It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer's disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly ...heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aβos. We here review the mechanisms by which Aβos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca
homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aβ*56 and spherical oligomers, and suggest that Aβos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aβos in AD human brain and examine the relationship between different Aβos and cognitive impairment.
The application of conventional metal–organic frameworks (MOFs) as electrode materials in supercapacitors is largely hindered by their conventionally poor electrical conductivity. This study reports ...the fabrication of conductive MOF nanowire arrays (NWAs) and the application of them as the sole electrode material for solid‐state supercapacitors. By taking advantage of the nanostructure and making full use of the high porosity and excellent conductivity, the MOF NWAs in solid‐state supercapacitor show the highest areal capacitance and best rate performance of all reported MOF materials for supercapacitors, which is even comparable to most carbon materials.
Conductive metal–organic framework (MOF) nanowire arrays (NWAs) are prepared as the sole electrode material for solid‐state supercapacitors. By taking advantage of their nanostructure and making full use of the high porosity and excellent conductivity, the MOF NWAs in the solid‐state supercapacitor show the highest areal capacitance and best rate performance of all reported MOF materials.
Immunogenic cell death (ICD) and tumour-infiltrating T lymphocytes are severely weakened by elevated reactive oxygen species (ROS) in the tumour microenvironment. It is therefore of critical ...importance to modulate the level of extracellular ROS for the reversal of immunosuppressive environment. Here, we present a tumour extracellular matrix (ECM) targeting ROS nanoscavenger masked by pH sensitive covalently crosslinked polyethylene glycol. The nanoscavenger anchors on the ECM to sweep away the ROS from tumour microenvironment to relieve the immunosuppressive ICD elicited by specific chemotherapy and prolong the survival of T cells for personalized cancer immunotherapy. In a breast cancer model, elimination of the ROS in tumour microenvironment elicited antitumour immunity and increased infiltration of T lymphocytes, resulting in highly potent antitumour effect. The study highlights a strategy to enhance the efficacy of cancer immunotherapy by scavenging extracellular ROS using advanced nanomaterials.Reactive oxygen species in the tumour microenvironment can have an immunosuppressive effect. Here, the authors devise a nanoparticle that anchors to the extracellular matrix within tumours and scavenges reactive oxygen species, resulting in an enhanced immune response within the tumour.
α-synuclein (α-syn) is a protein associated with the pathogenesis of Parkinson's disease (PD), the second most common neurodegeneration disease with no effective treatment. However, how α-syn drives ...the pathology of PD remains elusive. Recent studies suggest that α-syn oligomers are the primary cause of neurotoxicity and play a critical role in PD. In this review, we discuss the process of α-syn oligomers formation and the current understanding of the structures of oligomers. We also describe seed and propagation effects of oligomeric forms of α-syn. Then, we summarize the mechanism by which α-syn oligomers exert neurotoxicity and promote neurodegeneration, including mitochondrial dysfunction, endoplasmic reticulum stress, proteostasis dysregulation, synaptic impairment, cell apoptosis and neuroinflammation. Finally, we investigate treatment regimens targeting α-syn oligomers at present. Further research is needed to understand the structure and toxicity mechanism of different types of oligomers, so as to provide theoretical basis for the treatment of PD.
Fluorescence bioimaging affords a vital tool for both researchers and surgeons to molecularly target a variety of biological tissues and processes. This review focuses on summarizing organic dyes ...emitting at a biological transparency window termed the near‐infrared‐II (NIR‐II) window, where minimal light interaction with the surrounding tissues allows photons to travel nearly unperturbed throughout the body. NIR‐II fluorescence imaging overcomes the penetration/contrast bottleneck of imaging in the visible region, making it a remarkable modality for early diagnosis of cancer and highly sensitive tumor surgery. Due to their convenient bioconjugation with peptides/antibodies, NIR‐II molecular dyes are desirable candidates for targeted cancer imaging, significantly overcoming the autofluorescence/scattering issues for deep tissue molecular imaging. To promote the clinical translation of NIR‐II bioimaging, advancements in the high‐performance small molecule–derived probes are critically important. Here, molecules with clinical potential for NIR‐II imaging are discussed, summarizing the synthesis and chemical structures of NIR‐II dyes, chemical and optical properties of NIR‐II dyes, bioconjugation and biological behavior of NIR‐II dyes, whole body imaging with NIR‐II dyes for cancer detection and surgery, as well as NIR‐II fluorescence microscopy imaging. A key perspective on the direction of NIR‐II molecular dyes for cancer imaging and surgery is also discussed.
Among all existing near‐infrared (NIR)‐II fluorophores, the NIR‐II molecular dyes are the most remarkable in translating this imaging window into the clinical setting. Advanced NIR‐II dye‐derived bioconjugates will give doctors an unparalleled view into tissues for tumor detection at greater depths and contrast, allowing early detection during cancer screenings and solid tumor resection by delineation of the boundaries between healthy and cancerous tissues.
Tau pathology is a hallmark of Alzheimer's disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary ...tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment.
The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1β and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1β and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA.
We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition.
In combination with the previously reported therapeutic effects of rutin on Aβ pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aβ.
The greatest advantage of activatable fluorescence probes (AFPs) is the inherent responsiveness to manipulate spectroscopic properties by chemical/physical interactions with the biological ...analytes/microenvironmental factors. As alternatives to “always-on” fluorescence probes, AFPs in the first near-infrared (NIR-I) window expanded dramatically over the past decade and served as powerful tools in fluorescence biosensing and bioimaging. Benefiting from the deep tissue penetration, minimal tissue damage, and negligible background signal within longer wavelength, recent progress of fluorescent materials in the second near-infrared (NIR-II) window has been creating vast new opportunities in developing AFPs. Here, we review the current role of AFPs in biosensing and bioimaging, with emphasis on NIR-II AFPs developed for biomedical applications. The challenges and prospects of AFPs are also discussed by considering the clinical translation from bench to bedside.
Dendritic cell (DC) maturation and antigen presentation are key factors for successful vaccine‐based cancer immunotherapy. This study developed manganese‐based layered double hydroxide (Mn‐LDH) ...nanoparticles as a self‐adjuvanted vaccine carrier that not only promoted DC maturation through synergistically depleting endogenous glutathione (GSH) and activating STING signaling pathway, but also facilitated the delivery of model antigen ovalbumin (OVA) into lymph nodes and subsequent antigen presentation in DCs. Significant therapeutic‐prophylactic efficacy of the OVA‐loaded Mn‐LDH (OVA/Mn‐LDH) nanovaccine was determined by the tumor growth inhibition in the mice bearing B16‐OVA tumor. Our results showed that the OVA/Mn‐LDH nanoparticles could be a potent delivery system for cancer vaccine development without the need of adjuvant. Therefore, the combination of GSH exhaustion and STING pathway activation might be an advisable approach for promoting DC maturation and antigen presentation, finally improving cancer vaccine efficacy.
Manganese‐doped layered double hydroxide nanoparticles enhanced dendritic cell maturation via intracellular glutathione depletion and subsequent STING pathway activation. Effective antigen delivery and presentation mediated by the nanoparticles significantly triggered antitumor immune response and inhibited tumor growth in both therapeutic and prophylactic settings.
Regulating Lewis acid–base sites in catalysts to investigate their influence in the chemical fixation of CO2 is significant but challenging. A metal–organic framework (MOF) with open metal Co sites, ...{(NH2Me2)Co3(μ3‐OH)(BTB)2(H2O)⋅9 H2O⋅5 DMF}n (1), was obtained and the results of the catalytic investigation show that 1 can catalyze cycloaddition of CO2 and aziridines to give 99 % yield. The efficiency of the cyclization of CO2 with propargyl amines is only 32 %. To improve the catalytic ability of 1, ligand XN with Lewis base sites was introduced into 1 and coordinated with the open Co sites, resulting in a decrease of the Lewis acid sites and an increase in the Lewis base sites in a related MOF 2 ({(NH2Me2)Co3(μ3‐OH)(NHMe2)(BTB)2(XN)⋅8 H2O⋅4 DMF}n). Selective regulation of the type of active centers causes the yield of oxazolidinones to be enhanced by about 2.4 times, suggesting that this strategy can turn on/off the catalytic activity for different reactions. The catalytic results from 2 treated with acid solution support this conclusion. This work illuminates a MOF‐construction strategy that produces efficient catalysts for CO2 conversion.
Selective regulation of Lewis acid–base sites in metal–organic framework catalysts is an effective strategy to turn‐on/off the catalytic activity for different CO2 reactions.
Effectively activating macrophages against cancer is promising but challenging. In particular, cancer cells express CD47, a 'don't eat me' signal that interacts with signal regulatory protein alpha ...(SIRPα) on macrophages to prevent phagocytosis. Also, cancer cells secrete stimulating factors, which polarize tumor-associated macrophages from an antitumor M1 phenotype to a tumorigenic M2 phenotype. Here, we report that hybrid cell membrane nanovesicles (known as hNVs) displaying SIRPα variants with significantly increased affinity to CD47 and containing M2-to-M1 repolarization signals can disable both mechanisms. The hNVs block CD47-SIRPα signaling axis while promoting M2-to-M1 repolarization within tumor microenvironment, significantly preventing both local recurrence and distant metastasis in malignant melanoma models. Furthermore, by loading a stimulator of interferon genes (STING) agonist, hNVs lead to potent tumor inhibition in a poorly immunogenic triple negative breast cancer model. hNVs are safe, stable, drug loadable, and suitable for genetic editing. These properties, combined with the capabilities inherited from source cells, make hNVs an attractive immunotherapy.
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