Labile Zn2 Research Articles

Defective Hierarchical Pore Engineering of a Zn-Ni MOF by Labile Coordination Bonding Modulation.

The construction and modulation of hierarchical pore structure in metal-organic frameworks (MOFs) has become a hot topic owing to the advantages of hierarchical pore MOFs (HP-MOFs) in matter storage and mass transfer related applications. Herein, we report the engineering of crystalline defect in a bimetallic MOF for the construction and tuning of HP-MOF. A microporous MOF system showing metal-center-dependent water stability, namely, {[M3F(bdc)3 tpt] (solvents)}n (M = Zn2+ and Ni2+, H2bdc = 1,4-benzenedicarboxylic acid, tpt = 2,4,6-tris(4-pyridyl)triazine), was utilized as a platform for the construction of HP-MOF. By tuning the Zn2+/Ni2+ ratio in the reactant, a bimetallic MOF with a highly tunable Zn2+/Ni2+ ratio could be obtained. The relatively labile Zn2+-based coordination bonding in the bimetallic MOF could be readily and targeted broken through water treatment for the engineering of crystalline defects-based hierarchical pore structure. The resultant HP-MOF reveals a dramatically increased pore volume with the presence of mesopore and macropore. In addition, the anionic framework of HP-MOF could be utilized for the selective adsorption of a cationic dye methylene blue, and a relatively high capacity (250 mg·g-1, five times compared with the pristine microporous MOF) could be achieved.

Zn2+ influx activates ERK and Akt signaling pathways

Zinc (Zn2+) is an essential metal in biology, and its bioavailability is highly regulated. Many cell types exhibit fluctuations in Zn2+ that appear to play an important role in cellular function. However, the detailed molecular mechanisms by which Zn2+ dynamics influence cell physiology remain enigmatic. Here, we use a combination of fluorescent biosensors and cell perturbations to define how changes in intracellular Zn2+ impact kinase signaling pathways. By simultaneously monitoring Zn2+ dynamics and kinase activity in individual cells, we quantify changes in labile Zn2+ and directly correlate changes in Zn2+ with ERK and Akt activity. Under our experimental conditions, Zn2+ fluctuations are not toxic and do not activate stress-dependent kinase signaling. We demonstrate that while Zn2+ can nonspecifically inhibit phosphatases leading to sustained kinase activation, ERK and Akt are predominantly activated via upstream signaling and through a common node via Ras. We provide a framework for quantification of Zn2+ fluctuations and correlate these fluctuations with signaling events in single cells to shed light on the role that Zn2+ dynamics play in healthy cell signaling.

Adenine deficient yeast: A fluorescent biosensor for the detection of Labile Zn(II) in aqueous solution

Labile Zn(II) species play key roles in inducing bioresponse. Thus the development of a biosensor for labile Zn(II) quantification is important. In this study, we demonstrate that the autofluorescence intensity (FITC channel) of an adenine deficient yeast (Ade(−) yeast) was enhanced in the presence of Zn2+. Yeast cells were firstly cultured for 24 h to obtain the Ade(−) yeast, and the biomass (OD value) was optimized to be 0.03. After pre-culturing in D-glucose at 2.5 g/L for 1 h, the cells were transferred to 2.5 g/L D-glucose containing Zn2+ and the autofluorescence intensity was determined by flow cytometry after 1 h. The biosensor could detect Zn2+ at ultralow concentration (0.01 μM) in the optimized medium and accurately quantify the extracellular concentrations of Zn2+ ranging from 0.01 to 0.5 μM. High tolerance of Ade(−) yeast to salinity, pH variation and other metals enabled its application as a biosensor for labile Zn detection in complex media. Determining dissolved Zn2+ from a viscous sample (zinc cream), Ade(−) yeast accurately quantified the labile Zn2+ with a lower quantification limit than the chemosensor and higher simplicity than the conventional method (ICP-MS coupled with ultrafiltration). The study provides a novel biosensor based on an Ade(−) yeast and could be potentially used to detect labile Zn(II) species at trace levels in complex media.

Simultaneous Zn2+ tracking in multiple organelles using super-resolution morphology-correlated organelle identification in living cells

Zn2+ plays important roles in metabolism and signaling regulation. Subcellular Zn2+ compartmentalization is essential for organelle functions and cell biology, but there is currently no method to determine Zn2+ signaling relationships among more than two different organelles with one probe. Here, we report simultaneous Zn2+ tracking in multiple organelles (Zn-STIMO), a method that uses structured illumination microscopy (SIM) and a single Zn2+ fluorescent probe, allowing super-resolution morphology-correlated organelle identification in living cells. To guarantee SIM imaging quality for organelle identification, we develop a new turn-on Zn2+ fluorescent probe, NapBu-BPEA, by regulating the lipophilicity of naphthalimide-derived Zn2+ probes to make it accumulate in multiple organelles except the nucleus. Zn-STIMO with this probe shows that CCCP-induced mitophagy in HeLa cells is associated with labile Zn2+ enhancement. Therefore, direct organelle identification supported by SIM imaging makes Zn-STIMO a reliable method to determine labile Zn2+ dynamics in various organelles with one probe. Finally, SIM imaging of pluripotent stem cell-derived organoids with NapBu-BPEA demonstrates the potential of super-resolution morphology-correlated organelle identification to track biospecies and events in specific organelles within organoids.

The role of labile Zn2+ and Zn2+–transporters in the pathophysiology of mitochondria dysfunction in cardiomyocytes

An important energy supplier of cardiomyocytes is mitochondria, similar to other mammalian cells. Studies have demonstrated that any defect in the normal processes controlled by mitochondria can lead to abnormal ROS production, thereby high oxidative stress as well as lack of ATP. Taken into consideration, the relationship between mitochondrial dysfunction and overproduction of ROS as well as the relation between increased ROS and high-level release of intracellular labile Zn2+, those bring into consideration the importance of the events related with those stimuli in cardiomyocytes responsible from cellular Zn2+-homeostasis and responsible Zn2+-transporters associated with the Zn2+-homeostasis and Zn2+-signaling. Zn2+-signaling, controlled by cellular Zn2+-homeostatic mechanisms, is regulated with intracellular labile Zn2+ levels, which are controlled, especially, with the two Zn2+-transporter families; ZIPs and ZnTs. Our experimental studies in mammalian cardiomyocytes and human heart tissue showed that Zn2+-transporters localizes to mitochondria besides sarco(endo)plasmic reticulum and Golgi under physiological condition. The protein levels as well as functions of those transporters can re-distribute under pathological conditions, therefore, they can interplay among organelles in cardiomyocytes to adjust a proper intracellular labile Zn2+ level. In the present review, we aimed to summarize the already known Zn2+-transporters localize to mitochondria and function to stabilize not only the cellular Zn2+ level but also cellular oxidative stress status. In conclusion, one can propose that a detailed understanding of cellular Zn2+-homeostasis and Zn2+-signaling through mitochondria may emphasize the importance of new mitochondria-targeting agents for prevention and/or therapy of cardiovascular dysfunction in humans.

Quantitative Imaging of Labile Zn2+ in the Golgi Apparatus Using a Localizable Small-Molecule Fluorescent Probe

Fluorescent Zn2+ probes used for the quantitative analysis of labile Zn2+ concentration ([Zn2+]) in target organelles are crucial for understanding the role of Zn2+ in biological processes. Although several fluorescent Zn2+ probes have been developed to date, there is still a lack of consensus concerning the [Zn2+] in intracellular organelles. In this study, we describe the development of ZnDA-1H, a small-molecule fluorescent probe for Zn2+, which exhibits less pH sensitivity, high Zn2+ selectivity, and large fluorescence enhancement upon binding to Zn2+. Through protein labeling technology, ZnDA-1H was precisely targeted in various intracellular organelles, such as the nucleus, mitochondria, endoplasmic reticulum, and Golgi apparatus. ZnDA-1H exhibited a reversible fluorescence response toward labile Zn2+ in these organelles in live cells. Using this probe, the [Zn2+] in the Golgi apparatus was estimated to be 25± 1nM, suggesting that labile Zn2+ plays a physiological role in the secretory pathway.

Engineering hydrophobically associated hydrogels with rapid self‐recovery and tunable mechanical properties using metal‐ligand interactions

AbstractIn this contribution, hydrophobic association and metal‐ligand coordination have been employed in a dual physical crosslinking strategy to access hydrogels based on micellar copolymerization of acrylamide and a hydrophobic acrylic monomer (containing terpyridine (terpy) for metal‐ligand interaction). The mechanical properties of these hydrogels are strongly influenced by the thermodynamic stability and kinetic lability of the metal‐terpy crosslinks present in these materials. While the hydrogel tensile strength and stability on water exposure are enhanced by choosing stronger Fe2+‐terpy crosslinks, the weaker and more kinetically labile Zn2+‐terpy coordination bonds enable significantly higher energy dissipation under tensile loading and self‐healing in the resultant hydrogels.

Imaging of the mutual regulation between zinc cation and nitrosyl via two-photon fluorescent probes in cells and in vivo

The homeostatic disorder of intracellular Zn2+ pool is closely associated with severe diseases. It has been reported that the high level of free Zn2+ during ischemia/reperfusion (I/R) process can result in oxidative stress damage on nerve cells. Given that nitrosyl (HNO) can aggravate the nerve injury during cerebral I/R process, we assume that there may exist a mutual regulation between Zn2+ and HNO under certain physiological conditions. To reveal this potential small-signaling-molecule crosstalk, we synthesized two-photon fluorescent probes CHP-H and CHP-CH3 to monitor intracellular Zn2+ in cell and mice hippocampus I/R models. The probes consist of two moieties: coumarin derivative as the two-photon fluorescence transducer, 2-hydrazino pyridine as the fluorescence modulator and Zn2+ chelator. Both probes exhibit excellent analytical properties for Zn2+ detection in simulated physiological systems. Utilizing CHP-H and an HNO probe Cyto-JN, we perform fluorescent imaging of cell I/R models. The results confirm that HNO can stimulate Zn2+ release from labile Zn2+ pool, whereas, the increase of intracellular Zn2+ cannot upregulate the level of HNO. Combining with the deep tissue imaging of mice hippocampus tissues, our probes may provide potential approaches for the medical diagnostic assessment of HNO regulation effect on Zn2+ release in clinical cerebral I/R-related diseases.

Remodeling of Zn2+ homeostasis upon differentiation of mammary epithelial cells

Zinc is the second most abundant transition metal in humans and an essential nutrient required for growth and development of newborns. During lactation, mammary epithelial cells differentiate into a secretory phenotype, uptake zinc from blood circulation, and export it into mother's milk. At the cellular level, many zinc-dependent cellular processes, such as transcription, metabolism of nutrients, and proliferation are involved in the differentiation of mammary epithelial cells. Using mouse mammary epithelial cells as a model system, we investigated the remodeling of zinc homeostasis during differentiation induced by treatment with the lactogenic hormones cortisol and prolactin. RNA-Seq at different stages of differentiation revealed changes in global gene expression, including genes encoding zinc-dependent proteins and regulators of zinc homeostasis. Increases in mRNA levels of three zinc homeostasis genes, Slc39a14 (ZIP14) and metallothioneins (MTs) I and II were induced by cortisol but not by prolactin. The cortisol-induced increase was partially mediated by the nuclear glucocorticoid receptor signaling pathway. An increase in the cytosolic labile Zn2+ pool was also detected in lactating mammary cells, consistent with upregulation of MTs. We found that the zinc transporter ZIP14 was important for the expression of a major milk protein, whey acid protein (WAP), as knockdown of ZIP14 dramatically decreased WAP mRNA levels. In summary, our study demonstrated remodeling of zinc homeostasis upon differentiation of mammary epithelial cells resulting in changes in cytosolic Zn2+ and differential expression of zinc homeostasis genes, and these changes are important for establishing the lactation phenotype.

A FRET-based fluorescent Zn2+ sensor: 3D ratiometric imaging, flow cytometric tracking and cisplatin-induced Zn2+ fluctuation monitoring.

Monitoring labile Zn2+ homeostasis is of great importance for the study of physiological functions of Zn2+ in biological systems. Here we report a novel ratiometric fluorescent Zn2+ sensor, CPBT, which was constructed based on chelation-induced alteration of FRET efficiency. CPBT was readily cell membrane permeable and showed a slight preferential localization in the endoplasmic reticulum. With this sensor, 3D ratiometric Zn2+ imaging was first realized in the head of zebra fish larvae via Z-stack mode. CPBT could track labile Zn2+ in a large number of cells through ratiometric flow cytometric assay. More interestingly, both ratiometric fluorescence imaging and flow cytometric assay demonstrated that the labile Zn2+ level in MCF-7 cells (cisplatin-sensitive) decreased while that in SKOV3 cells (cisplatin-insensitive) increased after cisplatin treatment, indicating that Zn2+ may play an important role in cisplatin induced signaling pathways in these cancer cells.

Zinc Homeostasis in Platelet-Related Diseases.

Zn2+ deficiency in the human population is frequent in underdeveloped countries. Worldwide, approximatively 2 billion people consume Zn2+-deficient diets, accounting for 1–4% of deaths each year, mainly in infants with a compromised immune system. Depending on the severity of Zn2+ deficiency, clinical symptoms are associated with impaired wound healing, alopecia, diarrhea, poor growth, dysfunction of the immune and nervous system with congenital abnormalities and bleeding disorders. Poor nutritional Zn2+ status in patients with metastatic squamous cell carcinoma or with advanced non-Hodgkin lymphoma, was accompanied by cutaneous bleeding and platelet dysfunction. Forcing Zn2+ uptake in the gut using different nutritional supplementation of Zn2+ could ameliorate many of these pathological symptoms in humans. Feeding adult rodents with a low Zn2+ diet caused poor platelet aggregation and increased bleeding tendency, thereby attracting great scientific interest in investigating the role of Zn2+ in hemostasis. Storage protein metallothionein maintains or releases Zn2+ in the cytoplasm, and the dynamic change of this cytoplasmic Zn2+ pool is regulated by the redox status of the cell. An increase of labile Zn2+ pool can be toxic for the cells, and therefore cytoplasmic Zn2+ levels are tightly regulated by several Zn2+ transporters located on the cell surface and also on the intracellular membrane of Zn2+ storage organelles, such as secretory vesicles, endoplasmic reticulum or Golgi apparatus. Although Zn2+ is a critical cofactor for more than 2000 transcription factors and 300 enzymes, regulating cell differentiation, proliferation, and basic metabolic functions of the cells, the molecular mechanisms of Zn2+ transport and the physiological role of Zn2+ store in megakaryocyte and platelet function remain elusive. In this review, we summarize the contribution of extracellular or intracellular Zn2+ to megakaryocyte and platelet function and discuss the consequences of dysregulated Zn2+ homeostasis in platelet-related diseases by focusing on thrombosis, ischemic stroke and storage pool diseases.

Covalent Poly(2‐Isopropenyl‐2‐Oxazoline) Hydrogels with Ultrahigh Mechanical Strength and Toughness through Secondary Terpyridine Metal‐Coordination Crosslinks

AbstractThe present study reports the synthesis of poly(2‐isopropenyl‐2‐oxazoline) (PiPOx) dual‐crosslinked hydrogels by both covalent and physical (i.e., metal–ligand coordination) interactions. First, chemical crosslinking of a modified PiPOx polymer containing terpyridine (TPy) unit is achieved by reacting with azelaic acid (non‐anedioic acid). Transient crosslinks are subsequently introduced by complexation of the TPy units with different divalent transition metal ions. This strategy provides access to hydrogels with superior mechanical properties compared to the pure covalently crosslinked PiPOx hydrogels. The mechanical properties and water uptake of the hydrogels could be easily controlled by swelling in different aqueous metal ion solutions. PiPOx hydrogels swollen in Zn2+ solution are found to possess ultrahigh compression strength (9 MPa), remarkable toughness (99 MJ m−3) and outstanding self‐recoverability (98% toughness recovery after swelling for 60 min without external stimuli), which are among the highest reported in literature to date. These remarkable properties are assigned to the thermodynamically stable, but kinetically labile Zn2+‐TPy complexes that produce a dynamic network with fewer imperfections and better adaptive properties under mechanical stress compared to those with other metal ions.

Rapid Intramitochondrial Zn2+ Accumulation in CA1 Hippocampal Pyramidal Neurons After Transient Global Ischemia: A Possible Contributor to Mitochondrial Disruption and Cell Death

Mitochondrial Zn2+ accumulation, particularly in CA1 neurons, occurs after ischemia and likely contributes to mitochondrial dysfunction and subsequent neurodegeneration. However, the relationship between mitochondrial Zn2+ accumulation and their disruption has not been examined at the ultrastructural level in vivo. We employed a cardiac arrest model of transient global ischemia (TGI), combined with Timm's sulfide silver labeling, which inserts electron dense metallic silver granules at sites of labile Zn2+ accumulation, and used transmission electron microscopy (TEM) to examine subcellular loci of the Zn2+ accumulation. In line with prior studies, TGI-induced damage to CA1 was far greater than to CA3 pyramidal neurons, and was substantially progressive in the hours after reperfusion (being significantly greater after 4- than 1-hour recovery). Intriguingly, TEM examination of Timm's-stained sections revealed substantial Zn2+ accumulation in many postischemic CA1 mitochondria, which was strongly correlated with their swelling and disruption. Furthermore, paralleling the evolution of neuronal injury, both the number of mitochondria containing Zn2+ and the degree of their disruption were far greater at 4- than 1-hour recovery. These data provide the first direct characterization of Zn2+ accumulation in CA1 mitochondria after in vivo TGI, and support the idea that targeting these events could yield therapeutic benefits.

Phosphorescence Lifetime Imaging of Labile Zn2+ in Mitochondria via a Phosphorescent Iridium(III) Complex.

Phosphorescence lifetime Zn2+ imaging possesses the advantage over normal fluorescence imaging in offering the more accurate temporal-spatial Zn2+ information. Herein, we report a new phosphorescent cyclometalated Ir(III) complex with a Zn2+-chelator bearing 1,10-phenanthrolin acting as ancillary ligand, Zin-IrDPA, which displays the specific Zn2+-induced enhancement of phosphorescence and phosphorescence lifetime, and the mitochondria-targeting ability. Moreover, its Zn2+-induced phosphorescence lifetime enhancement factor is not affected by medium lipophilicity, viscosity, polarity, and especially ambient oxygen. The reversible tracking of introduced exogenous labile Zn2+ in MCF-7 and HeLa cells via phosphorescence imaging and phosphorescence lifetime imaging (PLIM) have been realized with Zin-IrDPA. Moreover, PLIM with Zin-IrDPA is able to track the SNOC-stimulated endogenous Zn2+ release in mitochondria.

A Brief Overview from the Physiological and Detrimental Roles of Zinc Homeostasis via Zinc Transporters in the Heart.

Zinc (mostly as free/labile Zn2+) is an essential structural constituent of many proteins, including enzymes in cellular signaling pathways via functioning as an important signaling molecule in mammalian cells. In cardiomyocytes at resting condition, intracellular labile Zn2+ concentration ([Zn2+]i) is in the nanomolar range, whereas it can increase dramatically under pathological conditions, including hyperglycemia, but the mechanisms that affect its subcellular redistribution is not clear. Therefore, overall, very little is known about the precise mechanisms controlling the intracellular distribution of labile Zn2+, particularly via Zn2+ transporters during cardiac function under both physiological and pathophysiological conditions. Literature data demonstrated that [Zn2+]i homeostasis in mammalian cells is primarily coordinated by Zn2+ transporters classified as ZnTs (SLC30A) and ZIPs (SLC39A). To identify the molecular mechanisms of diverse functions of labile Zn2+ in the heart, the recent studies focused on the discovery of subcellular localization of these Zn2+ transporters in parallel to the discovery of novel physiological functions of [Zn2+]i in cardiomyocytes. The present review summarizes the current understanding of the role of [Zn2+]i changes in cardiomyocytes under pathological conditions, and under high [Zn2+]i and how Zn2+ transporters are important for its subcellular redistribution. The emerging importance and the promise of some Zn2+ transporters for targeted cardiac therapy against pathological stimuli are also provided. Taken together, the review clearly outlines cellular control of cytosolic Zn2+ signaling by Zn2+ transporters, the role of Zn2+ transporters in heart function under hyperglycemia, the role of Zn2+ under increased oxidative stress and ER stress, and their roles in cancer are discussed.

Optical Recording of Zn2+ Dynamics in the Mitochondrial Matrix and Intermembrane Space with the GZnP2 Sensor.

The zinc ion (Zn2+) is emerging as an important signaling molecule. Here, we engineered an improved Zn2+ probe GZnP2 based on a previously developed fluorescent sensor GZnP1 to provide a higher fluorescent readout (2-fold higher) that is proportional to cellular labile Zn2+ concentrations. We further developed a set of GZnP2 derived imaging tools to determine the labile Zn2+ concentrations in the mitochondrial matrix, mitochondrial intermembrane space (IMS), and cytosol in four different cell lines (HeLa, Cos-7, HEK293, and INS-1). The labile Zn2+ concentration in the matrix was less than 1 pM, while the labile Zn2+ concentration in the IMS was comparable to the cytosol (∼100 pM). With these sensors, we showed that upon exposure to high Zn2+, only the cytosol and the IMS were overloaded with Zn2+, while the mitochondrial matrix was unable to sequester excess labile Zn2+ in depolarized INS-1 cells. This work highlighted the importance of distinguishing the labile Zn2+ concentrations and dynamics between the mitochondrial matrix and IMS.

Cytosolic increased labile Zn2+ contributes to arrhythmogenic action potentials in left ventricular cardiomyocytes through protein thiol oxidation and cellular ATP depletion

Intracellular labile (free) Zn2+-level ([Zn2+]i) is low and increases markedly under pathophysiological conditions in cardiomyocytes. High [Zn2+]i is associated with alterations in excitability and ionic-conductances while exact mechanisms are not clarified yet. Therefore, we examined the elevated-[Zn2+]i on some sarcolemmal ionic-mechanisms, which can mediate cardiomyocyte dysfunction. High-[Zn2+]i induced significant changes in action potential (AP) parameters, including depolarization in resting membrane-potential and prolongations in AP-repolarizing phases. We detected also the time-dependent effects such as induction of spontaneous APs at the time of ≥ 3 min following [Zn2+]i increases, a manner of cellular ATP dependent and reversible with disulfide-reducing agent dithiothreitol, DTT. High-[Zn2+]i induced inhibitions in voltage-dependent K+-channel currents, such as transient outward K+-currents, Ito, steady-state currents, Iss and inward-rectifier K+-currents, IK1, reversible with DTT seemed to be responsible from the prolongations in APs. We, for the first time, demonstrated that lowering cellular ATP level induced significant decreaeses in both Iss and IK1, while no effect on Ito. However, the increased-[Zn2+]i could induce marked activation in ATP-sensitive K+-channel currents, IKATP, depending on low cellular ATP and thiol-oxidation levels of these channels. The mRNA levels of Kv4.3, Kv1.4 and Kv2.1 were depressed markedly with increased-[Zn2+]i with no change in mRNA level of Kv4.2, while the mRNA level of IKATP subunit, SUR2A was increased significantly with increased-[Zn2+]i, being reversible with DTT. Overall we demonstrated that high-[Zn2+]i, even if nanomolar levels, alters cardiac function via prolonged APs of cardiomyocytes, at most, due to inhibitions in voltage-dependent K+-currents, although activation of IKATP is playing cardioprotective role, through some biochemical changes in cellular ATP- and thiol-oxidation levels. It seems, a well-controlled [Zn2+]i can be novel therapeutic target for cardiac complications under pathological conditions including oxidative stress.

Impact of Labile Zinc on Heart Function: From Physiology to Pathophysiology.

Zinc plays an important role in biological systems as bound and histochemically reactive labile Zn2+. Although Zn2+ concentration is in the nM range in cardiomyocytes at rest and increases dramatically under stimulation, very little is known about precise mechanisms controlling the intracellular distribution of Zn2+ and its variations during cardiac function. Recent studies are focused on molecular and cellular aspects of labile Zn2+ and its homeostasis in mammalian cells and growing evidence clarified the molecular mechanisms underlying Zn2+-diverse functions in the heart, leading to the discovery of novel physiological functions of labile Zn2+ in parallel to the discovery of subcellular localization of Zn2+-transporters in cardiomyocytes. Additionally, important experimental data suggest a central role of intracellular labile Zn2+ in excitation-contraction coupling in cardiomyocytes by shaping Ca2+ dynamics. Cellular labile Zn2+ is tightly regulated against its adverse effects through either Zn2+-transporters, Zn2+-binding molecules or Zn2+-sensors, and, therefore plays a critical role in cellular signaling pathways. The present review summarizes the current understanding of the physiological role of cellular labile Zn2+ distribution in cardiomyocytes and how a remodeling of cellular Zn2+-homeostasis can be important in proper cell function with Zn2+-transporters under hyperglycemia. We also emphasize the recent investigations on Zn2+-transporter functions from the standpoint of human heart health to diseases together with their clinical interest as target proteins in the heart under pathological condition, such as diabetes.

Near-Infrared-Activated Upconversion Nanoprobes for Sensitive Endogenous Zn2+ Detection and Selective On-Demand Photodynamic Therapy.

As a light-activated noninvasive cancer treatment paradigm, photodynamic therapy (PDT) has attracted extensive attention because of its high treatment efficacy and low side effects. Especially, spatiotemporal control of singlet oxygen (1O2) release is highly desirable for realizing on-demand PDT, which, however, still remains a huge challenge. To address this issue, a novel switchable near-infrared (NIR)-responsive upconversion nanoprobe has been designed and successfully applied for controlled PDT that can be optically activated by tumor-associated disruption of labile Zn2+ (denoted as Zn2+ hereafter) homeostasis stimuli. Upon NIR irradiation, this theranostic probe can not only quantitatively detect the intracellular endogenous Zn2+ in situ but also selectively generate a great deal of cytotoxic reactive oxygen species (ROS) for efficiently killing breast cancer cells under the activation of excessive endogenous Zn2+, so as to maximally avoid adverse damage to normal cells. This study aims to propose a new tumor-specific PDT paradigm and, more importantly, provide a new avenue of thought for efficient cancer theranostics based on our designed highly sensitive upconversion nanoprobes.

IL-4 Induces Metallothionein 3- and SLC30A4-Dependent Increase in Intracellular Zn2+ that Promotes Pathogen Persistence in Macrophages

SUMMARYAlternative activation of macrophages promotes wound healing but weakens antimicrobial defenses against intracellular pathogens. The mechanisms that suppress macrophage function to create a favorable environment for pathogen growth remain elusive. We show that interleukin (IL)-4 triggers a metallothionein 3 (MT3)- and Zn exporter SLC30A4- dependent increase in the labile Zn2+ stores in macrophages and that intracellular pathogens can exploit this increase in Zn to survive. IL-4 regulates this pathway by shuttling extracellular Zn into macrophages and by activating cathepsins that act on MT3 to release bound Zn. We show that IL-4 can modulate Zn homeostasis in both human monocytes and mice. In vivo, MT3 can repress macrophage function in an M2-polarizing environment to promote pathogen persistence. Thus, MT3 and SLC30A4 dictate the size of the labile Zn2+ pool and promote the survival of a prototypical intracellular pathogen in M2 macrophages.