Search

Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer's disease (AD) risk; however, the underlying mechanisms are not fully understood. Here, it is found that the injection of chondroitinase ABC (ChABC), mimicking ECM remodeling, into the medial prefrontal cortex (mPFC) reversed short‐term memory loss and reduced amyloid‐beta (Aβ) deposition in 5xFAD mice. ECM remodeling also reactivated astrocytes, reduced the levels of aggrecan in Aβ plaques, and enhanced astrocyte recruitment to surrounding plaques. Importantly, ECM remodeling enhanced the autophagy‐lysosome pathway in astrocytes, thereby mediating Aβ clearance and alleviating AD pathology. ECM remodeling also promoted Aβ plaque phagocytosis by astrocytes by activating the astrocytic phagocytosis receptor MERTK and promoting astrocytic vesicle circulation. The study identified a cellular mechanism in which ECM remodeling activates the astrocytic autophagy‐lysosomal pathway and alleviates AD pathology. Targeting ECM remodeling may represent a potential therapeutic strategy for AD and serve as a reference for the treatment of this disease. [ABSTRACT FROM AUTHOR]

De novo design has been a hotly pursued topic for many years. Most recent developments have involved the use of deep learning methods for generative molecular design. Despite increasing levels of algorithmic sophistication, the design of molecules that are synthetically accessible remains a major challenge. Reaction‐based de novo design takes a conceptually simpler approach and aims to address synthesisability directly by mimicking synthetic chemistry and driving structural transformations by known reactions that are applied in a stepwise manner. However, the use of a small number of hand‐coded transformations restricts the chemical space that can be accessed and there are few examples in the literature where molecules and their synthetic routes have been designed and executed successfully. Here we describe the application of reaction‐based de novo design to the design of synthetically accessible and biologically active compounds as proof‐of‐concept of our reaction vector‐based software. Reaction vectors are derived automatically from known reactions and allow access to a wide region of synthetically accessible chemical space. The design was aimed at producing molecules that are active against PARP1 and which have improved brain penetration properties compared to existing PARP1 inhibitors. We synthesised a selection of the designed molecules according to the provided synthetic routes and tested them experimentally. The results demonstrate that reaction vectors can be applied to the design of novel molecules of biological relevance that are also synthetically accessible. [ABSTRACT FROM AUTHOR]

The presence of antibiotics in aquatic environments has recently raised significant concerns due to their toxic effects as well as the propagation of antibiotic resistances. Thus, efforts are devoted to developing facile screening methods for sulfonamide antibiotics in waters. In this study, we designed a fluorescent array comprising three structurally different pyrene-based luminescent metal–organic framework (LMOF) sensors and applied it in the simultaneous screening of multiple sulfonamides. The pyrene-based LMOFs produced fluorescence quenching responses to sulfonamides via the static quenching mechanism and/or inner filter effect. The array was able to effectively sense and discriminate five structurally similar sulfonamides (sulfamethoxazole, sulfadiazine, sulfapyridine, sulfamerazine, and sulfamethazine), individual sulfonamide at different concentrations, and mixtures of two sulfonamides with various molar ratios. The detection limit of the pyrene-based MOF array for individual sulfonamide was lower than most previously reported fluorescent sensors. It also afforded a fast sulfonamide response (response equilibrium <2 min) owing to the open and uniform nanoporous structures of the LMOF array elements, which allowed a screening speed as fast as approximately 20 min/100 samples. The constructed array exhibited good performance in the discrimination of sulfonamides in real water samples, validating its practicability. This study provides a convenient strategy for the rapid screening of sulfonamide antibiotics in aquatic environments. It also validates the application potential of LMOF array in fluorescence sensing fields. [ABSTRACT FROM AUTHOR]

Reaction‐based de novo design refers to the generation of synthetically accessible molecules using transformation rules extracted from known reactions in the literature. In this context, we have previously described the extraction of reaction vectors from a reactions database and their coupling with a structure generation algorithm for the generation of novel molecules from a starting material. An issue when designing molecules from a starting material is the combinatorial explosion of possible product molecules that can be generated, especially for multistep syntheses. Here, we present the development of RENATE, a reaction‐based de novo design tool, which is based on a pseudo‐retrosynthetic fragmentation of a reference ligand and an inside‐out approach to de novo design. The reference ligand is fragmented; each fragment is used to search for similar fragments as building blocks; the building blocks are combined into products using reaction vectors; and a synthetic route is suggested for each product molecule. The RENATE methodology is presented followed by a retrospective validation to recreate a set of approved drugs. Results show that RENATE can generate very similar or even identical structures to the corresponding input drugs, hence validating the fragmentation, search, and design heuristics implemented in the tool. [ABSTRACT FROM AUTHOR]

The development of a rapid and sensitive method for the detection of fluoride ion (F−) in aqueous systems is of great significance for human health and environmental monitoring. In this study, a zirconium porphyrinic luminescent metal-organic framework (LMOF), PCN-222, was employed as a novel fluorescent probe for the ultrasensitive, rapid and selective detection of F− in water. The PCN-222 probe was prepared by a facile solvothermal method. It exhibited good fluorescence stability and was highly stable in water. The fluorescence emission of PCN-222 could be effectively and selectively quenched by F− due to the strong coordination affinity of F− to the zirconium clusters in PCN-222. The proposed fluorescence method for F− detection based on PCN-222 probe afforded a linear response range of 1–20 μmol/L and a very low detection limit (0.048–0.065 μmol/L) in reference to many reported F− fluorescent probes. Moreover, a rapid response time (<10 s) was obtained due to the open and uniform pore structure of PCN-222 that allowed the fast diffusion of F− to interact with the zirconium recognition sites. Finally, the PCN-222 probe was successfully applied for the fluorescence detection of F− in real water samples. These results highlight the great application potential of LMOF in the sensing fields. Image 1 • Highly stable zirconium-based LMOF (PCN-222) was successfully applied in F− detection in water. • PCN-222 afforded very short F− response time (<10 s) due to its open and uniform pore structure. • The LOD was markedly lower than WHO and US EPA guidelines and many reported F− sensors. [ABSTRACT FROM AUTHOR]

With no currently available disease-modifying drugs, Alzheimer's disease is the most common type of dementia affecting over 47 million people worldwide. In light of the most recent discoveries placing the cellular prion protein (PrPC) as a key player in amyloid β oligomer (Aβo)-induced neurodegeneration, we investigated whether the neuroprotective potential of nature-inspired flavonoids against Aβ-promoted toxicity would translate into the ability to disrupt PrPC-Aβo interactions. Hence, we synthesized a small library of flavones and studied their binding affinity towards Aβo by STD-NMR. C-glucosyl flavones exhibited improved binding affinity with morpholine, thiomorpholine or N-methylpiperazine rings attached to the flavone skeleton in ring B para position. Moreover, a N-methylpiperazinyl flavone displayed suitable physicochemical properties and optimal water solubility even without the sugar moiety, and a high interaction with Aβo involving the whole flavone core. Its C-glucosyl derivative, was, however, the best compound to inhibit PrPC-Aβo interactions in a dose-dependent manner, with 41 % of inhibition capacity at 10 μM. The potential of C-glucosyl flavones and their aglycones as protein-protein interaction inhibitors able to tackle PrPC-Aβo interactions is here presented for the first time, and supports this class of compounds as new prototypes for further development in the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Summary: β‐Aminobutyric acid (BABA) induces broad‐spectrum disease resistance, but also represses plant growth, which has limited its exploitation in crop protection. BABA perception relies on binding to the aspartyl‐tRNA synthetase (AspRS) IBI1, which primes the enzyme for secondary defense activity. This study aimed to identify structural BABA analogues that induce resistance without stunting plant growth. Using site‐directed mutagenesis, we demonstrate that the ( l)‐aspartic acid‐binding domain of IBI1 is critical for BABA perception. Based on interaction models of this domain, we screened a small library of structural BABA analogues for growth repression and induced resistance against biotrophic Hyaloperonospora arabidopsidis (Hpa). A range of resistance‐inducing compounds were identified, of which (R)‐β‐homoserine (RBH) was the most effective. Surprisingly, RBH acted through different pathways than BABA. RBH‐induced resistance (RBH‐IR) against Hpa functioned independently of salicylic acid, partially relied on camalexin, and was associated with augmented cell wall defense. RBH‐IR against necrotrophic Plectosphaerella cucumerina acted via priming of ethylene and jasmonic acid defenses. RBH‐IR was also effective in tomato against Botrytis cinerea. Metabolic profiling revealed that RBH, unlike BABA, does not majorly affect plant metabolism. RBH primes distinct defense pathways against biotrophic and necrotrophic pathogens without stunting plant growth, signifying strong potential for exploitation in crop protection. [ABSTRACT FROM AUTHOR]

Human mesenchymal stem cells (hMSCs) have been shown to have potential in regenerative approaches in bone and blood. Most protocols rely on their in vitro expansion prior to clinical use. However, several groups including our own have shown that hMSCs lose proliferation and differentiation ability with serial passage in culture, limiting their clinical applications. Cellular prion protein (PrP) has been shown to enhance proliferation and promote self-renewal of hematopoietic, mammary gland, and neural stem cells. Here we show, for the first time, that expression of PrP decreased in hMSC following ex vivo expansion. When PrP expression was knocked down, hMSC showed significant reduction in proliferation and differentiation. In contrast, hMSC expanded in the presence of small molecule 3/689, a modulator of PrP expression, showed retention of PrP expression with ex vivo expansion and extended lifespan up to 10 population doublings. Moreover, cultures produced a 300-fold increase in the number of cells generated. These cells showed a 10-fold increase in engraftment levels in bone marrow 5 weeks post-transplant. hMSC treated with 3/689 showed enhanced protection from DNA damage and enhanced cell cycle progression, in line with data obtained by gene expression profiling. Moreover, upregulation of superoxide dismutase-2 (SOD2) was also observed in hMSC expanded in the presence of 3/689. The increase in SOD2 was dependent on PrP expression and suggests increased scavenging of reactive oxygen species as mechanism of action. These data point to PrP as a good target for chemical intervention in stem cell regenerative medicine. S TEM C ELLS 2012;30:1134-1143 [ABSTRACT FROM AUTHOR]

Microwave-assisted, solvent-free condensation of 2-aminopyrimidine with aldehydes and isonitriles gave the desired 3-aminoimidazo[1,2-a]pyrimidine products with good to excellent regioselectivity. A hydrogen zeolite (‘zeolite HY’) was found to be a novel and effective promoter for the reaction, generally leading to clean conversion and also permitting use of the normally unreactive 4,6-dimethyl-2-aminopyrimidine. [ABSTRACT FROM AUTHOR]