The Directional Crystallization Process of Poly (triazine imide) Single Crystals in Molten Salts.

Poly (triazine imide) photocatalysts prepared via molten salt methods emerge as promising polymer semiconductors with one-step excitation capacity of overall water splitting. Unveiling the molecular conjugation, nucleation, and crystallization processes of PTI crystals is crucial for their controllable structure design. Herein, microscopy characterization was conducted at the PTI crystallization front from meso to nano scales. The heptazine-based precursor was found to depolymerize to triazine monomers within molten salts and KCl cubes precipitate as the leading cores that guide the directional stacking of PTI molecular units to form aggregated crystals. Upon this discovery, PTI crystals with improved dispersibility and enhanced photocatalytic performance were obtained by tailoring the crystallization fronts. This study advances insights into the directional assembling of PTI monomers on salt templates, placing a theoretical foundation for the ordered condensation of polymer crystals.

Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases.

BACKGROUND: Dysregulated activation of the inflammasome is involved in various human diseases including acute cerebral ischemia, multiple sclerosis and sepsis. Though many inflammasome inhibitors targeting NOD-like receptor protein 3 (NLRP3) have been designed and developed, none of the inhibitors are clinically available. Growing evidence suggests that targeting apoptosis-associated speck-like protein containing a CARD (ASC), the oligomerization of which is the key event for the assembly of inflammasome, may be another promising therapeutic strategy. Lonidamine (LND), a small-molecule inhibitor of glycolysis used as an antineoplastic drug, has been evidenced to have anti-inflammation effects. However, its anti-inflammatory mechanism is still largely unknown. METHODS: Middle cerebral artery occlusion (MCAO), experimental autoimmune encephalomyelitis (EAE) and LPS-induced sepsis mice models were constructed to investigate the therapeutic and anti-inflammasome effects of LND. The inhibition of inflammasome activation and ASC oligomerization by LND was evaluated using western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) in murine bone marrow-derived macrophages (BMDMs). Direct binding of LND with ASC was assessed using molecular mock docking, surface plasmon resonance (SPR), and drug affinity responsive target stability (DARTS). RESULTS: Here, we find that LND strongly attenuates the inflammatory injury in experimental models of inflammasome-associated diseases including autoimmune disease-multiple sclerosis (MS), ischemic stroke and sepsis. Moreover, LND blocks diverse types of inflammasome activation independent of its known targets including hexokinase 2 (HK2). We further reveal that LND directly binds to the inflammasome ligand ASC and inhibits its oligomerization. CONCLUSIONS: Taken together, our results identify LND as a broad-spectrum inflammasome inhibitor by directly targeting ASC, providing a novel candidate drug for the treatment of inflammasome-driven diseases in clinic.

Nutraceuticals for Diabetic Retinopathy: Recent Advances and Novel Delivery Systems.

Diabetic retinopathy (DR) is a major vision-threatening disease among the working-age population worldwide. Present therapeutic strategies such as intravitreal injection of anti-VEGF and laser photocoagulation mainly target proliferative DR. However, there is a need for early effective management in patients with early stage of DR before its progression into the more severe sight-threatening proliferative stage. Nutraceuticals, natural functional foods with few side effects, have been proposed to be beneficial in patients with DR. Over the decades, many studies, either in vitro or in vivo, have demonstrated the advantages of a number of nutraceuticals in DR with their antioxidative, anti-inflammatory, neuroprotective, or vasoprotective effects. However, only a few clinical trials have been conducted, and their outcomes varied. The low bioavailability and instability of many nutraceuticals have indeed hindered their utilization in clinical use. In this context, nanoparticle carriers have been developed to deliver nutraceuticals and to improve their bioavailability. Despite its preclinical nature, research of interventive nutraceuticals for DR may yield promising information in their clinical applications.

Metformin alleviates junctional epithelium senescence via the AMPK/SIRT1/autophagy pathway in periodontitis induced by hyperglycemia.

The junctional epithelium (JE) serves a crucial protective role in the periodontium. High glucose-related aging results in accelerated barrier dysfunction of the gingival epithelium, which may be associated with diabetic periodontitis. Metformin, an oral hypoglycemic therapeutic, has been proposed as a anti-aging agent. This study aimed to clarify the effect of metformin on diabetic periodontitis and explore its mechanism in ameliorating senescence of JE during hyperglycemia. The db/db mice was used as a diabetic model mice and alterations in the periodontium were observed by hematoxylin-eosin staining and immunohistochemistry. An ameloblast-like cell line (ALC) was cultured with high glucose to induce senescence. Cellular senescence and oxidative stress were evaluated by SA-ß-gal staining and Intracellular reactive oxygen species (ROS) levels. Senescence biomarkers, P21 and P53, and autophagy markers, LC3-II/LC3-I, were measured by western blotting and quantitative real-time PCR. To construct a stable SIRT1 (Sirtuin 1) overexpression cell line, we transfected ALCs with lentiviral vectors overexpressing the mouse SIRT1 gene. Cellular senescence was increased in the JE of db/db mice and the periodontium was destroyed, which could be alleviated by metformin. Moreover, oxidative stress and cellular senescence in a high glucose environment were reduced by metformin in in-vitro assays. The autophagy inhibitor 3-MA and SIRT1 inhibitor EX-527 could dampen the effects of metformin. Overexpression of SIRT1 resulted in increased autophagy and decreased oxidative stress and cellular senescence. Meanwhile, AMPK (AMP-activated protein kinase) inhibition reversed the anti-senescence effects of metformin. Overall, these results suggest that metformin alleviates periodontal damage in db/db mice and cellular senescence in ALCs under high glucose conditions via the AMPK/SIRT1/autophagy pathway.

TGF-ß1/Smad3 Signaling Is Required to Alleviate Fluoride-Induced Enamel Hypomineralization.

Excessive fluoride intake during enamel development can affect enamel mineralization, leading to dental fluorosis. However, its potential mechanisms remain largely unexplored. In the present study, we aimed to investigate the impact of fluoride on the expressions of RUNX2 and ALPL during mineralization and the effect of TGF-ß1 administration on fluoride treatment. A dental fluorosis model of newborn mice and an ameloblast cell line ALC were both used in the present study. The mice of the NaF group, including the mothers and newborns, were fed with water containing 150 ppm NaF after delivery to induce dental fluorosis. The mandibular incisors and molars showed significant abrasion in the NaF group. Immunostaining, qRT-PCR, and Western blotting analysis indicated that exposure to fluoride markedly down-regulated RUNX2 and ALPL in mouse ameloblasts and ALCs. Besides, fluoride treatment significantly decreased the mineralization level detected by ALP staining. Furthermore, exogenous TGF-ß1 up-regulated RUNX2 and ALPL and promoted mineralization, while the addition of SIS3 could block such TGF-ß1-induced up-regulation. In TGF-ß1 conditional knockout mice, the immunostaining of RUNX2 and ALPL was weaker compared with wild-type mice. Exposure to fluoride inhibited the expressions of TGF-ß1 and Smad3. Co-treatment of TGF-ß1 and fluoride up-regulated RUNX2 and ALPL compared with the fluoride alone treatment, promoting mineralization. Collectively, our data indicated that TGF-ß1/Smad3 signaling pathway was necessary for the regulatory effects of fluoride on RUNX2 and ALPL, and the fluoride-induced suppression of ameloblast mineralization was mitigated by activating TGF-ß1/Smad3 signaling pathway.

A novel function and mechanism of ischemia-induced retinal astrocyte-derived exosomes for RGC apoptosis of ischemic retinopathy.

Retinal ischemia is a common clinical event leading to retinal ganglion cell (RGC) death, resulting in irreversible vision loss. In the retina, glia-neuron communication is crucial for multiple functions and homeostasis. Extracellular vesicles, notably exosomes, play a critical role. The functions and mechanisms of retinal astrocyte-secreted exosomes remain unclear. Here, we isolated astrocyte-derived exosomes under hypoxia or normoxia and explored their role in an in vivo retinal ischemia-reperfusion (RIR) model. We found that hypoxia triggered astrocytes to produce a significantly increased number of exosomes, which could be internalized by RGCs in vivo or in vitro. Also, in the RIR model, the hypoxia-induced exosomes ameliorated the RIR injury and suppressed the RGC apoptosis. Furthermore, microRNA sequencing of retinal astrocyte-secreted exosomes revealed different patterns of exosomal miRNAs under hypoxia, particularly enriched with miR-329-5p. We verified that miR-329-5p was specifically bound to mitogen-activated protein kinase 8 mRNA, and subsequent JNK-pathway molecules were downregulated. We anticipated that the miR-329-5p/JNK pathway is a key to suppressing RGC apoptosis and preventing RIR injury. Such findings provided insights into the therapeutic potential of hypoxia-induced astrocyte-secreted exosomes and the miR-329-5p for treating retina ischemic diseases.

Pd-intercalated black phosphorus: An efficient electrocatalyst for CO2 reduction.

Nanoconfined catalysts enhance stabilization of reaction intermediates, facilitate electron transfer, and safeguard active centers, leading to superior electrocatalytic activity, particularly in CO2 reduction reactions (CO2RR). Despite their effectiveness, crafting nanoconfined catalysts is challenging due to unclear formation mechanisms. In this study, we introduce an electrochemical method to grow Pd clusters within the interlayers of two-dimensional black phosphorus, creating Pd cluster-intercalated black phosphorus (Pd-i-BP) as an electrocatalyst. Using in situ electrochemical liquid phase transmission electron microscopy (EC-TEM), we revealed the synthesis mechanism of Pd-i-BP, involving electrochemically driven Pd ion intercalation followed by reduction within the BP layers. The Pd-i-BP electrocatalyst exhibits exemplary CO2-to-formate conversion, achieving 90% Faradaic efficiency for formate production, owing to its distinct nanoconfined structure that stabilizes intermediates and enhances electron transfer. Density functional theory (DFT) calculations underscore the structural benefits for enhancing intermediate adsorption and catalyzing the reaction. Our insights deepen understanding of nanoconfined material synthesis, promising advanced, high-efficiency catalysts.

Classification of Vogt-Koyanagi-Harada disease using feature selection and classification based on wide-field swept-source optical coherence tomography angiography.

Background: Vogt-Koyanagi-Harada (VKH) disease is a common and easily blinded uveitis entity, with choroid being the main involved site. Classification of VKH disease and its different stages is crucial because they differ in clinical manifestations and therapeutic interventions. Wide-field swept-source optical coherence tomography angiography (WSS-OCTA) provides the advantages of non-invasiveness, large-field-of-view, high resolution, and ease of measuring and calculating choroid, offering the potential feasibility of simplified VKH classification assessment based on WSS-OCTA. Methods: 15 healthy controls (HC), 13 acute-phase and 17 convalescent-phase VKH patients were included, undertaken WSS-OCTA examination with a scanning field of 15 × 9 mm2. 20 WSS-OCTA parameters were then extracted from WSS-OCTA images. To classify HC and VKH patients in acute and convalescent phases, two 2-class VKH datasets (HC and VKH) and two 3-class VKH datasets (HC, acute-phase VKH, and convalescent-phase VKH) were established by the WSS-OCTA parameters alone or in combination with best-corrected visual acuity (logMAR BCVA) and intraocular pressure (IOP), respectively. A new feature selection and classification method that combines an equilibrium optimizer and a support vector machine (called SVM-EO) was adopted to select classification-sensitive parameters among the massive datasets and to achieve outstanding classification performance. The interpretability of the VKH classification models was demonstrated based on SHapley Additive exPlanations (SHAP). Results: Based on pure WSS-OCTA parameters, we achieved classification accuracies of 91.61% ± 12.17% and 86.69% ± 8.30% for 2- and 3-class VKH classification tasks. By combining the WSS-OCTA parameters and logMAR BCVA, we achieved better classification performance of 98.82% ± 2.63% and 96.16% ± 5.88%, respectively. Through SHAP analysis, we found that logMAR BCVA and vascular perfusion density (VPD) calculated from the whole field of view region in the choriocapillaris (whole FOV CC-VPD) were the most important features for VKH classification in our models. Conclusion: We achieved excellent VKH classification performance based on a non-invasive WSS-OCTA examination, which provides the possibility for future clinical VKH classification with high sensitivity and specificity.

Unveiling the charge transfer dynamics steered by built-in electric fields in BiOBr photocatalysts.

Construction of internal electric fields (IEFs) is crucial to realize efficient charge separation for charge-induced redox reactions, such as water splitting and CO2 reduction. However, a quantitative understanding of the charge transfer dynamics modulated by IEFs remains elusive. Here, electron microscopy study unveils that the non-equilibrium photo-excited electrons are collectively steered by two contiguous IEFs within binary (001)/(200) facet junctions of BiOBr platelets, and they exhibit characteristic Gaussian distribution profiles on reduction facets by using metal co-catalysts as probes. An analytical model justifies the Gaussian curve and allows us to measure the diffusion length and drift distance of electrons. The charge separation efficiency, as well as photocatalytic performances, are maximized when the platelet size is about twice the drift distance, either by tailoring particle dimensions or tuning IEF-dependent drift distances. The work offers great flexibility for precisely constructing high-performance particulate photocatalysts by understanding charge transfer dynamics.

Atomistic Observation of Temperature-Dependent Defect Evolution within Sub-stoichiometric WO3-x Catalysts.

Tunable crystalline defects endow WO3-x catalysts with extended functionalities for a broad range of photo- and electric-related applications. However, direct visualization of the defect structures and their evolution mechanism is lacking. Herein, aberration-corrected and in situ transmission electron microscopy was complemented by theoretical calculations to investigate the effect of temperature on the defect evolution behavior during hydrogenation treatment. Low processing temperature (100-300 °C) leads to the occurrence of randomly distributed oxygen vacancies within WO3-x nanosheets. At higher temperatures, oxygen vacancies become highly mobile and aggregate into stacking faults. Planar defects are prone to nucleate at the surface and develop in a zigzag form at 400 °C, while treating at 500 °C promotes the growth of {200}-type stacking faults. Our work clearly establishes that the atomic configuration of the defects in WO3-x samples could be manipulated by regulating the hydrogenation temperature. This study not only expands our understanding of the structure-function relationships of sub-stoichiometric tungsten oxides but also unlocks their full potential as advanced catalysts by tuning stoichiometry in a controlled manner.

Vascular Abnormalities in Peripapillary and Macular Regions of Behcet's Uveitis Patients Evaluated by Optical Coherence Tomography Angiography.

Purpose: To investigate the involvement of peripapillary zone vascular abnormalities in Behcet's uveitis (BU) and associated visual dysfunction. We evaluated the retinal and choroidal microvascular features in both macular and peripapillary areas of BU patients to identify vascular abnormalities contributing to reduced best-corrected visual acuity (BCVA) using optical coherence tomography angiography (OCTA). Methods: A prospective, observational study was conducted in 24 eyes of 13 patients with BU and 24 eyes of 15 healthy participants as controls. They received a standard eye examination and were recorded by OCTA measurements of macular and peripapillary areas. The vascular densities of superficial capillary plexus (SCP) and deep capillary plexus (DCP), choroidal flow area, radial peripapillary capillary network (RPCN) density, foveal avascular zone (FAZ) area and perimeter, full retinal thickness (FRT), and peripapillary retinal nerve fiber layer thickness (pRNFLT) were measured.Correlations among microvascular, structural, and functional changes were assessed. Results: Our findings uncovered that the vascular density was significantly reduced in the peripapillary zone of BU eyes compared to healthy eyes, especially in the inferior subfield of the RPCN. The vascular densities of SCP and DCP quadrants within the macular zone had no significant difference between BU and control groups except for DCP density of the nasal parafoveal quadrant. Both FAZ area and perimeter were greater but without statistical significance in the BU group. Compared to healthy eyes, the choriocapillaris flow area was smaller while the FRT and pRNFLT were greater in the BU group. Notably, there was a significant correlation between the reduction in RPCN vascular density and decreased BCVA in BU patients. Conclusion: Based on OCTA, vascular changes associated with BU are more prominent in the peripapillary zone than those in the macular zone. The vascular density of the RPCN could serve as a sensitive indicator to monitoring BU pathogenic progression and treatment response using a non-invasively method of OCTA.

Microvasculature Features of Vogt-Koyanagi-Harada Disease Revealed by Widefield Swept-Source Optical Coherence Tomography Angiography.

Background: Vogt-Koyanagi-Harada (VKH) disease is a multisystem autoimmune disorder which could induce bilateral panuveitis involving the posterior pole and peripheral fundus. Optical coherence tomography angiography (OCTA) provides several advantages over traditional fluorescence angiography for revealing pathological abnormalities of the retinal vasculature. Until recently, however, the OCTA field of view (FOV) was limited to 6 × 6 mm2 scans. Purpose: This study examined retinal vasculature and choriocapillaris abnormalities across multiple regions of the retina (15 × 9 mm2 wide field, macular, peripapillary regions) among acute and convalescent VKH patients using a novel widefield swept-source OCTA (WSS-OCTA) device and assessed correlations between imaging features and best-corrected visual acuity (BCVA). Methods: Twenty eyes of 13 VHK disease patients in the acute phase, 30 eyes of 17 patients in the convalescent phase, and 30 eyes of 15 healthy controls (HCs) were included in this study. Vascular length density (VLD) in superficial and deep vascular plexuses (SVP, DVP), vascular perfusion density (VPD) in SVP, DVP, and choriocapillaris (CC), and flow voids (FV) in CC were measured across multiple retinal regions via WSS-OCTA (PLEX Elite 9000, Carl Zeiss Meditec Inc., USA) using the 15 × 9 mm2 scan pattern centered on the fovea and quantified by ImageJ. Results: Compared to HCs, acute phase VKH patients exhibited significantly reduced SVP-VLD, SVP-VPD, and CC-VPD across multiple retinal regions (all p < 0.01). Notably, the FV area was more extensive in VKH patients, especially those in the acute phase (p < 0.01). These changes were reversed in the convalescent phase. Stepwise multiple linear regression analysis demonstrated that macular DVP-VLD and macular CC-VPD were the best predictive factors for BCVA in the acute and convalescent VKH groups. Conclusion: The wider field of SS-OCAT provides more comprehensive and detailed images of the microvasculature abnormalities characterizing VKH disease. The quantifiable and layer-specific information from OCTA allows for the identification of sensitive and specific imaging markers for prognosis and treatment guidance, highlighting WSS-OCTA as a promising modality for the clinical management of VKH disease.