•Astrocytic Kir6.1 knockout aggravates dopaminergic neurons degeneration.•Astrocytic Kir6.1 knockout inhibits mitophagy in astrocytes.•Astrocytic Kir6.1 knockout enhances NLRP3 inflammasome-mediated ...neuroinflammation.•Restoration of mitophagy rescues the deleterious effect of astrocytic Kir6.1 deletion.
ATP-sensitive potassium (K-ATP) channels, coupling cell metabolism to cell membrane potential, are involved in brain diseases, including Parkinson’s disease (PD). Kir6.1, a pore-forming subunit of K-ATP channel, is prominently expressed in astrocytes and participates in regulating its function. However, the precise role of astrocytic Kir6.1-contaning K-ATP channel (Kir6.1/K-ATP) in PD is not well characterized. In this study, astrocytic Kir6.1 knockout (KO) mice were used to examine the effect of astrocytic Kir6.1/K-ATP channel on dopaminergic (DA) neurodegeneration triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Here, we found that astrocytic Kir6.1 KO mice showed more DA neuron loss in substantia nigra compacta (SNc), lower level of dopamine in the striatum, and more severe motor dysfunction than controls. Interestingly, this companied by increased neuroinflammation and decreased autophagy level in SNc in vivo and astrocytes in vitro. Mechanistically, astrocytic Kir6.1 KO inhibited mitophagy which resulted in an increase in the accumulation of damaged mitochondria, production of reactive oxygen species and neuroinflammation in astrocytes. Restoration of astrocytic mitophagy rescued the deleterious effects of astrocytic Kir6.1 ablation on mitochondrial dysfunction, inflammation and DA neuron death. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel protects against DA neurodegeneration in PD via promoting mitophagy and suggest that astrocytic Kir6.1/K-ATP channel may be a promising therapeutic target for PD.
At present, poor stability and carrier transfer efficiency are the main problems that limit the development of perovskite‐based photoelectric technologies. In this work, hydrogen‐bonded ...cocrystal‐coated perovskite composite (PeNCs@NHS‐M) is easily obtained by inducing rapid crystallization of melamine (M) and N‐hydroxysuccinimide (NHS) with PeNCs as the nuclei. The outer NHS‐M cocrystal passivates the undercoordinated lead atoms by forming covalent bonds, thereby greatly reducing the trap density while maintaining good structure stability for perovskite nanocrystals. Moreover, benefiting from the interfacial covalent band linkage and long‐range ordered structures of cocrystals, the charge transfer efficiency is effectively enhanced and PeNCs@NHS−M displays superior photoelectric performance. Based on the excellent photoelectric performance and abundant active sites of PeNCs@NHS−M, photocatalytic reduction of uranium is realized. PeNCs@NHS−M exhibits U(VI) reduction removal capability of up to 810.1 mg g−1 in the presence of light. The strategy of cocrystals trapping perovskite nanocrystals provides a simple synthesis method for composites and opens up a new idea for simultaneously improving the stability and photovoltaic performance of perovskite.
The CsPbBr3 nanocrystals (PeNCs) are coated with hydrogen‐bonded cocrystals (N‐hydroxysuccinimide‐melamine, NHS‐M) to achieve defect passivation and structural stability enhancement. Moreover, this covalently linked heterostructure further promotes the electron transport of PeNCs and realizes the photocatalytic reduction of uranium through the binding sites on the cocrystal.
We report the first example of vinylene-linked covalent organic framework (Tp-TMT) with enhanced uranium adsorption through combined selective ligand binding, chemical reduction and photocatalytic ...reduction. The dense hydroxyl functional groups on the Tp-TMT framework had good selectivity and excellent chemical reduction performance for U(VI). Meanwhile, the synergistic effect of hydroxyl groups and triazine unit significantly enhanced the photocatalytic reduction activity. Thus Tp-TMT exhibited incredible adsorption kinetics and capacity for uranium.
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•COFs effectively capture uranium through three coordinated mechanisms.•Tp-TMT has excellent visible light conversion efficiency and low band gap.•Tp-TMT enhances uranium adsorption through selective ligand binding and reduction.•Tp-TMT exhibits incredible adsorption kinetics and capacity for uranium.
So far, it remains a challenge to synthesize uranium adsorbents with robust stability, high adsorption capacity, excellent photocatalytic activity and easy regeneration. Herein, we report the first example of vinylene-linked covalent organic framework (Tp-TMT) with enhanced uranium adsorption through combined selective ligand binding, chemical reduction and photocatalytic reduction. The unique structure and excellent photocatalytic activity of Tp-TMT make it very suitable for photo-enhanced uranium adsorption through three synergistic mechanisms, thus exhibiting an outstanding uranium adsorption capacity (2362.4 mg g−1). In the dark, a large number of hydroxyl groups in the Tp-TMT framework serve as selective binding sites for uranium, and reduce part of U(VI) to U(IV), thereby greatly improving the adsorption capacity. Meanwhile, the synergistic effect of the triazine units and hydroxyl groups in the highly conjugated framework greatly decreases the optical band gap of Tp-TMT, and an additional U(VI) photocatalytic reduction process can occur under light irradiation, further increasing the adsorption kinetics and capacity. This work explored the structural and functional design of covalent organic frameworks for the adsorption and reduction of uranium in nuclear industry wastewater.
Immunotherapy has emerged to play a rapidly expanding role in the treatment of cancers. Currently, many clinical trials of therapeutic agents are on ongoing with majority of immune checkpoint ...inhibitors (ICIs) especially programmed death receptor 1 (PD-1) and its ligand 1 (PD-L1) inhibitors. PD-1 and PD-L1, two main immune checkpoints, are expressed at high levels in thymic epithelial tumors (TETs) and could be predictors of the progression and immunotherapeutic efficacy of TETs. However, despite inspiring efficacy reported in clinical trials and clinical practice, significantly higher incidence of immune-related adverse events (irAEs) than other tumors bring challenges to the administration of ICIs in TETs. To develop safe and effective immunotherapeutic patterns in TETs, understanding the clinical properties of patients, the cellular and molecular mechanisms of immunotherapy and irAEs occurrence are crucial. In this review, the progress of both basic and clinical research on immune checkpoints in TETs, the evidence of therapeutic efficacy and irAEs based on PD-1 /PD-L1 inhibitors in TETs treatment are discussed. Additionally, we highlighted the possible mechanisms underlying irAEs, prevention and management strategies, the insufficiency of current research and some worthy research insights. High PD-1/PD-L1 expression in TETs provides a rationale for ICI use. Completed clinical trials have shown an encouraging efficacy of ICIs, despite the high rate of irAEs. A deeper mechanism understanding at molecular level how ICIs function in TETs and why irAEs occur will help maximize the immunotherapeutic efficacy while minimizing irAEs risks in TET treatment to improve patient prognosis.
Noncovalent and multifunctional hybrids have been generated via π–π stacking and electrostatic interactions by combining the nanometer‐scale graphene structure of graphene quantum dots (GQDs) with ...FeIII 5,10,15,20‐tetrakis(1‐methyl‐4‐pyridyl)porphine (FeTMPyP). The inner filter effect (IFE) of FeTMPyP on the GQDs results in substantial PL quenching of the GQDs. The quenched PL of GQDs by the FeTMPyP can be switched back “on” in response to the reaction between FeTMPyP and H2O2, which causes rupture of the cyclic tetrapyrrolic nucleus with consequential loss of iron from FeTMPyP, and then proceeds further to produce colorless dipyrroles and monopyrroles. This “turn on” system can be applied for simple and convenient H2O2 sensing and can be further extended to the detection of glucose in combination with the specific catalytic effect of glucose oxidase (GOx) through the oxidation of glucose and formation of H2O2. Because of the inherent synthetic control available for the design of metalloporphyrins, the GQDs‐based optical sensing approach described here has the potential to be highly versatile for other target analytes.
Self‐absorbed: The inner filter effect (IFE) of metalloporphyrins on assembled graphene quantum dots (GQDs) results in substantial photoluminescence (PL) quenching of the GQDs. The quenched PL of GQDs can be switched back “on” in response to the reaction between the metalloporphyrin FeTMPyP and H2O2, which can be applied to H2O2 sensing and further extended to the detection of glucose in combination with the specific catalytic effect of glucose oxidase (GOx).
This study reports a novel and convenient bimodal method for label-free and signal-off detection of arsenate in environmental samples. Cobalt oxyhydroxide (CoOOH) nanoflakes with facile preparation ...and intrinsic peroxidase-like activity as nanozyme can efficiently catalyze the conversion of chromogenic substrate such as 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) with the presence of H2O2 into green-colored oxidation products. CoOOH nanoflakes can specifically bind with arsenate via electrostatic attraction and As–O bond interaction, which gives rise to inhibition of the peroxidase-like activity of CoOOH. Thus, through arsenate specific inhibition of CoOOH nanozyme toward ABTS catalysis, a simple colorimetric method was developed for arsenate detection with a detection limit of 3.72 ppb. Based on the system of CoOOH nanozyme and ABTS substrate, this colorimetric method can be converted into an electrochemical sensor for arsenate assay by the utilization of CoOOH nanoflake-modified electrode. The electrochemical measurement can be realized by chronoamperometry, which showed more sensitive and a lower limit of detection as low as 56.1 ppt. The applicability of this bimodal method was demonstrated by measuring arsenate and total arsenic in different real samples such as natural waters and soil extracted solutions, and the results are of satisfactory accuracy as confirmed by inductively coupled plasma mass spectrometry analysis. The bimodal strategy offers obvious advantages including a label-free step, convenient operation, on-site assay, low cost, and high sensitivity, which is promising for reliable detection of arsenate and total arsenic in environmental samples.
Energy and fresh water are essential for the sustainable development of human society, and both could be obtained from seawater. Herein, we explored the first covalent organic framework (COF) sponge ...(named BHMS) by in situ loading the benzoxazole-linked COF (DBD-BTTH) onto a porous polymer scaffold (polydimethylsiloxane) as a synergistic platform for efficient solar desalination and selective uranium recovery. In natural seawater, BHMS shows a high evaporation rate (1.39 kg m–2 h–1) and an exceptional uranium recovery capacity (5.14 ± 0.15 mg g–1) under 1 sun, which are due to its desirable inbuilt structural hierarchy and elastic macroporous open cells providing adequate water transport, increased evaporation sites of seawater, and selective binding sites of uranyl. Besides, the excellent photothermal performance and photocatalytic activity endow the BHMS with high solar desalination efficiency and excellent anti-biofouling activity and promote selective coordination of uranyl.
Mercury is one of the most toxic elements in the environment. Recently, a number of covalent organic frameworks (COFs) were developed for simultaneous detection and removal of mercury. They rely on ...post-synthetically modified sulfur-based ligands for irreversible mercury binding. In addition, their rigid structures resulted in low fluorescence yields. Herein, a novel highly luminescent COF named TFPPy-CHYD with a quantum yield of 13.6% was designed by integrating a pyrene-based building block with a flexible carbohydrazide linker. The nitrogen-based ligand allows reversible and highly selective binding of Hg2+. As a sensing platform, it has an ultralow detection limit of 17 nM mercury. More importantly, TFPPy-CHYD exhibits excellent performance in removing mercury from both air and water, providing very high Hg0 and Hg2+ adsorption capacities of 232 and 758 mg g–1, respectively. This work demonstrates enormous potential of luminescent COF for metal detection and remediation. By rational introducing metal ligands, a suite of new COF materials might be synthesized for the detection and removal of other metal ions.
We design two artificial substrate peptides to synthesize blue-emissive Cu nanoclusters and red-emissive Au nanoclusters, respectively. In addition to the biomineralization function, these two ...peptides retain the biological activity to be phosphorylated by protein kinase and digested by carboxypeptidase Y. In the absence of protein kinase, the peptides capped on the nanoclusters suffer consecutive exocleavage by carboxypeptidase Y, resulting in oxidation and thus fluorescence quenching of the nanoclusters due to the losing of peptide protection. In the presence of protein kinase A and casein kinase II, the phosphorylation modification on corresponding substrate peptides protects the peptides against carboxypeptidase Y digestion and then the fluorescence of the nanoclusters can be retained. Since a single excitation wavelength can excite the both nanoclusters, blue and red emissive signals can be collected at the same time and then the quantitative determination of protein kinase A and casein kinase II can be achieved simultaneously.
Senescent astrocytes have been implicated in the aging brain and neurodegenerative disorders, including Parkinson's disease (PD). Astragaloside IV (AS-IV) is an antioxidant derivative from a ...traditional Chinese herbal medicine Astragalus membraneaceus Bunge and exerts anti-inflammatory and longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined.
Long culture-induced replicative senescence model and lipopolysaccharide/1-methyl-4-phenylpyridinium (LPS/MPP
)-induced premature senescence model and a mouse model of PD were used to investigate the effect of AS-IV on astrocyte senescence in vivo and in vitro. Immunocytochemistry, qPCR, subcellular fractionation, flow cytometric analyses, and immunohistochemistry were subsequently conducted to determine the effects of AS-IV on senescence markers.
We found that AS-IV inhibited the astrocyte replicative senescence and LPS/MPP
-induced premature senescence, evidenced by decreased senescence-associated β-galactosidase activity and expression of senescence marker p16, and increased nuclear level of lamin B1, and reduced pro-inflammatory senescence-associated secretory phenotype. More importantly, we showed that AS-IV protected against the loss of dopamine neurons and behavioral deficits in the mouse model of PD, which companied by reduced accumulation of senescent astrocytes in substantia nigra compacta. Mechanistically, AS-IV promoted mitophagy, which reduced damaged mitochondria accumulation and mitochondrial reactive oxygen species generation and then contributed to the suppression of astrocyte senescence. The inhibition of autophagy abolished the suppressive effects of AS-IV on astrocyte senescence.
Our findings reveal that AS-IV prevents dopaminergic neurodegeneration in PD via inhibition of astrocyte senescence through promoting mitophagy and suggest that AS-IV is a promising therapeutic strategy for the treatment of age-associated neurodegenerative diseases such as PD.
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