Using nanomaterials to mimic the function of protein enzymes is an interesting idea. Many nanomaterials have a similar size as enzymes and they also possess catalytic activity. Over the past decade, ...a surge of nanozyme work has emerged, likely due to the advancement in the synthesis and characterization of inorganic nanoparticles. Many typical enzymatic reactions mimicking oxidases, peroxidases, laccases, superoxide dismutases, and catalases have been realized by simple metal oxide and metal nanoparticles. In addition, small inorganic catalysts have been loaded in nanoparticles to create another type of nanozyme. The applications of nanozymes in biosensor design, environmental remediation, and therapeutics have been demonstrated. In this Topical Review, we briefly summarize the current status of the field and then focus our attention on some important problems faced by the field. These topics include developing better nanozymes with higher activity, better substrate selectivity, and engineering enzyme-like active sites. For practical applications, reliable methods for bioconjugation of nanozymes with affinity ligands need to be achieved, but not at the cost of losing the activity of nanozymes. Finally, fundamental mechanistic studies are needed to rationally design nanozymes and to obtain key insights into a few model systems.
Leptin, among the best known hormone markers for obesity, exerts pleiotropic actions on multiple organ systems. In this review, we summarize major leptin signaling pathways, namely Janus-activated ...kinase/signal transducers and activators of transcription and mitogen-activated protein kinase, including possible mechanisms of leptin resistance in obesity. The effects of leptin on the cardiovascular system are discussed in detail, including its contributions to hypertension, atherosclerosis, depressed myocardial contractile function, fatty acid metabolism, hypertrophic remodeling, and reduction of ischemic/reperfusion injury. The overall goal is to summarize current understanding of how altered leptin signaling in obesity contributes to obesity-related cardiovascular disease.
Intracellular pH is an important parameter associated with cellular behaviors and pathological conditions. Quantitative sensing pH and monitoring its changes by near-infrared (NIR) fluorescence ...imaging with high resolution in living systems are essential but challenging due to the lack of effective probes. To achieve good adaptability, in this study, a class of resolution-tunable ratiometric NIR fluorescent probes, which possess a stable NIR hemicyanine skeleton bearing different substituents, are rationally designed and synthesized, enabling detection through noninvasive optical imaging of organisms. Based on the protonation/deprotonation of the hydroxy group, a marked NIR emission shift provides a ratio signal in response to pH. Meanwhile, two states exhibit good photostability, sensitivity and reversibility, conducive to longtime monitoring of persistent pH changes without disturbance of other biological active species. Among the series, NIR-Ratio-BTZ modified with an electron-withdrawing substituent of benzothiazole exhibited the largest emission shift of about 76 nm from 672 to 748 nm with the pH environment changing from acidic to basic, which could be considered as a good candidate for high resolution pH imaging in live cells, tissues and organisms. Moreover, NIR-Ratio-BTZ has an ideal pK a value (pK a ≈ 7.2) for monitoring the minor fluctuations of physiological pH near neutrality. The ratiometric fluorescence measurement is beneficial to ensure the accuracy of quantitative measuring pH changes, as well as the real-time monitoring pH-related physiological effects both in living cells and living mice. The results demonstrate that NIR-Ratio-BTZ is a highly sensitive ratiometric pH probe in vivo, giving it potential for biological applications.
Nucleic acids, whether designed or selected in vitro, play important roles in biosensing, medical diagnostics, and therapy. Specifically, the conjugation of functional nucleic acid based probe ...molecules and nanomaterials has resulted in an unprecedented improvement in the field of molecular recognition. With their unique physical and chemical properties, nanomaterials facilitate the sensing process and amplify the signal of recognition events. Thus, the coupling of nucleic acids with various nanomaterials opens up a promising future for molecular recognition. The literature offers a broad spectrum of recent advances in biosensing by employing different nanoplatforms with designed nucleic acids, especially gold nanoparticles, carbon nanotubes, silica nanoparticles, and quantum dots. The advantages of these novel combinations are discussed from the perspective of molecular recognition in chemistry, biology, and medicine, along with the problems confronting future applications.
An approach for visual and fluorescent sensing of Hg2+ in aqueous solution is presented. This method is based on the Hg2+-induced conformational change of a thymine (T)-rich single-stranded DNA ...(ssDNA) and the difference in electrostatic affinity between ssDNA and double-stranded (dsDNA) with gold nanoparticles. The dye-tagged ssDNA containing T−T mismatched sequences was chosen as Hg2+ acceptor. At high ionic strength, introduction of the ssDNA to a colloidal solution of the aggregates of gold nanoparticles results in color change, from blue-gray to red of the solution, and the fluorescence quenching of the dye. Binding of Hg2+ with the ssDNA forms the double-stranded structure. This formation of dsDNA reduces the capability to stabilize bare nanoparticles against salt-induced aggregation, remaining a blue-gray in the color of the solution, but fluorescence signal enhancement compared with that without Hg2+. With the optimum conditions described, the system exhibits a dynamic response range for Hg2+ from 9.6 × 10−8 to 6.4 × 10−6 M with a detection limit of 4.0 × 10−8 M. Both the color and fluorescence changes of the system are extremely specific for Hg2+ even in the presence of high concentrations of other heavy and transition metal ions, which meet the selective requirements for biomedical and environmental application. The combined data from transmission electron microscopy, fluorescence anisotropy measurements, and dialysis experiments indicate that both the color and the fluorescence emission changes of the DNA-functioned gold nanoparticles generated by Hg2+ are the results of the metal-induced formation of dsDNA and subsequent formation of nanoparticle aggregates.
IMPORTANCE: Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. OBJECTIVE: To assess the efficacy of ...fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. PARTICIPANTS: Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. INTERVENTIONS: Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). MAIN OUTCOMES AND MEASURES: The primary end point was mean change in mean number of monthly migraine days during the 12-week period after the first dose. RESULTS: Among 875 patients who were randomized (mean age, 41.8 SD, 12.1 years; 742 women 85%), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of –1.5 days (95% CI, –2.01 to –0.93 days; P < .001) and with single higher dosing vs placebo of –1.3 days (95% CI, –1.79 to –0.72 days; P < .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). CONCLUSIONS AND RELEVANCE: Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3- to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02629861
Nucleic acids hold promise as biomolecules for future applications in biomedicine and biotechnology. Their well-defined structures and compositions afford unique chemical properties and biological ...functions. Moreover, the specificity of hydrogen-bonded Watson-Crick interactions allows the construction of nucleic acid sequences with multiple functions. In particular, the development of nucleic acid probes as essential molecular engineering tools will make a significant contribution to advancements in biosensing, bioimaging and therapy. The molecular beacon (MB), first conceptualized by Tyagi and Kramer in 1996, is an excellent example of a double-stranded nucleic acid (dsDNA) probe. Although inactive in the absence of a target, dsDNA probes can report the presence of a specific target through hybridization or a specific recognition-triggered change in conformation. MB probes are typically fluorescently labeled oligonucleotides that range from 25 to 35 nucleotides (nt) in length, and their structure can be divided into three components: stem, loop and reporter. The intrinsic merit of MBs depends on predictable design, reproducibility of synthesis, simplicity of modification, and built-in signal transduction. Using resonance energy transfer (RET) for signal transduction, MBs are further endowed with increased sensitivity, rapid response and universality, making them ideal for chemical sensing, environmental monitoring and biological imaging, in contrast to other nucleic acid probes. Furthermore, integrating MBs with targeting ligands or molecular drugs can substantially support their
in vivo
applications in theranositics. In this review, we survey advances in bioanalytical and biomedical applications of rationally designed MBs, as they have evolved through the collaborative efforts of many researchers. We first discuss improvements to the three components of MBs: stem, loop and reporter. The current applications of MBs in biosensing, bioimaging and therapy will then be described. In particular, we emphasize recent progress in constructing MB-based biosensors in homogeneous solution or on solid surfaces. We expect that such rationally designed and functionalized MBs will open up new and exciting avenues for biological and medical research and applications.
This review surveys advances in bioanalytical and biomedical applications of rationally designed MBs.
DNA performs a vital function as a carrier of genetic code, but in the field of nanotechnology, DNA molecules can catalyze chemical reactions in the cell, that is, DNAzymes, or bind with ...target-specific ligands, that is, aptamers. These functional DNAs with different modifications have been developed for sensing, imaging, and therapeutic systems. Thus, functional DNAs hold great promise for future applications in nanotechnology and bioanalysis. However, these functional DNAs face challenges, especially in the field of biomedicine. For example, functional DNAs typically require the use of cationic transfection reagents to realize cellular uptake. Such reagents enter the cells, increasing the difficulty of performing bioassays in vivo and potentially damaging the cell’s nucleus. To address this obstacle, nanomaterials, such as metallic, carbon, silica, or magnetic materials, have been utilized as DNA carriers or assistants. In this Account, we describe selected examples of functional DNA-containing nanomaterials and their applications from our recent research and those of others. As models, we have chosen to highlight DNA/nanomaterial complexes consisting of gold nanoparticles, graphene oxides, and aptamer–micelles, and we illustrate the potential of such complexes in biosensing, imaging, and medical diagnostics. Under proper conditions, multiple ligand–receptor interactions, decreased steric hindrance, and increased surface roughness can be achieved from a high density of DNA that is bound to the surface of nanomaterials, resulting in a higher affinity for complementary DNA and other targets. In addition, this high density of DNA causes a high local salt concentration and negative charge density, which can prevent DNA degradation. For example, DNAzymes assembled on gold nanoparticles can effectively catalyze chemical reactions even in living cells. And it has been confirmed that DNA–nanomaterial complexes can enter cells more easily than free single-stranded DNA. Nanomaterials can be designed and synthesized in needed sizes and shapes, and they possess unique chemical and physical properties, which make them useful as DNA carriers or assistants, excellent signal reporters, transducers, and amplifiers. When nanomaterials are combined with functional DNAs to create novel assay platforms, highly sensitive biosensing and high-resolution imaging result. For example, gold nanoparticles and graphene oxides can quench fluorescence efficiently to achieve low background and effectively increase the signal-to-background ratio. Meanwhile, gold nanoparticles themselves can be colorimetric reporters because of their different optical absorptions between monodispersion and aggregation. DNA self-assembled nanomaterials contain several properties of both DNA and nanomaterials. Compared with DNA–nanomaterial complexes, DNA self-assembled nanomaterials more closely resemble living beings, and therefore they have lower cytotoxicity at high concentrations. Functional DNA self-assemblies also have high density of DNA for multivalent reaction and three-dimensional nanostructures for cell uptake. Now and in the future, we envision the use of DNA bases in making designer molecules for many challenging applications confronting chemists. With the further development of artificial DNA bases using smart organic synthesis, DNA macromolecules based on elegant molecular assembly approaches are expected to achieve great diversity, additional versatility, and advanced functions.
A new near-infrared fluorescence off–on probe is developed and applied to fluorescence imaging of nitroreductase in zebrafish in vivo. The probe is readily prepared by connecting 4-nitrobenzene as a ...quenching and recognizing moiety to a stable hemicyanine skeleton that can be formed via the decomposition of IR 780. The fluorescence off–on response of the probe to nitroreductase is based on the enzyme-catalyzed reduction of the 4-nitrobenzene moiety, followed by the 1,6-rearrangement-elimination and the fluorophore release. Compared with the existing nitroreductase probes, the proposed probe exhibits superior analytical performance such as near-infrared fluorescence emission over 700nm as well as high selectivity and sensitivity, with a detection limit of 14ng/mL. More importantly, the probe has been successfully applied to visualize the distribution of nitroreductase in living zebrafish in vivo, revealing that nitroreductase might mainly exist in zebrafish yolk sac. The superior properties of the probe make it of great potential use in other biosystems and in vivo studies.
•A new near-infrared fluorescence off–on probe is developed for nitroreductase assay.•The probe has an emission over 700nm with high selectivity and sensitivity.•The probe is used to image the distribution of nitroreductase in zebrafish in vivo.•It is revealed that nitroreductase may mainly exist in zebrafish yolk sac.
The skin has important barrier, sensory, and immune functions, contributing to the health and integrity of the organism. Extensive skin injuries that threaten the entire organism require immediate ...and effective treatment. Wound healing is a natural response, but in severe conditions, such as burns and diabetes, this process is insufficient to achieve effective treatment. Epidermal stem cells (EPSCs) are a multipotent cell type and are committed to the formation and differentiation of the functional epidermis. As the contributions of EPSCs in wound healing and tissue regeneration have been increasingly attracting the attention of researchers, a rising number of therapies based on EPSCs are currently under development. In this paper, we review the characteristics of EPSCs and the mechanisms underlying their functions during wound healing. Applications of EPSCs are also discussed to determine the potential and feasibility of using EPSCs clinically in wound healing.
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