunit of the IGF-I receptor, was blocked by excess amount of unlabeled IGF-I. These results suggest that relatively low concentrations of IGF-I stimulate calcium influx in primed competent BALB/c 3T3 cells by activating a calcium-permeable cation channel via the IGF-I receptor and that calcium influx may be a critical intracellular message of the progression activity of IGF-I.
We investigated the effects of zinc deficiency on body composition by using intragastric force-feeding to obviate decreased food intake and altered eating patterns. Weanling male Sprague-Dawley rats were fed a purified zinc-deficient diet: the ad libitum-fed control group (AL; eight rats) was given powdered diet and water containing 25 ppm zinc; the zinc-replete group (ZN; nine rats) was force-fed a diet blended with water containing zinc in an amount of equal caloric intake to the AL group and allowed access to water containing zinc. The zinc intake of ZN rats was approximately twice that of AL rats based on water intake. The zinc-deficient group (ZD; 13 rats) was fed similarly to the ZN group except deionized water was used for diet preparation and drinking water. After 8 d, body and muscle weight were lower in the ZD group than in the ZN group. Femur weights were similar in the two groups. Serum, liver and femur zinc concentrations were 85, 22 and 42% lower, respectively, in the ZD group than in the ZN group. Serum glucose, relative liver weight, liver glycogen and liver lipids were higher, but muscle and liver DNA were lower in the ZD group than in control groups.
The insulin-like growth factor-I (IGF-I) receptor is a member of a large family of transmembrane signal transducing molecules. The defining characteristic of this class of receptors is the intrinsic tyrosine kinase activity of the cytoplasmic domain. While it has been demonstrated that this tyrosine kinase activity is necessary for the action of a number of transmembrane tyrosine kinase receptors, no evidence of this type has been adduced to date with respect to the signaling requirement of the IGF-I receptor. We have now shown that stably transfected NIH-3T3 cell lines overexpressing human IGF-I receptors display increased responses to IGF-I and an IGF-I-mimetic antibody, alpha IR-3, in terms of short, intermediate, and long term actions initiated by activation of the IGF-I receptor. These include receptor autophosphorylation, activation of phosphatidylinositol-3-kinase and 2-deoxyglucose uptake, induction of ornithine decarboxylase gene expression, and stimulation of thymidine incorporation. In short term responses, the kinetics seen with alpha IR-3 were slower than those seen with IGF-I. These effects were severely decreased in clones expressing human IGF-I receptors in which the lysine residue in the ATP-binding site of the tyrosine kinase domain had been mutated to alanine or arginine. This was true for both IGF-I and alpha IR-3. These results indicate that, for all parameters tested, the tyrosine kinase activity of the IGF-I receptor is necessary for activation of the IGF-I-stimulated signal transduction cascade. Additionally, the effects of alpha IR-3 also require tyrosine kinase activity.
Previous studies had indicated that lack of Zn2+ inhibits the expression of thymidine kinase activity and produces a corresponding reduction in the concentration of its mRNA. The present investigations have shown that with human thymidine kinase this is associated with increased binding of a specific protein to the gene's promoter in the region between -55 and -83 bp 5' to the transcription initiation site. A second binding site for the protein is present within the sixth exon of the human thymidine kinase gene.
Zinc deficiency results in defective central nervous system function and in peripheral neuropathy. Calcium serves as second messenger in both pre- and postsynaptic membranes. Presynaptic uptake of calcium occurs via voltage-gated channels, whereas postsynaptic uptake occurs by way of a glutamate-activated channel, the N-methyl-D-aspartate (NMDA) receptor-channel. This study was designed to determine the effect of zinc status on calcium uptake by synaptic membranes prepared from guinea pigs deprived of zinc. Within each group of three guinea pigs, one animal was allowed to consume a low zinc (< 1 mg/kg) diet ad libitum (-ZN), one an adequate zinc (100 mg/kg) diet ad libitum (+AL), and one the adequate zinc diet restricted (+RF). When the -ZN guinea pig within a group developed clinical signs of deficiency, synaptosomes were prepared from brain cortices and calcium uptake measured by use of 45Ca. Both high potassium- and glutamate-stimulated calcium uptakes by synaptosomes from zinc-deficient guinea pigs were significantly lower than those of controls, with the glutamate-stimulated uptake 40% lower. In vitro addition of either magnesium or zinc resulted in lower uptake in synaptosomes from all dietary groups. Regardless of in vitro conditions, calcium uptake was impaired by zinc deficiency. The impaired function of calcium channels may explain the neurological disturbances observed in zinc-deficient animals.
We previously reported that insulin-like growth factor-I (IGF-I) stimulated calcium entry (Kojima, I., Matsunaga, H., Kurokawa, K., Ogata, E., and Nishimoto, I. (1988) J. Biol. Chem. 263, 16561-16567) and production of 1,2-diacylglycerol in IGF-responsive "primed competent" Balb/c 3T3 cells (Kojima, I., Kitaoka, M., and Ogata, E. (1990) J. Biol. Chem. 265, 16846-16850). The present study was conducted to determine a role of protein kinase C (PKC) in the progression activity of IGF-I. To monitor the activity of PKC in intact cells, we measured phosphorylation of a synthetic KRTLRR peptide, a substrate of PKC, immediately after the permeabilization of the cells with digitonin. When 1 nM IGF-I was added to primed competent cells, KRTLRR peptide phosphorylation was augmented. IGF-I induced more than 2-fold increase in KRTLRR peptide phosphorylation that was blocked by PKC19-36, a pseudosubstrate of PKC, which blocks the activity of the kinase, and Ro31-8220, an inhibitor of PKC. The phosphorylation remained elevated for up to 6 h. To assess the role of PKC in cell cycle progression, IGF-I-induced nuclear labeling was measured in the presence of Ro31-8220. Ro31-8220 reduced the rate of entrance into S phase when added in the first quarter of the G1 phase, but did not affect cell cycle progression when added at the second quarter or later. In contrast, reduction of extracellular calcium completely blocked cell cycle progression when done in the first, second, and third quarter but had no effect in the last quarter. These results indicate that IGF-I persistently activates PKC in primed competent cells, but the activation is required only for the initiation of progression. We conclude that IGF-I promotes cell cycle progression by calcium-dependent mechanisms that are largely independent of PKC.
The control of eucaryotic cell proliferation is governed largely by a series of regulatory events which occur in the G1 phase of the cell cycle. When stimulated to proliferate, quiescent (G0) 3T3 fibroblasts require transcription, rapid translation, and three growth factors for the growth state transition. We examined exponentially growing 3T3 cells to relate the requirements for G1 transit to those necessary for the transition from the G0 to the S phase. Cycling cells in the G1 phase required transcription, rapid translation, and a single growth factor (insulin-like growth factor [IGF] I) to initiate DNA synthesis. IGF I acted post-transcriptionally at a late G1 step. All cells in the G1 phase entered the S phase on schedule if either insulin (hyperphysiological concentration) or IGF I (subnanomolar concentration) was provided as the sole growth factor. In medium lacking all growth factors, only cells within 2 to 3 h of the S phase were able to initiate DNA synthesis. Similarly, cells within 2 to 3 h of the S phase were less dependent on transcription and translation for entry into the S phase. Cells responded very differently to inhibited translation than to growth factor deprivation. Cells in the early and mid-G1 phases did not progress toward the S phase during transcriptional or translational inhibition, and during translational inhibition they actually regressed from the S phase. In the absence of growth factors, however, these cells continued progressing toward the S phase, but still required IGF at a terminal step before initiating DNA synthesis. We conclude that a suboptimal condition causes cells to either progress or regress in the cell cycle rather than freezing them at their initial position. By using synchronized cultures, we also show that in contrast to earlier events, this final, IGF-dependent step did not require new transcription. This result is in contrast to findings that other growth factors induce new transcription. We examined the requirements for G1 transit by using a chemically transformed 3T3 cell line (BPA31 cells) which has lost some but not all ability to regulate its growth. Early- and mid-G1-phase BPA31 cells required transcription and translation to initiate DNA synthesis, although they did not regress from the S phase during translational inhibition. However, these cells did not need IGF for entry into the S phase.
Depletion of zinc inhibits growth in animals and proliferation of cultured cells. Additionally, tint: can serve as an antioxidant protecting many compounds, including proteins, from oxidation. Regulation of cell division also involves insulin-like growth factor type I (IGF-I) and its receptor, especially during late G(1) phase, allowing progression of the cell to S phase with subsequent DNA synthesis. We examined the effects of zinc depletion from the culture media of Swiss 3T3 cells on the cell cycle and IGF-I receptor expression. Cells were exposed to reduced fetal bovine serum concentrations to induce growth arrest, then returned to normal fetal bovine serum concentrations with the divalent cation chelator diethylenetriamine pentaacetic acid. Reducing the fetal bovine serum concentration did not induce quiescence in the cells as previously suggested. Zinc depletion reduced the proliferative fraction (S and G(2)/M phases) of the cell cycle. The addition of glutathione to the zinc-depleted media partially returned the proliferative fraction to the central level, Fetal bovine serum deprivation reduced IGF-I receptor expression whereas the absence of zinc had little effect an receptor expression. We conclude that depletion of zinc from culture media inhibits 3T3 cell proliferation independent of insulin-like growth factor-I receptor expression, and part of this inhibition is due to the antioxidant capacity of this divalent cation.
The ability of human growth hormone (hGH) to alleviate the effects of zinc deficiency on growth was investigated in the rat. The 18-day experiment was a completely randomized block design with a 3×2 factorial combination of 3 dietary groups (<1 ppm zinc, 100 ppm zinc, and pair fed) and 2 hGH treatments (hGH in saline and saline alone). The hGH treatment began on Day 8 and continued for 10 days. Human GH treatment had no significant effect on food consumption, growth parameters or plasma IGF-I. Food consumption, tail length, liver weight, and tibia weight were significantly lower in the zinc deficient group. Body weight was significantly reduced in the zinc deficient and pair fed groups compared to the control. A significant interaction between zinc and hGH was found for tibial epiphyseal cartilage width but there were no significant differences between the groups receiving hGH and the respective shams. Plasma IGF-I was numerically lower in the zinc deficient rats compared to the pair fed rats but this difference did not reach statistical significance. Tissue zinc content and plasma alkaline phosphatase were significantly decreased by the dietary zinc deficiency. Plasma zinc was higher in the groups receiving hGH. Significant interactions between zinc and hGH was found for liver iron, tibial zinc, and tibial copper. Copper and iron showed a competitive interaction with zinc and were lower in the rats receiving the control diet. Both lowered zinc and food intake contributed to the effects of the zinc deficiency; however, these effects were not equally distributed. Food intake had the greater effect on growth and plasma IGF-I while tissue mineral content showed a greater effect for zinc intake.
Mitogen-activated protein kinases such as Erk1 and Erk2 serve as a paradigm for a growing family of proline-directed protein kinases that mediate entry, progression and exit from the cell cycle in diverse eukaryotic cells. These enzymes function within highly conserved modules of sequentially activating protein kinases that transduce signals from diverse extracellular stimuli. In vertebrates, at least three distinct kinases modules have been characterized. Mitogens induce the sequential activation of the kinases Raf1-->Mek1-->Erk2-->Rsk via the G-protein Ras. Stress factors stimulate c-Jun activation through a related kinase pathway involving Mekk-->Sek-->SAPK c-Jun, and hsp27 phosphorylation via the MKK3-->Hog-->MAPKAPK-2 hsp27 route. Genetic and biochemical studies, for example from budding yeast, imply the existence of several related protein kinase modules that can operate in parallel or within integrated systems.
The effect of zinc deficiency on the direct-growth effect of growth hormone (GH) on tibia growth in hypophysectomized rats was studied. There were three dietary groups. Zinc deficient (ZD) group (0.9 mg/kg diet), control (C) group (66 mg/kg diet) and zinc adequate pair fed (PF) group (66 mg zinc/kg diet). All rats in each group received local infusion of recombinant human-growth hormone (hGH) (1 microgram/d), except for half of the animals in the control group, which were sham-treated, receiving vehicle infusion only. The substances were infused continuously for 13 d by osmotic minipumps through a catheter implanted into the right femoral artery. Food intake was lower and body weight loss was greater in ZD, and PF animals compared with C animals (p < 0.001). Tissue-zinc concentration and plasma alkaline-phosphatase activity were decreased (p < 0.05) by dietary-zinc deficiency. GH infusion increased the tibial-epiphyseal width of the treated right limb, but not of the noninfused left limb in C and PF animals. However, in ZD rats, no difference was found between the infused and the noninfused limbs. These results demonstrate that zinc deficiency inhibits the direct-growth effect of GH on long-bone growth.
1. The effects of early zinc deficiency on DNA and protein metabolism of the liver, kidneys, testes and spleen of the young rat were studied. The investigations were carried out in two phases: before food consumption and growth were affected, and afterwards.
2. The incorporation of [ ³ H]thymidine into DNA was markedly affected by differences of less than a week in the age of the rats.
3. Zn deficiency significantly reduced the incorporation of [ ³ H]thymidine into DNA of liver, kidneys and spleen before growth and food consumption were affected. The degree of inhibition was of the order of 50% in the first 5 d. A similar but non-significant trend was observed for the testes.
4. The incorporation of [ ³ C]lysine into protein was not significantly affected in liver and testes during the initial period of Zn deficiency; the incorporation into kidneys and spleen was significantly inhibited but the magnitude of the effect was only of the order of 20% in 5d.
5. One week after the start of the second phase, the concentration of DNA in liver, testes, and spleen of Zn-deficient animals was not significantly different from that in pair-fed controls. The DNA content of the kidneys was significantly reduced by the deficiency hut only to 97% of that in pair-fed animalsgiven the Zn-supplcmenteddiet. The incorporation of [ ³ H]thymidine into DNA was not significantly different between deficient and control groups in any of the four organs investigated.
The studies discussed in this paper indicate that there are significant interactions between the endocrine system and trace metals such that at physiologic and biochemical levels trace metals influence hormones and conversely, hormones influence trace metal metabolism. These interactions take place at several loci in each system and involve complex interactions at several levels of activity including secretion, transport, and binding. These reported studies, although extensive, clearly represent only an initial attempt in our understanding of the complex and varied relationships which exist between these two important systems. The future holds promise for the carrying out of many studies by which these interrelationships may be determined. By understanding interactions which focus upon relationships such as structure function, receptor binding, and receptor inhibition the roles that trace metals play in hormone action and the many ways that hormones influence the activity of trace metals can be established. (128 references are cited).
Insulin and insulin-like growth factors are neuroactive peptides. We investigated the effect of insulin-like growth factor I (IGF-I) on Ca2+ channel currents in 108CC15 neuroblastoma x glioma (N x G) cells and a possible role of protein kinase C (PKC). Whereas the native IGF-I enhanced the Ca2+ channel current density in N x G cells, the boiled IGF-I had no effect. The effect of IGF-I occurred after 1-2 h incubation and reversed within 24 h. Ca2+ channel currents recorded in control cells were mainly of a low-threshold fast inactivating type and showed a mean density of 5.9 +/- 0.3 pA/pF. Current density in cells incubated with IGF-I (0.2 micrograms/ml) for 2 h increased to 9.2 +/- 0.8 pA/pF. Ca2+ channel currents in cells treated with IGF-I showed an enhanced amount of a high-threshold slowly inactivating Ca2+ current type sensitive to the dihydropyridine isradipine and the snail toxin omega-conotoxin. The effect of IGF-I was suppressed by coincubation with the PKC inhibitors 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7) and staurosporin which were both without effect on current density in control cells. Whereas the inactive phorbol ester phorbol 12-myristate 13-acetate (PMA) failed to modulate Ca2+ channels in N x G cells, stimulation of PKC by the active phorbol ester PMA mimicked the effect of IGF-I. The effects of IGF-I and phorbol ester were not additive. Our data suggest an intracellular mechanism dependent on PKC and we propose a physiological relevance of the observed Ca2+ channel modulation by IGF-I in the neuroactivity of the peptide.
Metal ion coordination in the regulatory domain of protein kinase C (PKC) is suggested by the conservation of six cysteines and two histidines in two homologous regions found therein. By monitoring x-ray fluorescence from a purified sample of rat PKC beta I overexpressed in insect cells, direct evidence has been obtained that PKC beta I tightly binds four zinc ions (Zn2+) per molecule. Extended x-ray absorption fine structure (EXAFS) data are best fit by an average Zn2+ coordination of one nitrogen and three sulfur atoms. Of the plausible Zn2+ coordination models, only those featuring nonbridged Zn2+ sites accommodate the EXAFS data and all of the conserved potential ligands.
Size-exclusion chromatography and sedimentation equilbrium studies demonstrated that zinc ion (Zn2+) induced the dimerization
of human growth hormone (hGH). Scatchard analysis of 65Zn2+ binding to hGH showed that two Zn2+ ions associate per dimer of
hGH in a cooperative fashion. Cobalt (II) can substitute for Zn2+ in the hormone dimer and gives a visible spectrum characteristic
of cobalt coordinated in a tetrahedral fashion by oxygen- and nitrogen-containing ligands. Replacement of potential Zn2+ ligands
(His18, His21, and Glu174) in hGH with alanine weakened both Zn2+ binding and hGH dimer formation. The Zn(2+)-hGH dimer was
more stable than monomeric hGH to denaturation in guanidine-HCl. Formation of a Zn(2+)-hGH dimeric complex may be important
for storage of hGH in secretory granules.
The effect of zinc status on external calcium uptake by rat platelets and the relation of uptake to aggregation malfunction were studied. For 11 d, immature male rats were fed either a low zinc diet (0.3 mg/kg) ad libitum, a zinc-adequate diet (100 mg/kg) ad libitum, or the adequate diet pair-fed. Washed platelets were loaded with fura-2 acetoxymethyl ester for measurement of cytosolic free calcium. The resting calcium concentration was higher in platelets from rats of low zinc status than in those from controls. When platelets were stimulated with a minimal level (0.12 mumol/L) of ADP, the free cytosolic calcium concentration increased to a greater extent when calcium was present in the external medium than in its absence. The difference was considered to be external uptake. Zinc status had no effect on internal release, but platelets from zinc-deficient rats took up significantly less external calcium. In conclusion, low zinc status in rats adversely affects calcium metabolism in platelets. Decreased uptake of external calcium by ADP-stimulated platelets is associated with defective aggregation.
Transit of 3T3 cells from quiescence to S phase requires an adequate supply of Zn2+ during the second half of the transition. The nature of this requirement has been investigated. Completion of the Zn2(+)-dependent process required ongoing mRNA and protein synthesis but could be accomplished in serum-free medium. Combination of low Zn2+ availability with inhibition of mRNA synthesis by 5,6-dichlororibofuranosylbenzimidazole or of protein synthesis by cycloheximide resulted in the cells almost completely reverting to a quiescent state. The results suggest that Zn2+ is required for the accumulation and maintenance of a protein involved in the progression of untransformed cells into S phase.
Putative binding sites for zinc are present in the regulatory domain of protein kinase C but a distinct role for zinc has not yet been proposed. Here we show that micromolar concentrations of zinc chloride cause pure rat brain protein kinase C to localize in a detergent-insoluble, cytoskeletal fraction of red cell membranes and to bind to isolated cytoskeleton in the presence of phosphatidylserine. Attachment of protein kinase C to cytoskeleton was accompanied by enhanced expression of binding sites for 3H-phorbol ester, a regulatory ligand of protein kinase C. The active factor in the cytoskeleton was labile to protease suggesting that protein kinase C binds to a cytoskeletal protein.
In 3T3 cells stimulated from quiescence by serum, impaired thymidine incorporation caused by inadequate supply of Zn2+ was associated with both decreased thymidine kinase activity and a comparable decrease in its mRNA concentration. In contrast, the amount of mRNA for ribosomal protein S6 was not affected, nor was the earlier increase in the activity of ornithine decarboxylase.
Human growth hormone (hGH) elicits a diverse set of biological activities including lactation that derives from binding to the prolactin (PRL) receptor. The binding affinity of hGH for the extracellular binding domain of the hPRL receptor (hPRLbp) was increased about 8000-fold by addition of 50 micromolar ZnCl2. Zinc was not required for binding of hGH to the hGH binding protein (hGHbp) or for binding of hPRL to the hPRLbp. Other divalent metal ions (Ca2+, Mg2+, Cu2+, Mn2+, and Co2+) at physiological concentrations did not support such strong binding. Scatchard analysis indicated a stoichiometry of one Zn2+ per hGH.hPRLbp complex. Mutational analysis showed that a cluster of three residues (His18, His21, and Glu174) in hGH and His188 from the hPRLbp (conserved in all PRL receptors but not GH receptors) are probable Zn2+ ligands. This polypeptide hormone.receptor "zinc sandwich" provides a molecular mechanism to explain why nonprimate GHs are not lactogenic and offers a molecular link between zinc deficiency and its association with altered functions of hGH.
Addition of the chelator DTPA to synchronized cultures of 3T3 cells inhibited thymidine incorporation by up to 90% and only Zn2+ of the divalent cations tested was effective in reversing this effect. Fe2+ given alone had no effect on the inhibition by DTPA but when added to Zn2+ supplemented cultures increased thymidine incorporation from approximately 80-90 to over 100% of that in control cultures. Investigations indicated that the major requirement for Zn2+ was within the period from 8 h after stimulation of quiescent cells with serum until 3 h before the start of S phase. There was also an indication of a further requirement for Zn2+ at the G/S transition.
DNA synthesis and adenosine(5')tetraphosphate(5')adenosine (Ap4A) levels decrease in cells treated with EDTA. The inhibitory effect of EDTA can be reversed with micromolar amounts of ZnCl2. ZnCl2 in micromolar concentrations also inhibits Ap4A hydrolase and stimulates amino acid-dependent Ap4A synthesis, suggesting that Zn2+ is modulating intracellular Ap4A pools. Serum addition to G1-arrested cells enhances uptake of Zn, whereas serum depletion leads to a fivefold decrease of the rates of zinc uptake. These results are discussed by regarding Zn2+ as a putative 'second messenger' of mitogenic induction and Ap4A as a possible 'third messenger' and trigger of DNA synthesis.
White male growing rats were fed rat chow diet for 4 days after which they were fasted for 72 h. At the end of fasting, rats were allotted into four dietary treatments that varied only in the level of zinc (Zn): Zn-deficient group (ZnD), 30, 90, and 140 ppm of Zn. A group of eight rats were not fasted and were fed the rat chow diet throughout the experimental period. Blood was obtained at intervals from all groups for the measurements of Zn and somatomedin C (SMC) in the plasma. Eight rats were randomly selected at zero time (t0) and at the end of fasting period were killed for the measurement of tibia Zn. At the end of refeeding, all rats were killed for tibia Zn determination as well. Results showed that plasma SMC decreased to the hypopituitary level at the 3rd day of fasting. At 48 and 72 h of refeeding, the levels of plasma SMC increased significantly in all experimental groups and the differences among groups were not significant. The levels of SMC in groups fed 140 and 90 ppm of Zn continued to increase significantly with progressive refeeding. However, in groups fed 30 ppm and ZnD diets the levels of SMC started to decline after 72 h of refeeding. The levels of plasma Zn followed similar trend as SMC levels. In addition, the levels of Zn in the tibia were comparable in all groups with SMC and plasma Zn levels at the end of fasting or refeeding period. Previous reports showed that plasma SMC level is a more reliable index used to monitor nutritional responses; thus, it could be concluded that the level of Zn in the diet should be considered carefully when planning nutritional intervention for severe malnutrition or starvation.
1. The objective of the present experiment was to study the level of plasma somatomedin-C (SM-C) and the status of zinc in rats as affected by three levels of Zn given in combinations with two levels of protein.
2. Six groups of rats were fed, for 21 d, on six different diets based on combinations of two levels of dietary protein (low protein, 75 g/kg; high protein, 200 g/kg) and three levels of zinc (low Zn, 0.9 pglkg; moderate Zn, 55 pg/kg; high Zn, 110 pglkg). All groups were pair-fed with the group receiving the low-Zn-low-protein diet. An additional group of six rats served as an ad lib.-fed control group and was fed on a diet that contained 55 pg Zn/kg and 200 g protein/kg ad lib.
3. Body-weight gain and food intake were recorded daily. Rats were killed at the end of the experimental period (21 d). Zn was assayed in plasma, tibia and liver by atomic absorption technique. Plasma SM-C was assayed by radioimmunoassay.
4. In rats given the low-Zn-low-protein diet, the level of plasma SM-C increased in response to the increase in the amount of Zn or Zn and protein in the diet. However, no change was observed when the level of protein alone was increased.
5. Among all groups tested, adlib.-fed rats showed the highest level of plasma SM-C. Thus it may be concluded that a balanced diet combined with adequate food intake is necessary to maintain an optimal level of plasma SM-C.
Weanling male rats were fed control ad libitum, zinc-deficient (ZD, 1 ppm zinc) or pair-fed (PF) control diets for 13 days. Rats subsequently were refed control diets for up to 8 days and serially killed. ZD and PF diets significantly decreased growth rate, feed intake, and feed efficiency compared to controls. Body weight and feed efficiency, but not feed intake, were significantly less in ZD compared to PF. Bone zinc was 315, 286, and 109 micrograms/g (p less than 0.0001) for control, PF, and ZD at the end of depletion. 35SO4 uptake by glycosaminoglycans (GAG) was significantly less in ZD compared to either control ad libitum or PF rats. Xylosyltransferase activity was decreased significantly below PF and control by ZD, suggesting depressed enzyme activity and/or decreased GAG acceptor sites. Bioassayable somatomedin (Sm) activity was 0.81, 0.42 and 0.33 +/- 0.09 relative activity for control, PF and ZD at the end of depletion. Sm was statistically less in ZD compared to PF at day 2 and 5 of refeeding, but not at the end of depletion. Sm activity and GAG metabolism returned to normal after refeeding for 2-5 days in PF and for 5-8 days in ZD rats. Serum insulin but not glucose was significantly depressed by ZD and PF diets. Thus, zinc deficiency depressed growth and cartilage metabolism and was associated with decreased Sm activity and insulin levels. Some of these changes could be attributed to decreased feed intake as a result of ZD.
Zinc is essential for the growth of various animal species, and recently its importance in human nutrition has been recognized. Several observations in the past indicate that zinc may have a role in the functions of the anterior pituitary. In this study, we investigated the effect of growth hormone administration on growth of zinc-deficient nonhypophysectomized rats and of zinc on growth of hypophysectomized rats. In addition, zinc and iron were assayed and activities of zinc-dependent enzymes determined histochemically in various tissues. Dietary zinc supplementation increased the growth rate of nonhypophysectomized zinc deficient rats considerably while growth hormone administration under the conditions of our experiments was without effect in the presence or absence of supplemental zinc. The growth rate of hypophysectomized rats was affected by both zinc and growth hormone, and these effects were independent. The zinc concentration of bone and testis of the nonhypophysectomized rats and of bone of the hypophysectomized rats was decreased in the zinc-deficient groups, and this was accompanied by decreased activities of the zinc-dependent enzymes. An increased concentration of iron in several tissues was observed in zinc-deficient rats, in both experiments, suggesting a physiological competition between zinc and this element. Zinc and growth hormone seem to regulate growth in rats by independent mechanisms. Our results are consistent with the hypothesis that the content of zinc in tissues most likely controls the metabolic processes through the formation and/or regulation of activities of zinc-dependent enzymes. Bone and testis in rats seem to be the two most susceptible tissues with respect to zinc deficiency.
The control of eucaryotic cell proliferation is governed largely by a series of regulatory events which occur in the G1 phase of the cell cycle. When stimulated to proliferate, quiescent (G0) 3T3 fibroblasts require transcription, rapid translation, and three growth factors for the growth state transition. We examined exponentially growing 3T3 cells to relate the requirements for G1 transit to those necessary for the transition from the G0 to the S phase. Cycling cells in the G1 phase required transcription, rapid translation, and a single growth factor (insulin-like growth factor [IGF] I) to initiate DNA synthesis. IGF I acted post-transcriptionally at a late G1 step. All cells in the G1 phase entered the S phase on schedule if either insulin (hyperphysiological concentration) or IGF I (subnanomolar concentration) was provided as the sole growth factor. In medium lacking all growth factors, only cells within 2 to 3 h of the S phase were able to initiate DNA synthesis. Similarly, cells within 2 to 3 h of the S phase were less dependent on transcription and translation for entry into the S phase. Cells responded very differently to inhibited translation than to growth factor deprivation. Cells in the early and mid-G1 phases did not progress toward the S phase during transcriptional or translational inhibition, and during translational inhibition they actually regressed from the S phase. In the absence of growth factors, however, these cells continued progressing toward the S phase, but still required IGF at a terminal step before initiating DNA synthesis. We conclude that a suboptimal condition causes cells to either progress or regress in the cell cycle rather than freezing them at their initial position. By using synchronized cultures, we also show that in contrast to earlier events, this final, IGF-dependent step did not require new transcription. This result is in contrast to findings that other growth factors induce new transcription. We examined the requirements for G1 transit by using a chemically transformed 3T3 cell line (BPA31 cells) which has lost some but not all ability to regulate its growth. Early- and mid-G1-phase BPA31 cells required transcription and translation to initiate DNA synthesis, although they did not regress from the S phase during translational inhibition. However, these cells did not need IGF for entry into the S phase.
1. Male weanling rats were fed on diets either adequate (55 mg/kg), or severely deficient (0.4 mg/kg) in zinc, either ad lib. or in restricted amounts in four experiments. Measurements were made of growth rates and Zn contents of muscle and several individual tissues.
2. Zn-deficient rats exhibited the expected symptoms of deficiency including growth retardation, cyclic changes in food intake and body-weight.
3. Zn deficiency specifically reduced whole body and muscle growth rates as indicated by the fact that ( a ) growth rates were lower in ad lib. -fed Zn-deficient rats compared with rats pair-fed on the control diet in two experiments, ( b ) Zn supplementation increased body-weights of Zn-deficient rats given a restricted amount of diet at a level at which they maintained weight if unsupplemented, ( c ) Zn supplementation maintained body-weights of Zn-deficient rats fed a restricted amount of diet at a level at which they lost weight if unsupplemented ( d ) since the ratio, muscle mass:body-weight was lower in the Zn-deficient rats than in the pair-fed control groups, the reduction in muscle mass was greater than the reduction in body-weight.
4. Zn concentrations were maintained in muscle, spleen and thymus, reduced in comparison to some but not all control groups in liver, kidney, testis and intestine, and markedly reduced in plasma and bone. In plasma, Zn concentrations varied inversely with the rate of change of body-weight during the cyclic changes in body-weight.
5. Calculation of the total Zn in the tissues examined showed a marked increase in muscle Zn with a similar loss from bone, indicating that Z