Exosome lncRNA IFNG-AS1 derived from mesenchymal stem cells of human adipose ameliorates neurogenesis and ASD-like behavior in BTBR mice.

BACKGROUND: The transplantation of exosomes derived from human adipose-derived mesenchymal stem cells (hADSCs) has emerged as a prospective cellular-free therapeutic intervention for the treatment of neurodevelopmental disorders (NDDs), as well as autism spectrum disorder (ASD). Nevertheless, the efficacy of hADSC exosome transplantation for ASD treatment remains to be verified, and the underlying mechanism of action remains unclear. RESULTS: The exosomal long non-coding RNAs (lncRNAs) from hADSC and human umbilical cord mesenchymal stem cells (hUCMSC) were sequenced and 13,915 and 729 lncRNAs were obtained, respectively. The lncRNAs present in hADSC-Exos encompass those found in hUCMSC-Exos and are associated with neurogenesis. The biodistribution of hADSC-Exos in mouse brain ventricles and organoids was tracked, and the cellular uptake of hADSC-Exos was evaluated both in vivo and in vitro. hADSC-Exos promote neurogenesis in brain organoid and ameliorate social deficits in ASD mouse model BTBR T + tf/J (BTBR). Fluorescence in situ hybridization (FISH) confirmed lncRNA Ifngas1 significantly increased in the prefrontal cortex (PFC) of adult mice after hADSC-Exos intraventricular injection. The lncRNA Ifngas1 can act as a molecular sponge for miR-21a-3p to play a regulatory role and promote neurogenesis through the miR-21a-3p/PI3K/AKT axis. CONCLUSION: We demonstrated hADSC-Exos have the ability to confer neuroprotection through functional restoration, attenuation of neuroinflammation, inhibition of neuronal apoptosis, and promotion of neurogenesis both in vitro and in vivo. The hADSC-Exos-derived lncRNA IFNG-AS1 acts as a molecular sponge and facilitates neurogenesis via the miR-21a-3p/PI3K/AKT signaling pathway, thereby exerting a regulatory effect. Our findings suggest a potential therapeutic avenue for individuals with ASD.

Methionine redox regulation of actin-interacting proteins primarily governs antioxidative signaling and response to the salvianolic acid B treatment in EA.hy926 cells.

Actin-interacting proteins are important molecules for filament assembly and cytoskeletal signaling within vascular endothelium. Disruption in their interactions causes endothelial pathogenesis through redox imbalance. Actin filament redox regulation remains largely unexplored, in the context of pharmacological treatment. This work focused on the peptidyl methionine (M) redox regulation of actin-interacting proteins, aiming at elucidating its role on governing antioxidative signaling and response. Endothelial EA.hy926 cells were subjected to treatment with salvianolic acid B (Sal B) and tert-butyl-hydroperoxide (tBHP) stimulation. Mass spectrometry was employed to characterize redox status of proteins, including actin, myosin-9, kelch-like erythroid-derived cap-n-collar homology-associated protein 1 (Keap1), plastin-3, prelamin-A/C and vimentin. The protein redox landscape revealed distinct stoichiometric ratios or reaction site transitions mediated by M sulfoxide reductase and reactive oxygen species. In comparison with effects of tBHP stimulation, Sal B treatment prevented oxidation at actin M325, myosin-9 M1489/1565, Keap1 M120, plastin-3 M592, prelamin-A/C M187/371/540 and vimentin M344. For Keap1, reaction site was transitioned within its scaffolding region to the actin ring. These protein M oxidation regulations contributed to the Sal B cytoprotective effects on actin filament. Additionally, regarding the Keap1 homo-dimerization region, Sal B preventive roles against M120 oxidation acted as a primary signal driver to activate nuclear factor erythroid 2-related factor 2 (Nrf2). Transcriptional splicing of non-POU domain-containing octamer-binding protein was validated during the Sal B-mediated overexpression of NAD(P)H dehydrogenase [quinone] 1. This molecular redox regulation of actin-interacting proteins provided valuable insights into the phenolic structures of Sal B analogs, showing potential antioxidative effects on vascular endothelium.

Optical design algorithm utilizing continuous-discrete variables grounded on stochastic processes.

This work proposes an optimization algorithm in optical design based on the concepts of ergodic and stochastic processes in statistical mechanics. In mixed-variable optimization problems, pseudo-random number and discrete-to-continuous variable conversion dramatically increase the speed at which the system solves for the optimal solution. Pseudo-random numbers are mainly applied in two important steps in the optimization algorithm: determining the combination of glasses involved and the order in which the successive glass parameters are replaced by real glasses. After two series of stochastic processes, the merit function value decreases rapidly along the steepest descent path, and thus the optical system approaches the optimal solution within a very short duration of time. By using the method proposed in this paper, a plan apochromatic objective with a long working distance was optimized, and finally, a high-quality optical system was obtained.

Breath Biopsy Reveals Systemic Immunothrombosis and Its Resolution through Bioorthogonal Dendritic Nanoprobes.

Immunothrombosis, an inflammation-dependent activation of the coagulation cascade, leads to microthrombi formations in small vessels. It is a dreaded complication of COVID-19 and a major cause of respiratory failure. Due to their size and disseminated nature, microthrombi are currently undetectable. Here, noninvasive detection of a volatile reporter in the exhaled air is introduced for assessment of systemic immunothrombosis. A dendritic nanoprobe, containing high loading of a thrombin-sensitive substrate, is selectively cleaved by thrombin, resulting in release of a synthetic bioorthogonal volatile organic compound (VOC). The VOC is quantitated in the exhaled air biopsies via gas chromatography-mass spectrometry (GC-MS), allowing near real-time assessment of systemic immunothrombosis. The VOC detection can be further improved with more rapid and sensitive MS-based technologies. The amount of the VOC in the exhaled air decreases with resolution of the microvascular inflammation and intravascular fibrin depositions. Through conjugation of the thrombin-sensitive peptide with a rhodol derivative, a novel thrombin-sensitive fluorescent nanoprobe is developed for intravital visualization of thrombin activity in actively growing thrombi. These results establish unprecedented detection of thrombin activity in vivo, addressing this unmet medical need. This novel approach facilitates diagnosis of immunothrombosis in diseases such as diabetic complications, disseminated intravascular coagulation, and COVID-19.

VEGFR-2 adhesive nanoprobes reveal early diabetic retinopathy in vivo.

Diabetic retinopathy (DR) is a debilitating organ manifestation of diabetes. Absent of early diagnosis and intervention, vision tends to drastically and irreversibly decline. Previously, we showed higher vascular endothelial growth factor receptor 2 (VEGFR-2) expression in diabetic microvessels, and the suitability of this molecule as a biomarker for early DR diagnosis. However, a hurdle to translation remained generation of biodegradable nanoprobes that are sufficiently bright for in vivo detection. Here, an adhesive fluorescent nanoprobe with high brightness was developed using biodegradable materials. To achieve that, a fluorophore with bulky hydrophobic groups was encapsulated in the nanoparticles to minimize fluorophore π-π stacking, which diminishes brightness at higher loading contents. The nanoprobe selectively targeted the VEGFR-2 under dynamic flow conditions. Upon systemic injection, the nanoprobes adhered in the retinal microvessels of diabetic mice and were visualized as bright spots in live retinal microscopy. Histology validated the in vivo results and showed binding of the nanoprobes to the microvascular endothelium and firmly adhering leukocytes. Leukocytes were found laden with nanoprobes, indicating the potential for payload transport across the blood-retinal barrier. Our results establish the translational potential of these newly generated nanoprobes in early diagnosis of DR.

Bidirectional crosstalk of the cAMP/ROS-dependent signaling pathways in inflammatory macrophage: An activation of formononetin.

Bacterial lipopolysaccharide (LPS) is a toxic stimulant to macrophage inflammation. Inflammation intersects cell metabolism and often directs host immunopathogenesis stress. We aim here at pharmacological discovering of formononetin (FMN) action, to which anti-inflammatory signaling spans across immune membrane receptors and second messenger metabolites. In ANA-1 macrophage stimulated by LPS, and simultaneous treatment with FMN, results show the Toll-like receptor 4 (TLR4) and estrogen receptor (ER) signals, in concert with reactive oxygen species (ROS) and cyclic adenosine monophosphate (cAMP), respectively. LPS stimulates inactivation of the ROS-dependent nuclear factor erythroid 2-related factor 2 (Nrf2) by upregulating TLR4, but it does not affect cAMP. However, FMN treatment not only activates Nrf2 signaling by TLR4 inhibition, but also it activates cAMP-dependent protein kinase activities by upregulating ER. The cAMP activity gives rise to phosphorylation (p-) of protein kinase A, liver kinase B1 and 5'-AMP activated protein kinase (AMPK). Moreover, bidirectional signal crosstalk is amplified between p-AMPK and ROS, as FMN combinational validation with AMPK activator/inhibitor/target small-interfering RNA or ROS scavenger. The signal crosstalk is well positioned serving as the 'plug-in' knot for rather long signaling axis, and the immune-to-metabolic circuit via ER/TLR4 signal transduction. Collectively, convergence of the FMN-activated signals drives significant reduction of cyclooxygenase-2, interleukin-6 and NLR family pyrin domain-containing protein 3, in LPS-stimulated cell. Although anti-inflammatory signaling is specifically related to the immune-type macrophage, the p-AMPK antagonizing effect arises from FMN combination with ROS scavenger H-bond donors. Information of our work assists in predictive traits against macrophage inflammatory challenges, using phytoestrogen discoveries.

Synthesis and Anti-Inflammatory Activity Evaluation of Benzoxazole Derivatives as New Myeloid Differentiation Protein 2 Inhibitors.

Myeloid differentiation protein 2 (MD2), a key TLR4 adaptor protein for sensing LPS, plays an important role in inflammatory process and has been identified as a promising target for the treatment of a variety of inflammatory diseases. In our study, a series of benzoxazolone derivatives were synthesized, characterized and tested for anti-inflammatory activity in vitro. The compounds 3c, 3d and 3g demonstrated the greatest anti-inflammatory activity against IL-6 with IC50 values of 10.14±0.08, 5.43±0.51 and 5.09±0.88 µM, respectively. Furthermore, the bis-ANS displacement assay revealed that these compounds competitively inhibited the binding between the probe bis-ANS and the MD2 protein. The most active compound 3g, revealed a directly bind with MD2 protein via Arg90 binding and a dissociation constant value of 1.52×10-6  mol L-1 as determined by the biological layer interference (BLI) assay. Our finding suggested that compounds 3g could be a promising lead compound as MD2 inhibitor for further anti-inflammatory agent development.

Pre-hyperglycemia immune cell trafficking underlies subclinical diabetic cataractogenesis.

BACKGROUND: This work elucidates the first cellular and molecular causes of cataractogenesis. Current paradigm presupposes elevated blood glucose as a prerequisite in diabetic cataractogenesis. Novel evidence in our model of diabetic cataract challenges this notion and introduces immune cell migration to the lens and epithelial-mesenchymal transformation (EMT) of lens epithelial cells (LECs) as underlying causes. METHODS: Paucity of suitable animal models has hampered mechanistic studies of diabetic cataract, as most studies were traditionally carried out in acutely induced hyperglycemic animals. We introduced diabetic cataract in the Nile grass rat (NGR) that spontaneously develops type 2 diabetes (T2D) and showed its closeness to the human condition. Specialized stereo microscopy with dual bright-field illumination revealed novel hyperreflective dot-like microlesions in the inner cortical regions of the lens. To study immune cell migration to the lens, we developed a unique in situ microscopy technique of the inner eye globe in combination with immunohistochemistry. RESULTS: Contrary to the existing paradigm, in about half of the animals, the newly introduced hyper reflective dot-like microlesions preceded hyperglycemia. Even though the animals were normoglycemic, we found significant changes in their oral glucose tolerance test (OGTT), indicative of the prediabetic stage. The microlesions were accompanied with significant immune cell migration from the ciliary bodies to the lens, as revealed in our novel in situ microscopy technique. Immune cells adhered to the lens surface, some traversed the lens capsule, and colocalized with apoptotic nuclei of the lens epithelial cells (LECs). Extracellular degradations, amorphous material accumulations, and changes in E-cadherin expressions showed epithelial-mesenchymal transformation (EMT) in LECs. Subsequently, lens fiber disintegration and cataract progression extended into cortical, posterior, and anterior subcapsular cataracts. CONCLUSIONS: Our results establish a novel role for immune cells in LEC transformation and death. The fact that cataract formation precedes hyperglycemia challenges the prevailing paradigm that glucose initiates or is necessary for initiation of the pathogenesis. Novel evidence shows that molecular and cellular complications of diabetes start during the prediabetic state. These results have foreseeable ramifications for early diagnosis, prevention and development of new treatment strategies in patients with diabetes.

PGC-1α/NRF1-dependent cardiac mitochondrial biogenesis: A druggable pathway of calycosin against triptolide cardiotoxicity.

Mitochondrion-related cardiotoxicity due to cardiotoxin stimuli is closely linked to abnormal activities of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), followed by co-inactivation of nuclear respiratory factor-1(NRF1). Pharmacological interventions targeting mitochondria may be effective for developing agents against cardiotoxicity. Herein, in triptolide-treated H9C2 cardiomyocytes, we observed defective mitochondrial biogenesis and respiration, characterized by depletion of mitochondrial mass and mitochondrial DNA copy number, downregulation of mitochondrial respiratory chain complexes subunits, and disorders of mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Dysregulation of mitochondria led to cardiac pathological features, such as myocardial fiber fracture, intercellular space enlargement, and elevation of serum aspartate aminotransferase, creatine kinase isoenzyme, lactate dehydrogenase, and cardiac troponin I. However, following calycosin treatment, an active compound from Astragali Radix, the mitochondrion-related disorders at both cell and tissue levels were significantly ameliorated, which was facilitated by the activation of PGC-1α via deacetylation, followed by NRF1 co-activation. Calycosin-enhanced PGC-1α deacetylation is impelled by increasing sirtuin-1 expression and NAD+/NADH ratio. PGC-1α/NRF1 signaling in calycosin-mediated mitochondrial biogenesis protection was further confirmed by NRF1 knockdown and PGC-1α inhibition with SR18292. We conclude that calycosin ameliorated triptolide-induced cardiotoxicity by protecting PGC-1α/NRF1-dependent cardiac mitochondrial biogenesis and respiration, which is the druggable pathway for cardiotoxicity mitigation.

Withaferin a Attenuates Retinal Ischemia-Reperfusion Injury via Akt-Dependent Inhibition of Oxidative Stress.

Background: Retinal ischemia-reperfusion (I/R) injury often results in intractable visual impairments. The survival of retinal capillary endothelial cells is crucial for the treatment of retinal I/R injury. How to protect retinal endothelia from damage is a challenging work. Withaferin A, a small molecule derived from plants, has antibacterial and anti-inflammatory effects and has been used for about millennia in traditional medicine. The present study aimed to investigate the potential protective effect of withaferin A on retinal I/R injury. Methods: The drug-likeness of withaferin A was evaluated by the SwissADME web tool. The potential protective effect of withaferin A on the I/R-induced injury of human retinal microvascular endothelial cells (HRMECs) was investigated using multiple approaches. RNA sequencing was performed and associated mechanistic signaling pathways were analyzed based on the Kyoto Encyclopedia of Genes and Genomes data. The analytical results of RNA sequencing data were further validated by in vitro and in vivo experiments. Results: Withaferin A reduced the I/R injury-induced apoptotic death of HRMECs in vitro with a good drug-like property. RNA sequencing and experimental validation results indicated that withaferin A increased the production of the crucial antioxidant molecules heme oxygenase 1 (HO-1) and peroxiredoxin 1 (Prdx-1) during I/R. In addition, withaferin A activated the Akt signaling pathway and increased the expression of HO-1 and Prdx-1, thereby exerting an antioxidant effect, attenuated the retinal I/R injury, and decreased the apoptosis of HRMECs. The blockade of Akt completely abolished the effects of withaferin A. Conclusions: The study identified for the first time that withaferin A can protect against the I/R-induced apoptosis of human microvascular retinal endothelial cells via increasing the production of the antioxidants Prdx-1 and HO-1. Results suggest that withaferin A is a promising drug candidate for the treatment of retinal I/R injury.

GSK3ß-dependent lysosome biogenesis: An effective pathway to mitigate renal fibrosis with LM49.

Renal fibrosis is an incurable disorder characterised by an imbalance of the extracellular matrix (ECM) favouring excess production over degradation. The identification of actionable pathways and agents that promote ECM degradation to restore ECM homeostasis may help mitigate renal fibrosis. In this study, we identified 5,2'-dibromo-2,4',5'-trihydroxydiphenylmethanone (LM49), a compound we previously synthesised, as a small-molecule inducer of ECM degradation. LM49 administration efficiently reduced ECM deposition in renal tissue of diabetic nephropathy rats and in transforming growth factor ß-treated renal fibroblast cells. LM49 promoted the cytosol-to-nucleus translocation of transcription factor EB (TFEB) to increase lysosome biogenesis, leading to lysosome-based degradation of the ECM. TFEB-mediated lysosome biogenesis was induced by LM49 directly inhibiting the activity of glycogen synthase kinase 3ß (GSK3ß) rather than mammalian target of rapamycin complex 1. LM49 inhibited GSK3ß kinase activity concentration-dependently via competing with ATP. Direct binding between LM49 and GSK3ß was confirmed by the bio-layer interferometry assay, cellular thermal shift assay, and drug affinity responsive target stability. A molecular docking and molecular dynamic simulation revealed that LM49 occupied the ATP pocket of GSK3ß, which was consistent with the kinase activity assay. In summary, LM49 enhances TFEB-mediated lysosome biogenesis by directly inhibiting GSK3ß, leading to the degradation of the ECM by lysosomes. The enhancement of GSK3ß-dependent lysosome biogenesis to rebalance the ECM may be a novel strategy to counteract renal fibrosis, and LM49 may be a viable clinical candidate for treating this disorder.

Improving endothelial cell junction integrity by diphenylmethanone derivatives at oxidative stress: A dual-action directly targeting caveolar caveolin-1.

Directly targeting caveolar caveolin-1 is a potential mechanism to regulate endothelial permeability, especially during oxidative stress, but little evidence on the topic limits therapeutics discoveries. In this study, we investigated the pharmacological effect of an antioxidant LM49 (5,2'-dibromo-2,4',5'-trihydroxydiphenylmethanoe) and its five diphenylmethanone derivatives on endothelial permeability and establish two distinct mechanisms of action. Multiplex molecular assays with theoretical modeling indicate that diphenylmethanone molecules, including LM49, directly bind the caveolin-1 steric pocket of ASN53/ARG54, ILE49/ASP50, ILE18, LEU59, ASN60, GLU48 and ARG19 residues. They also indicated dynamic binding-affinity for diphenylmethanone derivatives. First, this molecular interaction at caveolin-1 pocket inhibits its phosphorylation at TYR14 residue in H2O2-injured endothelial cell. A positive correlation was established between diphenylmethanone derivative binding-affinity and caveolin-1 phosphorylation inhibition. Inhibition of caveolin-1 phosphorylation, however, was independent of the LM49-mediated variation of protein tyrosine kinase activity, suggesting a direct blockage of adenosine triphosphate substrate diffusion into cavelion-1 structure. Second, LM49 increases the expression of cellular adhesive and tight junction proteins, VE-cadherin and occludin, in H2O2-injured cell, in a dose dependent manner. A leakage assay of fluorescein isothiocyanate-labeled dextran 40 across cell monolayer suggested improvement in endothelial barrier integrity with diphenylmethanone treatments. Our results demonstrate a direct targeting effect of caveolin-1 on endothelial permeability, and should guide the diphenylmethanone therapy against oxidative stress-induced junction dysfunction, especially at caveolar membrane invagination.

The effects of genetic distance, nutrient conditions, and recognition ways on outcomes of kin recognition in Glechoma longituba.

Kin recognition might help plants decrease competitive cost and improve inclusive fitness with close genes; thus it might interact with environmental factors to affect communities. Whether and how various factors, such as the genetic distance of neighbors, environmental stressors, or the way a plant recognizes its neighbors, might modify plant growth strategies remains unclear. To answer these questions, we conducted experiments in which ramets of a clonal plant, Glechoma longituba, were grown adjacent to different genetically related neighbors (clone kin / close kin / distant kin) in different nutrient conditions (high / medium / low), or with only root exudates from pre-treatment in culture solution. By comparing competitive traits, we found that: (1) kin recognition in G. longituba was enhanced with closer genetic distance; (2) the outcomes of kin recognition were influenced by the extent of nutrient shortage; (3) kin recognition helped to alleviate the nutrient shortage effect; (4) kin recognition via root exudates affected only below-ground growth. Our results provide new insights on the potential for manipulating the outcome of kin recognition by altering neighbor genetic distance, nutrient conditions and recognition ways. Moreover, kin recognition can help plants mitigate the effects of nutrient shortage, with potential implications in agricultural research.

Nanoarchitectonics for Photo-Controlled Intracellular Drug Release in Immune Modulation.

Local stimuli differentiate monocytes into M2-like macrophages that mechanistically drive the pathologies in cancer and age-related macular degeneration (AMD). A photo-controlled nanodrug that halts macrophage polarization through Rho-associated kinase (ROCK) inhibition was developed. A small-molecule ROCK inhibitor, fasudil, was conjugated to a photo-responsive group and a short poly(ethylene glycol) (PEG) chain. This resulted in the novel amphiphilic prodrug, PEG-2-(4'-(di(prop-2-yn-1-yl)amino)-4-nitro-[1,1'-biphenyl]-yl)propan-1-ol (PANBP)-Fasudil, that spontaneously formed micelles. Ultraviolet (UV) irradiation of PEG-PANBP-Fasudil nanoparticles rapidly released fasudil. For visualization of linker degradation, a reporter nanoprobe was synthesized, in which 2-Me-4-OMe TokyoGreen (TG), a fluorophore that does not fluoresce in conjugation, was incorporated. Irradiation of nanoprobe-laden monocytes activated the reporter fluorophore. Cytokine stimulation differentiated monocytes into macrophages, while UV irradiation prevented polarization of PEG-PANBP-Fasudil nanoparticle-laden monocytes. Nanoarchitectonics-based design opens new possibilities for intracellular drug delivery and precise spatiotemporal immune cell modulation toward the development of new therapies.

Excited-state intermediates in a designer protein encoding a phototrigger caught by an X-ray free-electron laser.

One of the primary objectives in chemistry research is to observe atomic motions during reactions in real time. Although X-ray free-electron lasers (XFELs) have facilitated the capture of reaction intermediates using time-resolved serial femtosecond crystallography (TR-SFX), only a few natural photoactive proteins have been investigated using this method, mostly due to the lack of suitable phototriggers. Here we report the genetic encoding of a xanthone amino acid (FXO), as an efficient phototrigger, into a rationally designed human liver fatty-acid binding protein mutant (termed XOM), which undergoes photo-induced C-H bond transformation with high selectivity and quantum efficiency. We solved the structures of XOM before and 10-300 ns after flash illumination, at 1.55-1.70 Å resolutions, and captured the elusive excited-state intermediates responsible for precise C-H bond activation. We expect that most redox enzymes can now be investigated by TR-SFX, using our method, to reveal reaction intermediates key for their efficiency and selectivity.

Isolated compounds from Dracaena angustifolia Roxb and acarbose synergistically/additively inhibit α-glucosidase and α-amylase: an in vitro study.

BACKGROUND: As a traditional herbal medicine, Dracaena angustifolia Roxb has been used as an anti-inflammatory agent by the Li people in Hainan, China. In preliminary phytochemical studies conducted in our lab, its fractions were found to inhibit α-glucosidase in vitro, indicating a potential for alleviating glucose dysregulation. METHODS: Through in vitro enzymatic assays, the abilities of the separated components to affect α-glucosidase and α-amylase were evaluated. By establishing concentration gradients and generating Lineweaver-Burk plots, the corresponding inhibition modes together with kinetic parameters were assessed. Following the evaluation of the outcomes of their combination with acarbose, computational docking and molecular dynamic simulations were carried out to analyse the interaction mechanisms and perform virtual screening against human enzymes. RESULTS: Compared with acarbose, 7 compounds, including flavonoid derivatives, amides and aromatic derivatives, with higher α-glucosidase inhibitory efficiencies were confirmed. It was found that those competitive/mixed candidates and acarbose interacted synergistically or additively on α-glucosidase. Moreover, 3 of them were able to inhibit α-amylase in mixed mode, and additive effects were observed in combination with acarbose. Through in silico docking, it was found that the active site residues as well as adjacent residues were involved in α-glucosidase and α-amylase binding, which were mainly achieved through hydrogen bonding. Among those dual-function flavonoids, Compound 9 was predicted to be a considerable inhibitor of human enzymes, as the formation of ligand-enzyme complexes was mediated by the residues responsible for substrate recognition and catalysis, the stabilities of which were reiterated by molecular dynamics simulations. CONCLUSION: Despite their mild effects on α-amylase, considerable α-glucosidase inhibitory efficiencies and potential synergy with acarbose were exhibited by these natural candidates. Furthermore, a stable ligand, human α-glucosidase, was predicted by the performed simulations, which provided useful information for the application of Dracaena angustifolia Roxb in diabetes treatment.

5,2'-Dibromo-2,4',5'-trihydroxydiphenylmethanone Inhibits LPS-Induced Vascular Inflammation by Targeting the Cav1 Protein.

Vascular inflammation is directly responsible for atherosclerosis. 5,2'-Dibromo-2,4',5'-trihydroxydiphenylmethanone (TDD), a synthetic bromophenol derivative, exhibits anti-atherosclerosis and anti-inflammatory effects. However, the underlying pathways are not yet clear. In this study, we first examined the effects of TDD on toll-like receptor-4 (TLR4) activity, the signaling receptor for lipopolysaccharide (LPS), and found that TDD does not inhibit LPS-induced TLR4 expression in EA.hy926 cells and the vascular wall in vivo. Next, we investigated the global protein alterations and the mechanisms underlying the action of TDD in LPS-treated EA.hy926 cells using an isobaric tag for the relative and absolute quantification technique. Western blot analysis revealed that TDD inhibited NF-κB activation by regulating the phosphorylation and subsequent degradation IκBα. Among the differentially expressed proteins, TDD concentration-dependently inhibited Caveolin 1(Cav1) expression. The interaction between Cav1 and TDD was determined by using biolayer interference assay, UV-vis absorption spectra, fluorescence spectrum, and molecular docking. We found that TDD can directly bind to Cav1 through hydrogen bonds and van der Waals forces. In conclusion, our results showed that TDD inhibited LPS-induced vascular inflammation and the NF-κB signaling pathway by specifically targeting the Cav1 protein. TDD may be a novel anti-inflammatory compound, especially for the treatment of atherosclerosis.

Loss of neurodevelopmental-associated miR-592 impairs neurogenesis and causes social interaction deficits.

microRNA-592 (miR-592) has been linked to neurogenesis, but the influence of miR-592 knockout in vivo remains unknown. Here, we report that miR-592 knockout represses IPC-to-mature neuron transition, impairs motor coordination and reduces social interaction. Combining the RNA-seq and tandem mass tagging-based quantitative proteomics analysis (TMT protein quantification) and luciferase reporter assays, we identified MeCP2 as the direct targetgene of miR-592 in the mouse cortex. In Tg(MECP2) mice, lipofection of miR-592 efficiently reduced MECP2 expression in the brains of Tg(MECP2) mice at E14.5. Furthermore, treatment with miR-592 partially ameliorated the autism-like phenotypes observed in adult Tg(MECP2) mice. The findings demonstrate that miR-592 might play a novel role in treating the neurodevelopmental-associated disorder.

Optimal Sensor Placement of the Artificial Lateral Line for Flow Parametric Identification.

The multi-sensor artificial lateral line system (ALLS) can identify the flow-field's parameters to realize the closed-loop control of the underwater robotic fish. An inappropriate sensor placement of ALLS may result in inaccurate flow-field parametric identification. Therefore, this paper proposes a method to optimize the sensor placement configuration of the ALLS, which mainly included three algorithms, the feature importance algorithm based on mean and variance (MVF), the feature importance algorithm based on distance evaluation (DF), and the information redundancy (IR) algorithm. The optimal sensor placement performance selected by this method is verified by simulation. In addition, further experimental verification was conducted using the ALLS. Compared with the uniform sensor placement configuration mentioned in recent studies, the experimental results suggest that the optimal sensor placement method can achieve a more effective prediction of the flow-field parameters, therefore strengthening the underwater robotic fish's perception and control function.

Human Exosomes Accelerate Cutaneous Wound Healing by Promoting Collagen Synthesis in a Diabetic Mouse Model.

Chronic wounds including diabetic foot ulcers are clinical emergencies that need careful management. Exosomes from human adipose-derived mesenchymal stem cells (hADSCs-Ex) are a new promising cell-free therapy for the regeneration of dermal wounds. We established a delayed wound healing model using diabetic female mice. A 1.5 cm2 full-thickness cutaneous wound was made ventrally in 6-week-old db/db mice. After treatment with phosphate-buffered saline, recombinant human epidermal growth factor, hADSCs-CM, or hADSCs-Ex three times a day for 2 weeks, we measured wound healing closure rates and performed histological analysis. Human dermal fibroblasts (WS1) were evaluated by PKH26-Exo co-localization test, CCK-8 test, cell scratch test, and the transwell test, while the expression of matrix metalloproteinase-1 (MMP1), MMP3, Collagen I, and Collagen III were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Wound closure and re-epithelialization were accelerated by hADSCs-Ex. Besides, hADSCs-Ex enhanced skin collagen production, angiogenesis, cell proliferation, inhibited apoptosis, promoted skin barrier function repair, and reduced inflammation in skin lesions. Furthermore, negative regulation of MMP1 and MMP3 enhanced collagen synthesis wound healing-promoting effects of hADSCs-Ex. hADSCs-Ex treatment for diabetic wounds provided a novel cell-free therapeutic strategy.