Regulation of caspase activation and apoptosis by cellular zinc fluxes and zinc deprivation: A review.

Non-toxic agents that target intracellular signalling pathways in apoptosis may have potential therapeutic use in many diseases. One such agent is the transition metal Zn, a dietary cytoprotectant and anti-oxidant, which stimulates cell proliferation and suppresses apoptosis. Zn is maintained in discrete subcellular pools that are critical for the functional and structural integrity of cells. The present review initially describes the current state of knowledge on the cellular biology of Zn, especially the critical free or loosely bound (labile) pools of Zn, which are thought to regulate apoptosis. We then review the evidence relating Zn to apoptosis, including studies from our laboratory showing potent synergy between intracellular Zn deficiency and the short chain fatty acid butyrate in induction of caspase activation and the downstream events of apoptosis. Our studies have also reported the suppressive effects of micromolar concentrations of Zn on caspase-3 activation in cell-free models. Other key issues that will be discussed include the identification of the putative molecular targets of Zn and the evidence that systemic changes in labile Zn levels are sufficient to alter susceptibility to apoptosis and lead to physiopathological changes in the human body. Finally, we propose that labile Zn may serve as a coordinate regulator of mitosis and apoptosis to regulate tissue growth.     

Taurine bromamine (TauBr) - its role in immunity and new perspectives for clinical use

This review is an attempt to summarize our knowledge about taurine bromamine (TauBr) properties, its role in innate immunity and its therapeutic potential.TauBr and taurine chloramine (TauCl) are major haloamines generated by eosinophils and neutrophils at a site of inflammation. Both haloamines share anti-inflammatory and anti-oxidant properties. TauBr, similarly to TauCl, decreases the production of proinflammatory mediators. Their anti-inflammatory and anti-oxidant activities are enhanced by their ability to induce the expression of heme oxygenase-1 (HO-1). TauCl is more stable than TauBr. On the other hand, only TauBr was found to be highly membrane-permeable showing stronger microbicidal activity than TauCl.In the light of the anti-inflammatory and antimicrobial properties of TauBr we discuss its therapeutic potential in local treatment of inflammation, especially acne vulgaris, the most common inflammatory skin disorder. TauBr, at non-cytotoxic concentrations, is able to kill Propionibacterium acnes, the skin bacteria involved in pathogenesis of acne vulgaris.As topical antibiotics used in the therapy of acne are associated with the emergence of resistant bacteria, topical TauBr seems to be a good candidate for an alternative therapy.Recently, in a double blind trial, the efficacy of TauBr was compared with the efficacy of clindamycin, one of the most common topical antibiotics used in acne therapy. Comparable reduction of acne lesions was observed in the TauBr and clindamycin groups of patients with mild and moderate inflammatory facial acne vulgaris. We conclude that this pilot study supports our concept that TauBr can be used as a topical agent in the treatment of acne vulgaris, especially in patients who have already developed antibiotic resistance. Further studies are necessary to substantiate the more extended use of TauBr as an anti-inflammatory and anti-oxidant agent in human medicine.     

The role of nitric oxide in the regulation of ion channels in airway epithelium: Implications for diseases of the lung

The human respiratory tract is covered with airway surface liquid (ASL) that is essential for lung defense and normal airway function. The quantity and composition of ASL is regulated by active ion transport across the airway epithelium. Abnormal electrolyte transport produces changes in ASL volume and composition, inhibits mucociliary clearance and leads to chronic infection of airway surfaces, as is evident in cystic fibrosis. Agonists that induce intracellular increases in cAMP or Ca²⁺ are generally associated with electrolyte secretion. While these mechanisms have been studied in detail for many years, modulation of ion channels by nitric oxide (NO) has emerged only recently as a significant determinant of ion channel function. NO is a physiological regulator of transepithelial ion movement and alterations of its generation and action may play an important role in the pathogenesis of lung disorders characterized by hypersecretion of ASL. This review presents the current understanding of regulation of airway epithelial ion channels by NO and attempts to highlight the importance of this regulation for lung defense.     

Visualization of labile zinc and its role in apoptosis of primary airway epithelial cells and cell lines

The respiratory epithelium is vulnerable to noxious substances, resulting in the shedding of cells and decreased protection. Zinc (Zn), an antioxidant and cytoprotectant, can suppress apoptosis in a variety of cells. Here we used the novel Zn-specific fluorophore Zinquin to visualize and quantify labile intracellular Zn in respiratory epithelial cells. Zinquin fluorescence in isolated ciliated tracheobronchial epithelial cells and intact epithelium from sheep and pigs revealed an intense fluorescence in the apical and mitochondria-rich cytoplasm below the cilia. Zinquin fluorescence was quenched by the Zn chelator N,N,N', N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) and increased by the Zn ionophore pyrithione. We also assessed whether changes in intracellular labile Zn would influence susceptibility of these cells to apoptosis by hydrogen peroxide. Our results confirm that Zn deficiency enhanced hydrogen peroxide-induced caspase activation from 1.24 +/- 0.12 to 2.58 +/- 0.53 units. microg protein(-1). h(-1) (P 相似文献   

Zinc nutrition and arbuscular mycorrhizal symbiosis effects on maize (Zea mays L.) growth and productivity

Zinc (Zn) is an essential micronutrient required to enhance crop growth and yield. In the arid – semiarid region, Zn deficiency is expected due to alkaline calcareous soil. Contrarily, Zn toxicity is also becoming an environmental concern due to increasing anthropogenic activities (metal smelting, copper industry, etc.). Therefore, balanced Zn application is necessary to save resources and achieve optimum crop growth and yield. Most scientists suggest biological approaches to overcome the problem of Zn toxicity and deficiency. These biological approaches are mostly environment-friendly and cost-effective. In these biological approaches, the use of arbuscular mycorrhizae fungi (AMF) symbiosis is becoming popular. It can provide tolerance to the host plant against Zn-induced stress. Inoculation of AMF helps in balance uptake of Zn and enhances the growth and yield of crops. On the other hand, maize (Zea mays L.) is an important cereal crop due to its multifarious uses. As maize is an effective host for mycorrhizae symbiosis, that’s why this review was written to elaborate on the beneficial role of arbuscular mycorrhizal fungi (AMF). The review aimed to glance at the recent advances in the use of AMF to enhance nutrient uptake, especially Zn. It was also aimed to discuss the mechanism of AMF to overcome the toxic effect of Zn. We have also discussed the detailed mechanism and physiological improvement in the maize plant. In conclusion, AMF can play an imperative role in improving maize growth, yield, and balance uptake of Zn by alleviating Zn stress and mitigating its toxicity.     

The role of nitric oxide in the regulation of ion channels in airway epithelium: implications for diseases of the lung

The human respiratory tract is covered with airway surface liquid (ASL) that is essential for lung defense and normal airway function. The quantity and composition of ASL is regulated by active ion transport across the airway epithelium. Abnormal electrolyte transport produces changes in ASL volume and composition, inhibits mucociliary clearance and leads to chronic infection of airway surfaces, as is evident in cystic fibrosis. Agonists that induce intracellular increases in cAMP or Ca²⁺ are generally associated with electrolyte secretion. While these mechanisms have been studied in detail for many years, modulation of ion channels by nitric oxide (NO) has emerged only recently as a significant determinant of ion channel function. NO is a physiological regulator of transepithelial ion movement and alterations of its generation and action may play an important role in the pathogenesis of lung disorders characterized by hypersecretion of ASL. This review presents the current understanding of regulation of airway epithelial ion channels by NO and attempts to highlight the importance of this regulation for lung defense.     

Zinc homeostasis and signaling in health and diseases

The essential trace element zinc (Zn) is widely required in cellular functions, and abnormal Zn homeostasis causes a variety of health problems that include growth retardation, immunodeficiency, hypogonadism, and neuronal and sensory dysfunctions. Zn homeostasis is regulated through Zn transporters, permeable channels, and metallothioneins. Recent studies highlight Zn’s dynamic activity and its role as a signaling mediator. Zn acts as an intracellular signaling molecule, capable of communicating between cells, converting extracellular stimuli to intracellular signals, and controlling intracellular events. We have proposed that intracellular Zn signaling falls into two classes, early and late Zn signaling. This review addresses recent findings regarding Zn signaling and its role in physiological processes and pathogenesis.     

Vibrio cholerae periplasmic superoxide dismutase: isolation of the gene and overexpression of the protein

Superoxide dismutases are ubiquitous enzymes which play an important role in protecting cells against oxidative damage and which have also been shown to contribute to the pathogenicity of many bacterial species. Here we demonstrate that Vibrio cholerae, the causative agent of cholerae, expresses an active periplasmic Cu,Zn superoxide dismutase. Moreover, we have set up an expression system yielding large amounts of V. cholerae recombinant Cu,Zn superoxide dismutase in the periplasm of Escherichia coli and a procedure to obtain the enzyme in a highly purified form. Unlike the bovine enzyme, V. cholerae Cu,Zn superoxide dismutase has been proved to be highly resistant to inactivation by hydrogen peroxide. This property, which appears to be common to other bacterial enzymes of this class, might improve the ability of Cu,Zn superoxide dismutase to protect bacteria against the reactive oxygen species produced by phagocytes.     

Zinc binding to the gills of rainbow trout: the effect of long-term exposure to sublethal zinc

The effects of sublethal waterborne Zn (2·28 μmol l⁻¹) on Zn binding kinetics to the apical gill surface were studied in juvenile rainbow trout ( Oncorhynchus mykiss ). Two separate radiotracer techniques were employed to ascertain this information. First, in vitro binding kinetic experiments were performed at extremely elevated zinc concentrations (up to 20 mmol l⁻¹) to measure relatively low-affinity binding sites at the gill epithelium. There were no differences in Zn binding parameters ( K_m and B _max) for fish sublethally exposed to Zn for 21 days and their simultaneous controls. Nevertheless, Ca did have an increased inhibitory effect on Zn binding in Zn-exposed fish suggesting that the anionic groups on the gill epithelium of these fish had been altered in some manner. Additionally, in vivo Zn binding kinetics were investigated using environmentally relevant waterborne Zn concentrations (low μmol l⁻¹ range) to isolate high-affinity Zn binding sites (Ca transporters). No appreciable alterations in the Km and B _max values for Zn binding were seen between the Zn-exposed group and its simultaneous control following 15 days of exposure. Furthermore, no significant differences in CC morphometry were observed between treatments. Despite these lack of treatment effects, there were temporal alterations in K_m , B _max and CC fractional surface area in both groups. It is proposed that these fluctuations are controlled by hormonal factors (such as stanniocalcin), believed to play a role in Ca influx.     

Host defense peptides and the new line of defence against multiresistant infections

Increasing antibiotic resistance has led to an urgent need for new therapeutic approaches. Host defense peptides are known to be antimicrobial and have revealed broad immunomodulatory functions for both innate and adaptive immunity. This review will focus on the role of host defense peptides in infection and immune response and discuss its potential and limitations as a future therapeutical agent.     

Melatonin binding site MT3 is QR2: state of the art

Melatonin is a neurohormone primarily synthesized in the pineal gland at night. It has numerous functions in various pathophysiological situations, including anti-oxidant properties at pharmacological concentrations (1 microM and above). It is believed that melatonin acts through three main targets: two 7TM receptors (MT1 and MT2) and one atypical binding site called MT3. This last binding site has been purified in our laboratory and is designated as quinone reductase 2 (QR2, E.C. 1.10.99.2). This enzyme has several individualistic features. It does not recognize standard nicotinamide derivatives as co-substrates, but rather, it recognizes rare ones such as N-ribosylnicotinamide. Among other features of this enzyme, two are of major importance: 1) experiments from Dr Jaiswal (Houston, Texas) laboratory with QR2-/- mice and with cells derived from them demonstrated that this enzyme is implicated in the toxicological activation of menadione, and thus, may have an activation rather than a detoxification role, as formerly believed, and 2) the polyphenol resveratrol, a molecule with anti-oxidant properties, is a potent inhibitor of QR2 ( approximately 30 nM). This talk will briefly summarize these findings, and will present our working hypotheses, molecular tools and findings on several aspects of the possible relationship between QR2 and melatonin, in particular those suggesting a mechanism for the anti-oxidant activity of melatonin.     

Epithelial effects of proteinase-activated receptors in the gastrointestinal tract

The intestinal epithelium plays a crucial role in providing a barrier between the external environment and the internal milieu of the body. A compromised mucosal barrier is characteristic of mucosal inflammation and is a key determinant of the development of intestinal diseases such as Crohn's disease and ulcerative colitis. The intestinal epithelium is regularly exposed to serine proteinases and this exposure is enhanced in numerous disease states. Thus, it is important to understand how proteinase-activated receptors (PARs), which are activated by serine proteinases, can affect intestinal epithelial function. This review surveys the data which demonstrate the wide distribution of PARs, particularly PAR-1 and PAR-2, in the gastrointestinal tract and accessory organs, focusing on the epithelium and those cells which communicate with the epithelium to affect its function. PARs have a role in regulating secretion by epithelia of the salivary glands, stomach, pancreas and intestine. In addition, PARs located on subepithelial nerves, fibroblasts and mast cells have important implications for epithelial function. Recent data outline the importance of the cellular site of PAR expression, as PARs expressed on epithelia may have effects that are countered by PARs expressed on other cell types. Finally, PARs and their ability to promote epithelial cell proliferation are discussed in terms of colon cancer.     

Searching for the real function of mTOR signaling in the regulation of PD-L1 expression

The mammalian target of rapamycin (mTOR), via forming two important complexes: mTOR complex 1 (mTORC1) and complex 2 (mTORC2), plays an important role in the regulation of immunity in addition to exerting many other biological funcions. Beyond its regulatory effects on immune cells, the mTOR axis also regulates the expression of programmed death-ligand 1 (PD-L1) in cancer cells; accordingly, inhibition of mTOR alters PD-L1 levels in different cancer cell types. However, the currently published studies on mTOR inhibition-induced PD-L1 alteration have generated conflicting results. This review will focus on summarizing current findings in this regard and discussing possible reasons for the discrepancies and their potential implications for PD-L1 modulation in cancer therapy.     

Therapeutic uses of antioxidant liposomes

This review will focus on the therapeutic uses of antioxidant liposomes. Antioxidant liposomes have a unique ability to deliver both lipid- and water-soluble antioxidants to tissues. This review will detail the varieties of antioxidants which have been incorporated into liposomes, their modes of administration, and the clinical conditions in which antioxidant liposomes could play an important therapeutic role. Antioxidant liposomes should be particularly useful for treating diseases or conditions in which oxidative stress plays a significant pathophysiological role because this technology has been shown to suppress oxidative stress. These diseases and conditions include cancer, trauma, irradiation, retinotherapy or prematurity, respiratory distress syndrome, chemical weapon exposure, and pulmonary infections.     

小鼠胎肺分支形态发生的分子机制

哺乳动物在早期胚胎发育过程中,肺发育经历了气管分支的形态发生、树样结构上皮管道的形成,并伴随着血管的发育而发生的气体通路和肺泡的分化等过程.肺发生涉及到许多复杂的分子机制.肺形态学的变化受到一系列持家基因、激素、核转录因子、生长因子及其他因素的综合调控.目前已经发现决定肺分支形态发生的许多重要因子.本文根据目前最新研究进展,阐述了小鼠胚胎肺在分支形态发生过程中,上皮与间充质之间诱导的信号通路之间的相互作用及其对呼吸树形态建成的调控机制.     

Tissue distribution of the secretory protein, SPLUNC1, in the human fetus

We previously identified a tissue-specific gene, short palate, lung, and nasal epithelium clone 1 (SPLUNC1), in nasopharyngeal epithelial tissues. SPLUNC1 was differentially expressed in nasopharyngeal carcinoma. Bioinformatic analysis revealed that SPLUNC1 has the bactericidal permeability-increasing protein/lipid-binding protein (BPI/LBP) domain and a 19 amino acid signal peptide, which suggest that it is a secretory protein. Its precise cellular localization in the respiratory tract is mainly in mucous cells and ducts of submucosal glands. However, little is known about its expression pattern in various human tissues. We generated a highly specific antibody and analyzed its distribution in the human fetus by immunohistochemistry to more precisely determine SPLUNC1 protein localization in human tissues. The results were further validated by RT-PCR. Our results showed that SPLUNC1 protein is expressed at not only the serous glands and epithelium of the upper respiratory tract and digestive tract, but also in the oculi of human embryos. Interestingly, we also found positive staining in fetus adipose tissue, a result not previously reported in studies of adult human tissues. Western blot analysis detected a 24 kDa SPLUNC1 protein in the compounds of nasopharyngeal secretions. This secretory protein was also detected in saliva and tears. Our research suggests that SPLUNC1 protein may not only be an antimicrobial peptide that plays an important role in the maintenance of homeostasis in the upper respiratory tract, oculi, and alimentary tract, it may also be important in the development and lipid metabolism of the adipose tissue.     

Anti-oxidant, pro-oxidant properties of tannic acid and its binding to DNA

Tannic acid has numerous food and pharmacological applications. It is an additive in medicinal products, and is used as a flavouring agent and as an anti-oxidant in various foods and beverages. We have previously shown that tannic acid in the presence of Cu(II) causes DNA degradation through generation of reactive oxygen species. On the other hand, it exhibits antimutagenic and anticarcinogenic activities, and induces apoptosis in animal cells. It is known that most plant-derived polyphenolic anti-oxidants also act as pro-oxidants under certain conditions. In this paper, we compare the anti-oxidant and pro-oxidant properties of tannic acid and its structural component gallic acid. It is shown that tannic acid is the most efficient generator of the hydroxyl radical in the presence of Cu(II), as compared with gallic acid and its analogues syringic acid and pyrogallol. The anti-oxidant activity of tannic acid was studied by its effect on hydroxyl radical and singlet oxygen mediated cleavage of plasmid DNA. Again, tannic acid provided the maximum protection against cleavage, while gallic acid and its structural analogues were found to be non-inhibitory or partially inhibitory. The results suggest that the structural features of tannic acid that are important for its anti-oxidant action are also those that contribute to the generation of hydroxyl radicals in the presence of Cu(II). Restriction analysis of treated phage DNA and thermal melting profiles of calf thymus DNA indicated that tannic acid strongly binds to DNA. Indirect evidence indicates that modification of DNA bases may also occur.     

吸烟小鼠呼吸道上皮细胞上皮钙粘附素表达的研究

通过免疫荧光法检测不同吸烟时间小鼠呼吸道上皮细胞上皮钙粘附素（Ｅｃａｄｈｅｒｉｎ,Ｅｃｄ）表达的动态变化,并采用显微荧光光度术进行定量分析。结果表明,首次吸烟１ｈ后呼吸道上皮细胞Ｅｃｄ表达与正常对照组比较明显下调（Ｐ＜００１）,４６Ｗ后降到最低水平。以后逐渐上调,吸烟８Ｗ后Ｅｃｄ表达恢复正常,气管上皮细胞表达高于正常（Ｐ＜００１）。提示,Ｅｃｄ表达的动态变化在呼吸道上皮细胞损伤与修复过程中起重要作用     

Human airway xenograft models of epithelial cell regeneration

Regeneration and restoration of the airway epithelium after mechanical, viral or bacterial injury have a determinant role in the evolution of numerous respiratory diseases such as chronic bronchitis, asthma and cystic fibrosis. The study in vivo of epithelial regeneration in animal models has shown that airway epithelial cells are able to dedifferentiate, spread, migrate over the denuded basement membrane and progressively redifferentiate to restore a functional respiratory epithelium after several weeks. Recently, human tracheal xenografts have been developed in immunodeficient severe combined immunodeficiency (SCID) and nude mice. In this review we recall that human airway cells implanted in such conditioned host grafts can regenerate a well-differentiated and functional human epithelium; we stress the interest in these humanized mice in assaying candidate progenitor and stem cells of the human airway mucosa.