Dynamically Visualized Mechano-Responsive Supramolecular Self-Assembly System for Small Molecule Release.

The mechano-responsiverelease of small molecules has received extensive attention in ultrasound (US)-controlled drug release in recent years because it can achieve non-invasive, spatiotemporally controlled precise drug release. However, the vast majority of small molecules mechano-release reported so far are based on polymer systems, which suffer from complex preparations and single mechano-response. Here, an isoguanosine (isoG) visualized mechano-responsive supramolecular self-assembly (isoG-VMRSS) system was successfully constructed by a one-pot reaction. It is completely composed of small molecules, which allows for multiple mechano-responsive releases of isoG (at least 9 times) and ultimately has potential for application in US drug release. A combined experimental-computational approach reveals the supramolecular network structure (formed by the joint action of related metal coordination bonds, boronate ester bonds and hydrogen bonds mediated by isoG) gradually formed inside the system is the underlying internal mechanism. Therefore, it provides a new and effective idea of small molecule release in the field of mechanochemistry.

Self-Immolative Polythiophene for Sunlight Inactivation of Harmful Cyanobacteria.

Harmful cyanobacterial blooms and the released microcystins (MCs) caused serious environmental and public health concerns to drinking water safety. Photo-oxidation is an appealing treatment option and alternative to conventional flocculation and microbial antagonists, but the performances of current photosensitizers (either inorganic or organic) are unsatisfactory. Here, a polythiophene photosensitizer (PT10) with both high yield of reactive oxygen species (ROS) production (mainly 1O2, ΦΔ = 0.51, > 8 h continuous generation) and moderate photostability was used as a powerful algaecide to inhibit Microcystis aeruginosa. Due to the positive charge of PT10, the algal cells were quickly flocculated, followed by efficient inactivation in 4 h under white light irradiation (96.7%, 10 mW/cm2). Meanwhile, PT10 was self-immolated in about 6 h. Upon biosafety evaluation with adult zebrafish, the low toxicity of PT10 and the degradation products of PT10 and algae (early logarithmic growth stage) were confirmed. In addition, microcystin-LR (MC-LR), a toxic microcystin that will be released during the destruction of the algal cells, was also degraded. Therefore, PT10-based photoinactivation of M. aeruginosa featured both high performance and low secondary pollution. In real-world aquatic systems, PT10 was confirmed to be capable of sunlight-assisted inactivation of M. aeruginosa and prevent algal blooms, thus making it appealing for environmental remediation.

Portable biosensor-based oral pathogenic bacteria detection for community and family applications.

Detection of oral pathogens is essential in the management of oral diseases, as their occurrence and progression are closely linked to an imbalance in these microorganisms. Detection techniques such as microbial cultures, enzyme-linked immunosorbent assays and polymerase chain reactions are highly dependent on complex testing procedures and specialized laboratory equipment, making prevention and early diagnosis of oral diseases difficult. To comprehensively implement oral disease prevention and early diagnosis in social groups, there is an urgent need for portable testing methods for oral pathogenic bacteria that can be applied in community and home settings. In this review, several common portable biosensors for pathogenic bacteria are first described. Based on the goal of achieving primary prevention and diagnosis of oral diseases, we elaborate and summarize portable biosensors for common oral pathogenic bacteria in terms of how to achieve portability of the technique. This review aims to reflect the current status of portable biosensors for common oral pathogens and to lay the foundation for the further realization of portable detection of oral pathogens.

Nitro-Activated Nucleobase Exchange in the Synthesis of 2'-Fluoro-2'-Deoxyribonucleosides.

Functionalized nucleosides bearing pyrimidine or purine bases can be prepared by activation of accessible pyrimidine nucleosides and subsequent transglycosylation. Nitration of lumicitabine, a 2'-fluoro-2'-deoxycytidine class antiviral agent, and its 2'-fluoro-2'-deoxyuridine precursor produce the same 5-nitro-2'-fluoro-2'-deoxyuridine. Under Vorbrüggen conditions, 5-nitrouracil serves as the leaving nucleobase and enables exchange with pyrimidine and purine nucleobases to anomeric 2'-fluoro-2'-deoxyribonucleosides in favor of ß-anomers generally. The strategy is also applied in the isotopic labeling of 2'-fluoro-2'-deoxyuridines.

Filter-Assisted Separation of Multiple Nanomaterials: Mechanism and Application in Atomic/Mass Spectrometry/Fluorescence Label-Free Multimode Bioassays.

Atomic spectrometry (AS) has been widely used in bioassay, but it requires steps to immobilize or separate the signal molecules. In this work, based on the phenomenon that the filter membrane can selectively separate multiple nanomaterials (nanoparticles (NPs) and quantum dots (QDs)) and its related ions, including poly(thymine)-templated Cu NPs and free Cu2+, Ag NPs and free Ag+, CdTe QDs and Cd2+, we constructed multimode and label-free biosensors by chemical vapor generation-atomic fluorescence spectrometry (CVG-AFS), inductively coupled plasma mass spectrometry (ICP-MS), and fluorescence. In this strategy, terminal deoxynucleotidyl transferase (TdT) and polynucleotide kinase (PNK), H2O2, and mucin 1 can be sensitively detected using Cu2+, Ag+, and Cd2+ as the signal probe, respectively. As a result, TdT and T4 PNK in single cells level can be accurately quantified. In addition, the possible separation mechanism of filter membrane was proposed, both Donnan repulsion by charged functional layer and entrapment effect by nanomaterials size contributed to the outstanding separation performance. Subsequently, on the basis that CdTe QDs can selectively identify Cu NPs/Cu2+, Ag NPs/Ag+, and C-Ag+-C/Ag+, cation-exchange reaction (CER) was introduced in this platform due to its unique advantages, including improving the sensitivity of the above system (an order of magnitude), converting the non-CVG metal elements into CVG elements, and using low-cost AFS to substitute the high-cost ICP-MS. In addition, we performed theoretical calculations of the selective CER using density functional theory (DFT). Therefore, this label-free and simple separation AS/ICP-MS sensing platform shows great potential for biomarker analysis.

[Research Progress in Biomimetic Synthesis of Nano-Hydroxyapatite in Bone Tissue Engineering].

Nano hydroxyapatite (nHAp), a main component of the inorganic composition of human bones and teeth, is widely used in bone tissue engineering, bone defect repair and replacement, for example, for its biocompatibility, bioactivity, bioaffinity and the ability to induce bone regeneration. Nano hydroxyapatite contains calcium and phosphorus, elements that can be replaced through the normal metabolic channels of the human body. Therefore, after implantation, it can be partially or completely absorbed and replaced by human tissues and can effectively assist bone regeneration, which makes it an ideal material for bone repair. However, traditional nHAp material is brittle and hard to be degraded in human body. In addition, nHAp has poor stability due to its high surface energy and tendency for agglomeration, which causes rapid attenuation of its mechanical strength and limits its clinical application. At present, the mechanical properties and biocompatibility of nHAp can be effectively improved by loading the related growth factors, proteins, peptides and other bioactive molecules, so as to better meet the biological requirements of bone repair materials. However, the traditional physicochemical modification methods are complicated and may interfere with the bioactivity of nHAp. It is simple to biomimetically synthesize nanomaterials by direct utilization of the molecular recognition and self-assemble capabilities of biomolecules or living microorganisms. Furthermore, the properties of the synthesized nanomaterials are stable, and the method has been extensively studied in recent years. Due to the unique crystaline structure and physicochemical properties of nHAp, results of a large number of studies have shown that its affinity with biological molecules can be used to produce bioactive nHAp by biomimetic synthesis methods. Biomimetically synthesized nHAp is expected to become the mainstream bone tissue engineering scaffold material. Analyzing and summarizing the biomimetic synthetic process and the characteristics of different nHAp materials will facilitate further development of bone defect repair materials with better mechanical and biological properties. Herein we reviewed methods of biomimetic synthesis of nHAp based on different biomolecular templates. Furthermore, we also discussed applications of biomimetic synthesized nHAp in bone tissue engineering, which can used as reference information for further research and development of new-generation bone repair biomaterials.

Pegylated carbon nitride nanosheets for enhanced reactive oxygen species generation and photodynamic therapy under hypoxic conditions.

The application of photodynamic therapy (PDT) is of ever-increasing importance in the treatment of malignant tumors; however, there are several major constraints that make it impossible to achieve optimal therapeutic effects. Our objective is to develop a novel photosensitizing drug for skin cancer. In the experiment, we fabricated four-arm-poly ethylene glycol modified amino-rich graphite phase carbon nitride nanosheets (AGCN-PEG), which have good stability in physiological solution and show selective accumulation in tumor cells. Under hypoxic conditions, the AGCN-PEG induced PDT can effectively inhibit growth on A431 human epidermoid carcinoma cells in vivo and in vitro. What's more, after being combined with TMPyP4, the therapeutic effect of AGCN-PEG was greatly improved.

The efficacy of platelet-rich fibrin as a scaffold in regenerative endodontic treatment: a retrospective controlled cohort study.

BACKGROUND: Blood Clot (BC) or platelet concentrates have been used as scaffold in regenerative endodontic treatment (RET). The aim of this retrospective study was to compare the performance of platelet-rich fibrin (PRF) with BC in inducing root development and periapical lesion healing after tooth revascularization. METHODS: Five patients receiving RET using PRF as a scaffold were matched 1:1 to a previous cohort of 5 patients who underwent tooth revascularization by provoking periapical bleeding. Clinical signs and symptoms were examined at follow-ups. Periapical lesion healing and root development were monitored radiographically. The resolution of clinical signs and symptoms as well as periapical radiolucency was observed in all patients (100%). RESULTS: Root elongation, dentinal wall thickening and apex closure were found in most cases (80% in both groups). There was no significant difference between the groups in terms of clinical sign resolution, root development and periapical healing. CONCLUSIONS: Within the limits of this study, PRF achieved comparable outcomes to BC in terms of clinical sign and symptom resolution, periapical lesion healing and continued root development in RET.

Parahydrogen-induced polarization by pairwise replacement catalysis on Pt and Ir nanoparticles.

Pairwise and random addition processes are ordinarily indistinguishable in hydrogenation reactions. The distinction becomes important only when the fate of spin correlation matters, such as in parahydrogen-induced polarization (PHIP). Supported metal catalysts were not expected to yield PHIP signals given the rapid diffusion of H atoms on the catalyst surface and in view of the sequential stepwise nature of the H atom addition in the Horiuti-Polanyi mechanism. Thus, it seems surprising that supported metal hydrogenation catalysts can yield detectable PHIP NMR signals. Even more remarkably, supported Pt and Ir nanoparticles are shown herein to catalyze pairwise replacement on propene and 3,3,3-trifluoropropene. By simply flowing a mixture of parahydrogen and alkene over the catalyst, the scalar symmetrization order of the former is incorporated into the latter without a change in molecular structure, producing intense PHIP NMR signals on the alkene. An important indicator of the mechanism of the pairwise replacement is its stereoselectivity, which is revealed with the aid of density matrix spectral simulations. PHIP by pairwise replacement has the potential to significantly diversify the substrates that can be hyperpolarized by PHIP for biomedical utilization.

Parahydrogen enhanced NMR reveals correlations in selective hydrogenation of triple bonds over supported Pt catalyst.

Parahydrogen induced polarization using heterogeneous catalysis can produce impurity-free hyperpolarized gases and liquids, but the comparatively low signal enhancements and limited scope of substrates that can be polarized pose significant challenges to this approach. This study explores the surface processes affecting the disposition of the bilinear spin order derived from parahydrogen in the hydrogenation of propyne over TiO2-supported Pt nanoparticles. The hyperpolarized adducts formed at low magnetic field are adiabatically transported to high field for analysis by proton NMR spectroscopy at 400 MHz. For the first time, the stereoselectivity of pairwise addition to propyne is measured as a function of reaction conditions. The correlation between partial reduction selectivity and stereoselectivity of pairwise addition is revealed. The systematic trends are rationalized in terms of a hybrid mechanism incorporating non-traditional concerted addition steps and well-established reversible step-wise addition involving the formation of a surface bound 2-propyl intermediate.

Shaped Ceria Nanocrystals Catalyze Efficient and Selective Para-Hydrogen-Enhanced Polarization.

Intense para-hydrogen-enhanced NMR signals are observed in the hydrogenation of propene and propyne over ceria nanocubes, nano-octahedra, and nanorods. The well-defined ceria shapes, synthesized by a hydrothermal method, expose different crystalline facets with various oxygen vacancy densities, which are known to play a role in hydrogenation and oxidation catalysis. While the catalytic activity of the hydrogenation of propene over ceria is strongly facet-dependent, the pairwise selectivity is low (2.4% at 375 °C), which is consistent with stepwise H atom transfer, and it is the same for all three nanocrystal shapes. Selective semi-hydrogenation of propyne over ceria nanocubes yields hyperpolarized propene with a similar pairwise selectivity of (2.7% at 300 °C), indicating product formation predominantly by a non-pairwise addition. Ceria is also shown to be an efficient pairwise replacement catalyst for propene.

Fast imaging of eccrine latent fingerprints with nontoxic Mn-doped ZnS QDs.

Fingerprints are unique characteristics of an individual, and their imaging and recognition is a top-priority task in forensic science. Fast LFP (latent fingerprint) acquirement can greatly help policemen in screening the potential criminal scenes and capturing fingerprint clues. Of the two major latent fingerprints (LFP), eccrine is expected to be more representative than sebaceous in LFP identification. Here we explored the heavy metal-free Mn-doped ZnS quantum dots (QDs) as a new imaging moiety for eccrine LFPs. To study the effects of different ligands on the LFP image quality, we prepared Mn-doped ZnS QDs with various surface-capping ligands using QDs synthesized in high-temperature organic media as starting material. The orange fluorescence emission from Mn-doped ZnS QDs clearly revealed the optical images of eccrine LFPs. Interestingly, N-acetyl-cysteine-capped Mn-doped ZnS QDs could stain the eccrine LFPs in as fast as 5 s. Meanwhile, the levels 2 and 3 substructures of the fingerprints could also be simultaneously and clearly identified. While in the absence of QDs or without rubbing and stamping the finger onto foil, no fluorescent fingerprint images could be visualized. Besides fresh fingerprint, aged (5, 10, and 50 days), incomplete eccrine LFPs could also be successfully stained with N-acetyl-cysteine-capped Mn-doped ZnS QDs, demonstrating the analytical potential of this method in real world applications. The method was also robust for imaging of eccrine LFPs on a series of nonporous surfaces, such as aluminum foil, compact discs, glass, and black plastic bags.

Characterization of local white matter microstructural alterations in Alzheimer's disease: A reproducible study.

Alzheimer's disease (AD) is a neurodegenerative disease with a close association with microstructural alterations in white matter (WM). Current studies lack the characterization and further validation of specific regions in WM fiber tracts in AD. This study subdivided fiber tracts into multiple fiber clusters on the basis of automated fiber clustering and performed quantitative analysis along the fiber clusters to identify local WM microstructural alterations in AD. Diffusion tensor imaging data from a public dataset (53 patients with AD and 70 healthy controls [HCs]) and a clinical dataset (27 patients with AD and 19 HCs) were included for mutual validation. Whole-brain tractograms were automatically subdivided into 800 clusters through the automatic fiber clustering approach. Then, 100 segments were divided along the clusters, and the diffusion properties of each segment were calculated. Results showed that patients with AD had significantly lower fraction anisotropy (FA) and significantly higher mean diffusivity (MD) in some regions of the fiber clusters in the cingulum bundle, uncinate fasciculus, external capsule, and corpus callosum than HCs. Importantly, these changes were reproducible across the two datasets. Correlation analysis revealed a positive correlation between FA and Mini-Mental State Examination (MMSE) scores and a negative correlation between MD and MMSE in these clusters. The accuracy of the constructed classifier reached 89.76% with an area under the curve of 0.93. This finding indicates that this study can effectively identify local WM microstructural changes in AD and provides new insight into the analysis and diagnosis of WM abnormalities in patients with AD.

Solution-free, in situ preparation of nano/micro CuO/ZnO in dielectric barrier discharge for sensitive cataluminescence sensing of acetic acid.

The present work describes a new solution-free strategy for preparation of cluster-like nano/micro CuO/ZnO particles in dielectric barrier discharge (DBD) in which the brass acts as the inner electrode. The cataluminescence (CTL) behaviour of such prepared material for acetic acid was studied for analytical application. Under the optimized conditions, the linear range of CTL intensity versus concentration of acetic acid are 6 mg L(-1) to 500 mg L(-1) with the limit of detection (LOD) of 3 mg L(-1), no significant interference was found. The new method shows great advantages because it is a process without any solution and complex equipment. The synthetic material was directly used for the cataluminescence sensing of acetic acid without other preliminary treatment and it shows high selectivity, satisfactory stability, and better sensitivity and linearity.

A simple method for fabricating drugs containing a cis-o-diol structure into guanosine-based supramolecular hydrogels for drug delivery.

Supramolecular hydrogels are attractive biomaterials for local drug delivery owing to their excellent self-healing, injectable, biodegradable, and biocompatible properties. However, traditional drug-loading approaches based on non-covalent encapsulation and covalent bonding have shown problems such as rapid or difficult drug release, complex reaction processes, low reaction efficiency, and decreased drug activity. Therefore, there is a need to find a simple and efficient method to load drugs into hydrogels, which possess stable drug release ability without impairing drug efficacy. In this study, we introduce dynamic borate ester bonds via a simple one-pot method to load cis-o-diol-containing drugs into guanosine (G)-based supramolecular hydrogels. The experimental results confirm that the dynamic covalent borate ester bonds are formed based on the cis-o-diol groups of the drug and the G in these hydrogels. Meanwhile, the as-prepared G-based hydrogels not only possess self-healing properties and injectability but also have satisfactory biodegradability and biocompatibility. Additionally, the drug can be released from the G-based hydrogel according to the pH-responsive cleavage of the borate ester bonds without affecting drug activity. Overall, these results indicate that the simple one-pot method of utilizing the dynamic borate bond can provide a valuable reference for the design of hydrogel dosage forms.

Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists.

Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) has been exploited as a promising target for the new small molecule therapeutics to treat inflammatory and autoimmune diseases via modulating the interleukin-17 (IL-17) production by T helper 17 (Th17) cells. Herein, we reported a series of triazine-based derivatives as novel RORγt inverse agonists. By screening of our in-house compound library, the hit compound 1 was identified with weak RORγt inhibitory activity. Subsequently, we engineered detailed structural modifications to explore the structure-activity relationships (SARs) of triazines derivatives, which led to discovery of a number of potent RORγt inverse agonists with IC50 values in the range of 7 nM-50 nM in RORγt dual FRET assay. Among them, compound 14g displayed potent RORγt inverse agonistic activity with an IC50 value of 22.9 nM in dual FRET assay. In a cell-based reporter gene assay, compound 14g showed an IC50 value of 0.428 µM and maximum inhibition rate of 108.9%. Compound 14g also exhibited good metabolic stability and a decent pharmacokinetic profile with a low clearance (CL = 0.229 L/h/kg) and a reasonable oral exposure (AUC0-Last = 5058 ng/mL*h). Most importantly, 14g alleviated the severity of imiquimod-induced psoriasis in mice. Taken together, triazine-based derivatives represent a new chemical class of RORγt inverse agonists as potential therapeutic agents against autoimmune diseases.

Discovery of Pyridinone Derivatives as Potent, Selective, and Orally Bioavailable Adenosine A2A Receptor Antagonists for Cancer Immunotherapy.

Recent studies and clinical evidence have strongly supported the development of adenosine A2A receptor (A2AR) antagonists as novel approaches for cancer immunotherapy. By screening our in-house compound library, a pyridinone hit compound (1) with weak A2AR antagonistic activity was identified. Further structure-activity relationship studies revealed a series of pyridinone derivatives with strong potency. Compound 38 stood out with a potent A2AR antagonistic activity (IC50 = 29.0 nM), good mouse liver microsomal metabolic stability (t1/2 = 86.1 min), and excellent oral bioavailability (F = 86.1%). Of note, 38 effectively enhanced the activation and killing ability of T cells in vitro by down-regulation of immunosuppressive molecules (LAG-3 and TIM-3) and up-regulation of effector molecules (GZMB, IFNG, and IL-2). Moreover, 38 exhibited excellent in vivo antitumor activity with a tumor growth inhibition (TGI) of 56.0% in the MC38 tumor model via oral administration, demonstrating its potential as a novel A2AR antagonist candidate for cancer immunotherapy.

Discovery of novel BTK PROTACs with improved metabolic stability via linker rigidification strategy.

Bruton's Tyrosine Kinase (BTK) functions as a key regulator of B-cell receptor (BCR) signaling pathway, which is frequently hyperactivated in a variety of lymphoma cancers. Using Proteolysis Targeting Chimera (PROTAC) technology, we have recently discovered a highly potent ARQ-531-derived BTK PROTAC 6e, inducing effective degradation of both wild type (WT) and C481S mutant BTK proteins. However, the poor metabolic stability of PROTAC 6e have limited its further in vivo studies. Herein, we present our structure-activity relationship (SAR) studies on modifying PROTAC 6e using linker rigidification strategy to identify a novel cereblon (CRBN)-recruiting compound 3e that induced BTK degradation in a concentration-dependent manner but had no effect on reducing the level of CRBN neo-substrates. Moreover, compound 3e suppressed the cell growth more potently than the small molecule inhibitors ibrutinib and ARQ-531 in several cells. Furthermore, compound 3e with the rigid linker displayed a significantly improved metabolic stability profile with the T1/2 increased to more than 145 min. Overall, we discovered a highly potent and selective BTK PROTAC lead compound 3e, which could be further optimized as potential BTK degradation therapy for BTK-associated human cancers and diseases.

Polythiophene as a near full pH photo-antimicrobial.

Microbial infections are currently one of the world's major public health concerns, the evolution of which has resulted in the development of multiple tolerances (not just drug or antibiotic resistance), including pH (from extremely acidic to alkaline). Currently various types of antimicrobials have been developed. Although effective, they seldom work in the full pH range due to the existence of acid-/base-reaction sites. Here, we found that polythiophene (PT10), a cationic polymer, was capable of both broad-spectrum photo-antimicrobial activity (Gram positive, Gram negative, Fungal, and cyano-bacteria) and broad pH responsiveness (constant 1O2 generation at pH 2-13). The half-maximal inhibitory concentrations (IC50) of PT10 for bacteria living in acidic, neutral, and alkaline media were generally lower than 2 µg mL-1 (except M. aeruginosa, pH 12, ∼30 µg mL-1), which were much lower than common antibiotics and other photosensitizers. Besides, the excellent photostability of PT10 allowed long-term light irradiation for antimicrobial performance. In real-world applications, PT10 was explored for the successful in vivo therapy of oral Candidiasis infection under extreme acidic conditions (pH < 3) and the removal of M. aeruginosa at pH 12. Such near full pH, broad-spectrum photo-antimicrobial activity of polythiophene is appealing for extremely acidic or alkaline applications, such as oral infections, vaginitis, and blooms.

Universal "Three-in-One" Matrix to Maximize Reactive Oxygen Species Generation from Food and Drug Administration-Approved Photosensitizers for Photodynamic Inactivation of Biofilms.

Biofilms, an accumulation of microorganisms, cause persistent bacterial infection and low cure rate due to the remarkable drug resistance. Photodynamic inactivation (PDI) is a promising treatment modality for bacterial infections, but the formation of biofilms raises new challenges for photosensitizers (PSs), particularly the reactive oxygen species (ROS) generation efficiency. Herein, through targeting the Jablonski energy diagram, we proposed a universal "three-in-one" matrix of Gd3+-ADP assembly for encapsulation and fixing of PSs to inhibit non-radiative transitions and promoting intersystem crossing (ISC) by the heavy atom and paramagnetic effects of Gd3+, eventually resulted in boosted ROS generation from the existing PSs (1.5-9.0-fold). Particularly, photophysical studies indicated that the matrix resulted in simultaneous ISC promotion and triplet-state lifetime lengthening, which is essential for ROS boosting. The PDI performance of the matrix was confirmed through fast and effective elimination of bacterial biofilms in 10-30 min. Moreover, successful therapy of a Pseudomonas aeruginosa biofilm-infected all-thickness third-degree burn wound was achieved within 11 days with Ce 6@CNs (matrix) but not feasible for matrix-free PSs (Ce 6 only), which highlighted the role of "three-in-one" matrix in ROS boosting.