Eu3+-Doped Anionic Zinc-Based Organic Framework Ratio Fluorescence Sensing Platform: Supersensitive Visual Identification of Prescription Drugs.

Advanced techniques for both environmental and biological prescription drug monitoring are of ongoing interest. In this work, a fluorescent sensor based on an Eu3+-doped anionic zinc-based metal-organic framework (Eu3+@Zn-MOF) was constructed for rapid visual analysis of the prescription drug molecule demecycline (DEM), achieving both high sensitivity and selectivity. The ligand 2-amino-[1,1'-biphenyl]-4,4'-dicarboxylic acid (bpdc-NH2) not only provides stable cyan fluorescence (467 nm) for the framework through intramolecular charge transfer of bpdc-NH2 infinitesimal disturbanced by Zn2+ but also chelates Eu3+, resulting in red (617 nm) fluorescence. Through the synergy of photoinduced electron transfer and the antenna effect, a bidirectional response to DEM is achieved, enabling concentration quantification. The Eu3+@Zn-MOF platform exhibits a wide linear range (0.25-2.5 µM) to DEM and a detection limit (LOD) of 10.9 nM. Further, we integrated the DEM sensing platform into a paper-based system and utilized a smartphone for the visual detection of DEM in water samples and milk products, demonstrating the potential for large-scale, low-cost utilization of the technology.

Glutaminase 1 deficiency confined in forebrain neurons causes autism spectrum disorder-like behaviors.

An abnormal glutamate signaling pathway has been proposed in the mechanisms of autism spectrum disorder (ASD). However, less is known about the involvement of alterations of glutaminase 1 (GLS1) in the pathophysiology of ASD. We show that the transcript level of GLS1 is significantly decreased in the postmortem frontal cortex and peripheral blood of ASD subjects. Mice lacking Gls1 in CamKIIα-positive neurons display a series of ASD-like behaviors, synaptic excitatory and inhibitory (E/I) imbalance, higher spine density, and glutamate receptor expression in the prefrontal cortex, as well as a compromised expression pattern of genes involved in synapse pruning and less engulfed synaptic puncta in microglia. A low dose of lipopolysaccharide treatment restores microglial synapse pruning, corrects synaptic neurotransmission, and rescues behavioral deficits in these mice. In summary, these findings provide mechanistic insights into Gls1 loss in ASD symptoms and identify Gls1 as a target for the treatment of ASD.

Tracking of Intestinal Probiotics In Vivo by NIR-IIb Fluorescence Imaging.

The ability to accurately characterize microorganism distribution in the intestinal tract is helpful for understanding intrinsic mechanisms. Within the intestine, traditional optical probes used for microorganism labeling commonly suffer from a low imaging penetration depth and poor resolution. We report a novel observation tool useful for microbial research by labeling near-infrared-IIb (NIR-IIb, 1500-1700 nm) lanthanide nanomaterials NaGdF4:Yb3+,Er3+@NaGdF4,Nd3+ (Er@Nd NPs) onto the surface of Lactobacillus bulgaricus (L. bulgaricus) via EDC-NHS chemistry. We monitor microorganisms in tissue by two-photon excitation (TPE) microscopy and in vivo with NIR-IIb imaging. This dual-technique approach offers great potential for determining the distribution of transplanted bacteria in the intestinal tract with a higher spatiotemporal resolution.

Lanthanide/Cu2-xSe Nanoparticles for Bacteria-Activated NIR-II Fluorescence Imaging of Infection.

A material system enabling specific NIR-II fluorescence imaging of Gram-positive bacteria is described. The material system is based on the electrostatic binding of Cu2-xSe and vancomycin-modified NaGdF4:Nd,Yb@NaGdF4 downconversion nanoparticles (DCNPs), the fluorescence of which is weak owing to the spectral overlap of Cu2-xSe absorption with the DCNP NIR emission. The presence of Gram-positive bacteria precisely disconnects the bond between vancomycin-modified DCNPs and Cu2-xSe, thus enabling a strong fluorescent signal. In vivo studies show that the material system can be specifically activated at the site of Gram-positive bacterial infection but is essentially nonfluorescent in the area of Gram-negative bacterial infection.

An Ag2S@ZIF-Van nanosystem for NIR-II imaging of bacterial-induced inflammation and treatment of wound bacterial infection.

Bacterial diseases pose a serious threat to human health. Continued development of precise diagnostic methods and synergistic therapy techniques for combating bacteria are needed. Herein a hybrid nanosystem (Ag2S@ZIF-Van NS) was constructed by one-step self-assembly of Zn2+, vancomycin (Van) and Ag2S quantum dots (QDs). The nanosystem possesses excellent second near-infrared transparency window (NIR-II) fluorescence properties (∼1200 nm emission wavelength), good photothermal conversion properties, and biocompatibility. The material system enables precise, targeted NIR-II fluorescent imaging of bacterial inflammation in vivo as well as promoting anti-bacterial and wound healing effects.

Microglial glutaminase 1 deficiency mitigates neuroinflammation associated depression.

Glutaminase 1 (GLS1) has recently been reported to be expressed in microglia and plays a crucial role in neuroinflamation. Significantly increased level of GLS1 mRNA expression together with neuroinflammation pathway were observed in postmortem prefrontal cortex from depressed patients. To find out the function of microglial GLS1 in depression and neuroinflammation, we generated transgenic mice (GLS1 cKO), postnatally losing GLS1 in microglia, to detect changes in the lipopolysaccharide (LPS)-induced depression model. LPS-induced anxiety/depression-like behavior was attenuated in GLS1 cKO mice, paralleled by a significant reduction in pro-inflammatory cytokines and an abnormal microglia morphological phenotype in the prefrontal cortex. Reduced neuroinflammation by GLS1 deficient microglia was a result of less reactive astrocytes, as GLS1 deficiency enhanced miR-666-3p and miR-7115-3p levels in extracellular vesicles released from microglia, thus suppressing astrocyte activation via inhibiting Serpina3n expression. Together, our data reveal a novel mechanism of GLS1 in neuroinflammation and targeting GLS1 in microglia may be a novel strategy to alleviate neuroinflammation-related depression and other disease.

Bioactive Core-Shell CaF2 Upconversion Nanostructure for Promotion and Visualization of Engineered Bone Reconstruction.

Inorganic ion metabolism plays significant roles in various life processes including signal transduction, substance exchange, and cellular constructions. Regulation and monitoring of ion metabolism offer great promise to modulate biological activities and provide insights into related mechanisms. Here, a synergistic nanodepot based on a bioactive core-shell CaF2 upconversion nanostructure that integrates multiple mineral ions for metabolic regulation was built for the acceleration and monitoring of the biomineralization process. Multiple mineral ions released from the nanodepots can accelerate the growth of inorganic crystals and enhance the production of organic matrixes, synergistically facilitating the regeneration of bone defects in vivo. During the process, such a nanodepot can be constructed to specifically recognize osteoblasts for the monitoring of biomineralization. This nanoprobe represents an efficient strategy to promote and monitor biomineralization-related metabolic activities with applications in fundamental research, disease diagnosis, and regenerative medicine.

Glutaminase 1 Regulates Neuroinflammation After Cerebral Ischemia Through Enhancing Microglial Activation and Pro-Inflammatory Exosome Release.

Cerebral ischemia induces a robust neuroinflammatory response that is largely mediated by the activation of CNS resident microglia. Activated microglia produce pro-inflammatory molecules to cause neuronal damage. Identifying regulators of microglial activation bears great potential in discovering promising candidates for neuroprotection post cerebral ischemia. Previous studies demonstrate abnormal elevation of glutaminase 1 (GLS1) in microglia in chronic CNS disorders including Alzheimer's disease and HIV-associated neurocognitive disorders. Ectopic expression of GLS1 induced microglia polarization into pro-inflammatory phenotype and exosome release in vitro. However, whether GLS1 is involved in neuroinflammation in acute brain injury remains unknown. Here, we observed activation of microglia, elevation of GLS1 expression, and accumulation of pro-inflammatory exosomes in rat brains 72 h post focal cerebral ischemia. Treatment with CB839, a glutaminase inhibitor, reversed ischemia-induced microglial activation, inflammatory response, and exosome release. Furthermore, we found that the application of exosome secretion inhibitor, GW4869, displayed similar anti-inflammatory effects to that of CB839, suggesting GLS1-mediated exosome release may play an important role in the formation of neuroinflammatory microenvironment. Therefore, GLS1 may serve as a key mediator and promising target of neuroinflammatory response in cerebral ischemia.

Electronic structure engineering and biomedical applications of low energy-excited persistent luminescence nanoparticles.

Persistent luminescence nanoparticles (PLNPs) are new luminescent materials that can store the excitation energy quickly and persistently emit it after ceasing excitation sources. Due to the advantages of long-lasting luminescence without constant excitation, PLNPs have been widely used in biomedical applications. Visible light excitable PLNPs (VPLNPs) and near-infrared excitable PLNPs (NPLNPs) are two kinds of novel and promising PLNPs. Compared to conventional PLNPs, VPLNPs and NPLNPs have the characteristics of low tissue damage, deep tissue penetration, and high signal-to-noise ratio. With these special features, they have great potential in applications such as long-term tracing, deep-tissue bioimaging, and precise treatment. In this review, we introduce the common strategy of constructing VPLNPs and NPLNPs based on electronic structure engineering and the applications of VPLNPs and NPLNPs in biomedicine. This review article aims to offer valuable information about the progress and development direction of VPLNPs and NPLNPs, promoting more applications in biomedicine, materials science, energy engineering, and environmental technologies in the future.

The diabetes drug semaglutide reduces infarct size, inflammation, and apoptosis, and normalizes neurogenesis in a rat model of stroke.

Stroke is a condition with few medical treatments available. Semaglutide, a novel Glucagon-like peptide-1 (GLP-1) analogue, has been brought to the market as a treatment for diabetes. We tested the protective effects of semaglutide against middle cerebral artery occlusion injury in rats. Animals were treated with 10 nmol/kg bw ip. starting 2 h after surgery and every second day for either 1, 7, 14 or 21 days. Semaglutide-treated animals showed significantly reduced scores of neurological impairments in several motor and grip strength tasks. The cerebral infarction size was also reduced, and the loss of neurons in the hippocampal areas CA1, CA3 and the dentate gyrus was much reduced. Chronic inflammation as seen in levels of activated microglia and in the activity of the p38 MAPK - MKK - c-Jun- NF-κB p65 inflammation signaling pathway was reduced. In addition, improved growth factor signaling as shown in levels of activated ERK1 and IRS-1, and a reduction in the apoptosis signaling pathway C-raf, ERK2, Bcl-2/BAX and Caspase-3 was observed. Neurogenesis had also been normalized by the drug treatment as seen in increased neurogenesis (DCX-positive cells) in the dentate gyrus and a normalization of biomarkers for neurogenesis. In conclusion, semaglutide is a promising candidate for re-purposing as a stroke treatment.

Glutaminase C Regulates Microglial Activation and Pro-inflammatory Exosome Release: Relevance to the Pathogenesis of Alzheimer's Disease.

Microglial activation is a key pathogenic process at the onset of Alzheimer's disease (AD). Identifying regulators of microglial activation bears great potential in elucidating causes and mechanisms of AD and determining candidates for early intervention. Previous studies demonstrate abnormal elevation of glutaminase C (GAC) in HIV-infected or immune-activated microglia. However, whether GAC elevation causes microglial activation remains unknown. In this study, we found heightened expression levels of GAC in early AD mouse brain tissues compared with those in control littermates. Investigations on an in vitro neuroinflammation model revealed that GAC is increased in primary mouse microglia following pro-inflammatory stimulation. To model GAC elevation we overexpressed GAC by plasmid transfection and observed that GAC-overexpression shift the microglial phenotype to a pro-inflammatory state. Treatment with BPTES, a glutaminase inhibitor, reversed LPS-induced microglial activation and inflammation. Furthermore, we discovered that GAC overexpression in mouse microglia increased exosome release and changed exosome content, which includes specific packaging of pro-inflammatory miRNAs that activate microglia. Together, our results demonstrate a causal effect of GAC elevation on microglial activation and exosome release, both of which promote the establishment of a pro-inflammatory microenvironment. Therefore, GAC may have important relevance to the pathogenesis of AD.

Two novel dual GLP-1/GIP receptor agonists are neuroprotective in the MPTP mouse model of Parkinson's disease.

Type 2 diabetes mellitus (T2DM) is a risk factors for developing Parkinson's disease (PD). Insulin desensitization is observed in the brains of PD patients, which may be an underlying mechanism that promotes neurodegeneration. Incretin hormones are growth factors that can re-sensitize insulin signalling. We have previously shown that analogues of the incretins GLP-1 or GIP have neuroprotective effects in the MPTP mouse model of PD. Novel dual GLP-1/GIP receptor agonists have been developed as treatments for T2DM. We have tested 3 novel dual receptor agonists DA-JC1, DA-JC4 and DA-CH5 in comparison with the GLP-1 analogue liraglutide (all drugs at 25 nmol/kg ip once-daily for 6 days) in the MPTP mouse model of PD (4 × 25 mg/kg ip). In the Rotarod and grip strength assessment, DA-CH5 performed best in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA-CH5 was the best drug to reverse this. Pro-inflammatory cytokines were best reduced by DA-CH5, while expression levels of the neuroprotective growth factor Glial-Derived Neurotrophic Factor (GDNF) was most increased by DA-JC4. Synapses were protected best by DA-JC4 and DA-CH5. Both DA-JC1 and liraglutide showed inferior effects. These results show that a combination of GLP-1 and GIP receptor activation is more efficient compared to single GLP-1 receptor activation. We conclude that dual agonists are a promising novel treatment for PD. The GLP-1 mimetic exendin-4 has previously shown disease modifying effects in two clinical trials in Parkinson patients.

Self-production of oxygen system CaO2 /MnO2 @PDA-MB for the photodynamic therapy research and switch-control tumor cell imaging.

Photodynamic therapy (PDT) holds promise in biochemical study and tumor treatment. A novel multifunctional nanosystem CaO2 /MnO2 @polydopamine (PDA)-methylene blue (MB) nanosheet (CMP-MB) was designed. CaO2 nanoparticles were encapsulated by MnO2 nanosheet, and then PDA was coated on the surface of CaO2 /MnO2 nanosheets, which could adsorb photosensitizer MB through hydrophobic interaction or π-π stacking. In this nanosystem, CaO2 /MnO2 had the ability of self-production of oxygen, which solved the problem of tumor hypoxia largely. Moreover, it is worth mentioning that the fluorescence of MB was suppressed by MnO2 , while its emission was triggered in the simulated tumor microenvironment. Therefore, CMP-MB nanosheet could be used to switch-control cell imaging potentially. 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide testing and Live/Dead assay confirmed CMP-MB nanosheet had fewer side effects without illumination while it destroyed Hela cell with the illumination of light. Vitro cell experiment demonstrated CMP-MB nanosheet could achieve tumor microenvironment responsive imaging and inhibit tumor cell growth under illumination effectively. Therefore, the system has great potential for PDT application and switch-control tumor cell imaging. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2544-2552, 2018.

A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease.

Type 2 diabetes mellitus (T2DM) is one of the risk factors for Parkinson's disease (PD). Insulin desensitisation has been observed in the brains of patients, which may promote neurodegeneration. Incretins are a family of growth factors that can re-sensitise insulin signalling. We have previously shown that mimetics of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD. Recently, dual GLP-1/GIP receptor agonists have been developed. We therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide. The results demonstrate that the combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients.

Smart Multifunctional Magnetic Nanoparticle-Based Drug Delivery System for Cancer Thermo-Chemotherapy and Intracellular Imaging.

In this research, a thermoresponsive drug release system was synthesized, which encapsulated the magnetic nanoparticles Fe3O4 and the drug model 5-fluorouracil with thermosensitive polymer poly(N-isopropylacrylamide) (PNIPAM). Mesoporous SiO2 was used as the channel of drug release, which could enhance the rate of drug loading and reduce drug loss. Chitosan (CHI) is a natural cationic linear polymer. The results showed successful coating of chitosan and rhodamine 6G (R6G) on the surface of the SiO2 sphere. The intermolecular interactions of the nanocomposites were confirmed by Fourier transform infrared spectroscopy. R6G is a typical fluorochrome which could be applied for cell imaging. Fluorescent imaging studies by confocal laser scanning microscopy indicated that the prepared nanocomposites Fe3O4/PNIPAM/5-Fu@mSiO2-CHI/R6G could specifically target tumor cells. Therefore, our work shows great potential in drug delivery and cancer therapy.

A novel dual GLP-1 and GIP receptor agonist is neuroprotective in the MPTP mouse model of Parkinson's disease by increasing expression of BNDF.

The incretins glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are growth factors with neuroprotective properties. GLP-1 mimetics are on the market as treatments for type 2 diabetes and are well tolerated. Both GLP-1 and GIP mimetics have shown neuroprotective properties in animal models of Parkinson's and Alzheimer's disease. In addition, the GLP-1 mimetic exendin-4 has shown protective effects in a clinical trial in Parkinson's disease (PD) patients. Novel GLP-1/GIP dual-agonist peptides have been developed and are tested in diabetic patients. Here we demonstrate the neuroprotective effects of a novel dual agonist (DA-JC1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP was injected once-daily (20 mg/kg i.p.) for 7 days, and the dual agonist was injected 30 min later i.p. (50 nmol/kg bw). The PI3k inhibitor LY294002 (0.6 mg/kg i.v.) was co-injected in one group. DA-JC1 reduced or reversed most of the MPTP induced motor impairments in the rotarod and in a muscle strength test. The number of tyrosine hydroxylase (TH) positive neurons in the substantia nigra (SN) was reduced by MPTP and increased by DA-JC1. The ratio of anti-inflammatory Bcl-2 to pro-inflammatory BAX as well as the activation of the growth factor kinase Akt was reduced by MPTP and reversed by DA-JC1. The PI3k inhibitor had only limited effect on the DA-JC1 drug effect. Importantly, levels of the neuroprotective brain derived neurotropic factor (BDNF) were reduced by MPTP and enhanced by DA-JC1. The results demonstrate that DA-JC1 shows promise as a novel treatment for PD.

Neuroprotective effects of glucose-dependent insulinotropic polypeptide in Alzheimer's disease.

Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormones and growth factors. Neurons express the GIP receptor, and GIP and its agonists can pass through the blood brain barrier and show remarkable neuroprotective effects by protecting synapse function and numbers, promoting neuronal proliferation, reducing amyloid plaques in the cortex and reducing the chronic inflammation response of the nervous system. Long-acting analogues of GIP that are protease resistant had been developed as a treatment for type 2 diabetes. It has been found that such GIP analogues show good protective effects in animal models of Alzheimer's disease. Novel dual agonist peptides that activate the GIP receptor and another incretin receptor, glucagon-like peptide -1 (GLP-1), are under development that show superior effects in diabetic patients compared to single GLP-1 agonists. The dual agonists also show great promise in treating neurodegenerative disorders, and there are currently several clinical trials ongoing, testing GLP-1 mimetics in people with Alzheimer's or Parkinson's disease.