Syringaresinol Alleviates Early Diabetic Retinopathy by Downregulating HIF-1α/VEGF via Activating Nrf2 Antioxidant Pathway.

SCOPE: Early diabetic retinopathy (DR) is characterized by chronic inflammation, excessive oxidative stress, and retinal microvascular damage. Syringaresinol (SYR), as a natural polyphenolic compound, has been proved to inhibit many disease progression due to its antiinflammatory and antioxidant properties. The present study focuses on exploring the effect of SYR on hyperglycemia-induced early DR as well as the underlying mechanisms. METHODS AND RESULTS: Wild-type (WT) and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout C57BL/6 mice of type 1 diabetes and high glucose (HG)-induced RF/6A cells are used as in vivo and in vitro models, respectively. This study finds that SYR protects the retinal structure and function in diabetic mice and reduces the permeability and apoptosis of HG-treated RF/6A cells. Meanwhile, SYR distinctly mitigates inflammation and oxidative stress in vivo and vitro. The retinal microvascular damages are suppressed by SYR via downregulating hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. Whereas, SYR-provided protective effects are diminished in Nrf2-knockout mice, indicating that SYR improves DR progression by activating Nrf2. Similarly, SYR cannot exert protective effects against HG-induced oxidative stress and endothelial injury in small interfering RNA (siRNA)-Nrf2-transfected RF/6A cells. CONCLUSION: In summary, SYR suppresses oxidative stress via activating Nrf2 antioxidant pathway, which ameliorates retinal microvascular damage by downregulating HIF-1α/VEGF, thereby alleviating early DR progression.

Melatonin attenuates diabetic cardiomyopathy by increasing autophagy of cardiomyocytes via regulation of VEGF-B/GRP78/PERK signaling pathway.

AIMS: Diabetic cardiomyopathy (DCM) is a major cause of mortality in patients with diabetes, and the potential strategies for treating DCM are insufficient. Melatonin (Mel) has been shown to attenuate DCM, however, the underlying mechanism remains unclear. The role of vascular endothelial growth factor-B (VEGF-B) in DCM is little known. In present study, we aimed to investigate whether Mel alleviated DCM via regulation of VEGF-B and explored its underlying mechanisms. METHODS AND RESULTS: We found that Mel significantly alleviated cardiac dysfunction and improved autophagy of cardiomyocytes in type 1 diabetes mellitus (T1DM) induced cardiomyopathy mice. VEGF-B was highly expressed in DCM mice in comparison with normal mice, and its expression was markedly reduced after Mel treatment. Mel treatment diminished the interaction of VEGF-B and Glucose-regulated protein 78 (GRP78) and reduced the interaction of GRP78 and protein kinase RNA -like ER kinase (PERK). Furthermore, Mel increased phosphorylation of PERK and eIF2α, then up-regulated the expression of ATF4. VEGF-B-/- mice imitated the effect of Mel on wild type diabetic mice. Interestingly, injection with Recombinant adeno-associated virus serotype 9 (AAV9)-VEGF-B or administration of GSK2656157 (GSK), an inhibitor of phosphorylated PERK abolished the protective effect of Mel on DCM. Furthermore, rapamycin, an autophagy agonist displayed similar effect with Mel treatment; while 3-Methyladenine (3-MA), an autophagy inhibitor neutralized the effect of Mel on high glucose-treated neonatal rat ventricular myocytes. CONCLUSIONS: These results demonstrated that Mel attenuated DCM via increasing autophagy of cardiomyocytes, and this cardio-protective effect of Mel was dependent on VEGF-B/GRP78/PERK signaling pathway.

GSDME-dependent pyroptosis signaling pathway in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the serious chronic microvascular complications of diabetes, and leads to the increased morbidity and mortality in diabetic patients. Gasdermin E (GSDME)-dependent pyroptosis signaling pathway plays important roles in a variety of physiological and pathological processes. However, its role and mechanism in DN are still unclear. In this study, we established a rat DN model by intraperitoneal injection of streptozotocin (STZ) successfully. Structural and functional disorders in the kidney were exhibited on the 12th week after STZ injection; the expressions of caspase-3 and GSDME at protein level in renal cortex were significantly up-regulated. At the 20th week, GSDME-N increased significantly, accompanied by the upregulation of caspase-1 in renal cortex and the release of mature IL-1ß (mIL-1ß) in serum. Furthermore, we found the protein levels of GSDME, caspase-3, caspase-1 and IL-1ß were all increased in HK2 and HBZY-1 cells under high-glucose conditions. We also found that the expression of GSDME-N significantly decreased when caspase-3 was knockdown. In contrast, knockdown of GSDME has no effect on caspase-3. Interestingly, either caspase-3, caspase-1 or GSDME knockdown reduced the release of mIL-1ß. Finally, injection of adeno-associated virus (AAV) 9-shGSDME into the rat kidney reduced kidney damage and renal cell pyroptosis in comparison with wild-type diabetic rats. These results indicated that the activation of caspase-1 induced IL-1ß maturation, and the activation of caspase-3 mediated cleavage of GSDME responsible for the formation of plasma membrane pore, followed by cytoplasmic release of mIL-1ß. Overall, we identified a pro-pyroptosis role for GSDME in DN, which does provide an important basis for clinical therapeutic studies.

Syringaresinol protects against diabetic nephropathy by inhibiting pyroptosis via NRF2-mediated antioxidant pathway.

Diabetic nephropathy (DN) is one of the serious complications of diabetes that has limited treatment options. As a lytic inflammatory cell death, pyroptosis plays an important role in the pathogenesis of DN. Syringaresinol (SYR) possesses anti-inflammatory and antioxidant properties. However, the therapeutic effects and the underlying mechanism of SYR in DN remain unclear. Herein, we showed that SYR treatment ameliorated renal hypertrophy, fibrosis, mesangial expansion, glomerular basement membrane thickening, and podocyte foot process effacement in streptozotocin (STZ)-induced diabetic mice. Mechanistically, SYR prevented the abundance of pyroptosis-related proteins such as NOD-like receptor family pyrin domain containing 3 (NLRP3), cysteinyl aspartate-specific proteinase 1 (Caspase-1), and gasdermin D (GSDMD), and the biosynthesis of inflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 18 (IL-18). In addition, SYR promoted the nuclear translocation of nuclear factor E2-related factor 2 (NRF2) and enhanced the downstream antioxidant enzymes heme oxygenase 1 (HO-1) and manganese superoxide dismutase (MnSOD), thereby effectively decreasing excess reactive oxygen species (ROS). Most importantly, knockout of NRF2 abolished SYR-mediated renoprotection and anti-pyroptotic activities in NRF2-KO diabetic mice. Collectively, SYR inhibited the NLRP3/Caspase-1/GSDMD pyroptosis pathway by upregulating NRF2 signaling in DN. These findings suggested that SYR may be promising a therapeutic option for DN.

Longitudinal Immune Profiling Highlights CD4+ T Cell Exhaustion Correlated with Liver Fibrosis in Schistosoma japonicum Infection.

Schistosomiasis remains an important public health concern. The eggs deposited in livers invoke a Th2-dominant response, which mediates the fibrotic granulomatous response. However, the mechanisms involved in this immunopathological process are still not perfectly clear. Here, we report a single-cell transcriptional landscape of longitudinally collected BALB/c mouse splenocytes at different time points after Schistosoma japonicum infection. We found that exhausted CD4+ T cells were enriched after infection, changing from coproducing multiple cytokines to predominantly producing the Th2 cytokine IL-4. Regulatory B cells had high expression of Fcrl5, Ptpn22, and Lgals1, potentially regulating exhausted CD4+ T cells via direct PD-1-PD-L2 and PD-1-PD-L1 interactions. Within the myeloid compartment, the number of precursor and immature neutrophils sharply increased after infection. Moreover, dendritic cells, macrophages, and basophils showed inhibitory interactions with exhausted CD4+ T cells. Besides, in mouse livers, we found that exhausted CD4+ T cells were distributed around egg granuloma, promoting collagen expression in primary mouse hepatic stellate cells via IL-4 secretion, resulting in liver fibrosis. Our study provides comprehensive characterization of the composition and cellular states of immune cells with disease progression, which will facilitate better understanding of the mechanism underlying liver fibrotic granulomatous response in schistosomiasis.

Identification and validation of a prognostic risk-scoring model for AML based on m7G-associated gene clustering.

Background: Acute myeloid leukemia (AML) patients still suffer from poor 5-year survival and relapse after remission. A better prognostic assessment tool is urgently needed. New evidence demonstrates that 7-methylguanosine (m7G) methylation modifications play an important role in AML, however, the exact role of m7G-related genes in the prognosis of AML remains unclear. Methods: The study obtained AML expression profiles and clinical information from TCGA, GEO, and TARGET databases. Using the patient data from the TCGA cohort as the training set. Consensus clustering was performed based on 29 m7G-related genes. Survival analysis was performed by KM curves. The subgroup characteristic gene sets were screened using WGCNA. And tumor immune infiltration correlation analysis was performed by ssGSEA. Results: The patients were classified into 3 groups based on m7G-related genebased cluster analysis, and the differential genes were screened by differential analysis and WGCNA. After LASSO regression analysis, 6 characteristic genes (including CBR1, CCDC102A, LGALS1, RD3L, SLC29A2, and TWIST1) were screened, and a prognostic risk-score model was constructed. The survival rate of low-risk patients was significantly higher than that of high-risk patients (p < 0.0001). The area under the curve values at 1, 3, and 5 years in the training set were 0.871, 0.874, and 0.951, respectively, indicating that this predictive model has an excellent predictive effect. In addition, after univariate and multivariate Cox regression screening, histograms were constructed with clinical characteristics and prognostic risk score models to better predict individual survival. Further analysis showed that the prognostic risk score model was associated with immune cell infiltration. Conclusion: These findings suggest that the scoring model and essential risk genes could provide potential prognostic biomarkers for patients with acute myeloid leukemia.

Alleviation of Fufang Fanshiliu decoction on type II diabetes mellitus by reducing insulin resistance: A comprehensive network prediction and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Fanshiliu decoction (FFSLD) is a Chinese herbal medicine prescription that has been used in type 2 diabetes mellitus (T2DM), while the underlying mechanism remains unclear. AIM OF THE STUDY: To validate the efficacy and explore the potential mechanisms of FFSLD in treating T2DM via integrating a network pharmacological approach and experimental evaluation. MATERIALS AND METHODS: T2DM mice model induced by high-fat diet feeding combined with streptozotocin injection was selected to investigate the alleviation of FFSLD against T2DM, via detecting the levels of glucose, insulin, glucagon (GC), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Network pharmacological analysis was used to predict the potential mechanisms, including the pharmacokinetics and drug-likeness screening, active ingredients and potential targets prediction, network analysis, and enrichment analysis. The candidate bioactive molecules of FFSLD, and targets information excavated through TCMSP, Uniprot, GeneCards, OMIM databases, were combined for comprehensive analysis by constructing "drug-compound-target-disease" and "protein-protein interaction" networks. Enrichment analysis was performed via Gene Ontology (GO) and Koto Encyclopedia of Genes and Genomes (KEGG) databases. HepG2 insulin-resistance (IR) cells model induced by high glucose was used to verify the potential mechanisms of FFSLD against T2DM which were predicted by the network pharmacology. RESULTS: The animal study showed that FFSLD significantly decreased the blood glucose, and reversed the abnormal levels of insulin, GC, TG, TC, HDL-C, and LDL-C in T2DM mice. Network pharmacological analysis indicated that 106 active compounds of FFSLD might be correlated with 628 targets in treating T2DM, and the mechanism would probably be related to insulin resistance that harbored a high response value (P = 5.88844 E-33) though regulating Akt1, ESR1, oxidoreductase activity, and JAK/STAT signalings. Experimental validation showed that FFSLD reduced the ROS level, up-regulated the expressions of p-AKT, Nrf-2, and ESR1, and down-regulated the expressions of JAK2, STAT3, and Keap-1 in the HepG2-IR cells model. CONCLUSIONS: This study demonstrated that the therapeutic effect of FFSLD on T2DM was related to IR alleviation. The underlying mechanisms were associated with the regulation of PI3K/AKT, JAK/STAT, oxidative stress, and ESR signaling pathways.

Exercise Training Protects Against Heart Failure Via Expansion of Myeloid-Derived Suppressor Cells Through Regulating IL-10/STAT3/S100A9 Pathway.

BACKGROUND: Exercise training (ET) has a protective effect on the progression of heart failure, however, the specific mechanism has not been fully explored. Myeloid-derived suppressor cells (MDSCs) are a group of myeloid-derived immunosuppressive cells, which showed a protective effect in the progression of heart failure. Thus, we hypothesized that the protective effect of ET on heart failure may be related to the infiltration of MDSCs. METHODS: C57BL/6 mice were made to run on a treadmill 6× a week for 4 weeks followed by isoproterenol injection from third week. Heart function was evaluated by echocardiography and the proportion of MDSCs was detected by flow cytometry. Hypertrophic markers, cardiac fibrosis, and inflammatory factors were detected by real-time PCR, ELISA, histological staining, and Western blot. RESULTS: ET treatment in isoproterenol-induced heart failure mice (n=7) enhanced cardiac function (57% increase in FS%, P=0.002) and improved morphological changes compared with isoproterenol mice (n=17). ET further caused 79% increasing in cardiac MDSCs in isoproterenol mice (P<0.001). In addition, depletion of MDSCs by 5-Fluorouracil blunted the cardio-protective effect of ET. T-cell proliferation assay showed that ET did not affect the suppressive activity of MDSCs. Furthermore, we found that ET activated the secretion of IL (interleukin)-10 by macrophages in isoproterenol mice. MDSCs expansion and cardio protection was not present in tamoxifen-inducible macrophage-specific IL-10 knockout mice. Western blot results confirmed that IL-10 regulated the differentiation of MDSCs through the translocation of p-STAT3 (signal transducer and activator of transcription 3)/S100A9 (S100 calcium-binding protein A9) to the nucleus. CONCLUSIONS: ET could increase MDSCs by stimulating the secretion of IL-10 from macrophage, which was through IL-10/STAT3/S100A9 signaling pathway, thereby achieving the role of heart protection.

Chronic stress promotes breast carcinoma metastasis by accumulating myeloid-derived suppressor cells through activating ß-adrenergic signaling.

Numerous studies have found that chronic stress could promote tumor progression and this may be related to inhibtion of immune system. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells with immunosuppressive activity. MDSCs may represent a key link between chronic stress and tumor progression. However, the role of stress-induced MDSCs in breast cancer progression is unclear. The present study showed that pre-exposure of chronic stress could lead to MDSCs elevation and facilitated breast cancer metastasis in tumor-bearing mice. Adoptive transfer of MDSCs could significantly increase lung metastatic foci. In contrast, lung metastasis could be alleviated by depleting endogenous MDSCs with Gr-1 antibody. The concentration of norepinephrine in serum and the expression of tyrosine hydroxylase in bone marrow could be significantly elevated by chronic stress. Moreover, propranolol, an inhibitor of ß-adrenergic signaling, could inhibit breast carcinoma metastasis and prevent the expansion of chronic stress-induced MDSCs. Further study revealed that the expressions of IL-6 and JAK/STAT3 signaling pathways were upregulated by chronic stress in mice, and this upregulation could be inhibited by propranolol. Blocking the IL-6 signal or inhibiting the activation of the JAK/STAT3 signaling pathway could reduce tumor growth and metastasis by attenuating the accumulation of MDSCs in vivo. Besides, propranolol inhibited the expression of IL-6 in supernatant of 4T1 cells induced by isoproterenol and reduced the proportion of inducible MDSCs in vitro. Taken together, these data indicated that chronic stress may accumulate MDSCs via activation of ß-adrenergic signaling and IL-6/STAT3 pathway, thereby promoting breast carcinoma metastasis.

Clinical Evidence-Guided Anti-rheumatoid Arthritis Study of Shuji Tablet in Adjuvant-Induced Arthritis Rats and Mechanism Exploration via Network Pharmacological Approach.

Background: Rheumatoid arthritis (RA) is a kind of chronic autoimmune disease with several tissues damaged. Shuji tablet (SJT) is a prescription approved for treating lumbago and leg pain in the clinic. However, the efficacy of SJT against RA is still unknown. This study aims to evaluate the therapeutic effect of SJT on adjuvant-induced arthritis (AIA) rats and explore the mechanism via a network pharmacological approach. Methods: AIA rats were treated with SJT for 30 days at the dosages of 3.6, 1.8, and 0.9 g/kg, respectively, and the anti-RA effect was determined by measuring paw swelling, systemic symptoms score, arthritis index, and histopathological change. ELISA assay was used to evaluate the level of inflammatory cytokines in serum. The mechanism exploration and target prediction of SJT against RA were performed via a network pharmacological approach. Results: SJT showed excellent alleviation on AIA rats, with evidence of reducing paws swelling, decreasing systemic symptoms score, and arthritis index. Furthermore, SJT significantly reduced the serum cytokines of IL-6, IL-1ß, TNF-α in AIA rats. Histopathological examination showed SJT remarkably reduced synovial hyperplasia, cartilage damage, and inflammatory infiltration in the secondary-side paws. According to network pharmacological analysis, 208 candidate compounds and 445 potential targets of SJT were identified, and 4465 RA therapy-related targets were searched out. Subsequently, 292 target genes of SJT were speculated to be associated with RA treatment, among which the top 5 "response values" targets were STAT3, AKT1, JUN, HSP90AA1, TNF. GO and KEGG enrichment analysis suggested that 45 signaling pathways were associating with SJT treating RA. The top 10 signaling pathways were PI3K-Akt, MAPK, AGE-RAGE pathway in diabetic complications, Ras, HIF-1, TNF, Chemokine, IL-17, FoxO, and Rap1. Conclusion: Our experimental study showed that SJT significantly alleviated rheumatoid arthritis of AIA rats. Network pharmacology showed that the key targets of SJT against RA probably were STAT3, AKT1, JUN, HSP90AA1, TNF, and the potential mechanism was associated with modulation on the signaling pathways of PI3K-Akt, MAPK, Ras, AGE-RAGE, HIF-1, TNF, chemokine, IL-17, FoxO, Rap 1. Our study strongly provides evidence for Shuji tablet in RA therapy and would enlarge its application in the clinic.

Protection of Ficus pandurata Hance against acute alcohol-induced liver damage in mice via suppressing oxidative stress, inflammation, and apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ficus pandurata Hance (FPH) is a traditional Chinese herbal medicine, which is commonly used for liver protection in the folk of Southeast China. However, the medicinal part and pharmacological mechanism have not been clarified yet. AIM OF THE STUDY: This study aims to investigate the medicinal part of FPH for liver protection and uncover the potential mechanism. MATERIALS AND METHODS: Acute alcoholic liver damage (ALD) mice model induced by intragastric administration with 50% alcohol was used to evaluate the liver protection of FPH. Different parts of FPH, including the root (FPHR), stem (FPHS), leaf (FPHL), and whole plant (FPHWP), were selected to investigate the liver-protected efficacy and determine which part is the medicinal part. Acute oral toxicity (AOT) test was performed to determine the acute toxicity of FPH on Kunming mice. The liver-protected effect of FPH was determined by evaluating the liver function, liver morphological changes, and liver pathological changes. The underlying mechanism was investigated by evaluating the effect on oxidative stress, inflammation, and apoptosis in liver tissues via ELISA, H&E staining, Western Blot, and TUNEL staining assays. RESULTS: In the screening test for medicinal parts of FPH, all of the extracts from FPHR, FPHS, FPHL, and FPHWP could alleviate the acute ALD of mice, including reducing abnormal levels of AST, ALT, and relative liver weight. Especially, the alleviated efficacies of FPHS and FPHL were better than those of FPHWP and FPHR, showing that the aerial part (FPHAP, including the stem and leaf), is probably the medicinal part of FPH against acute ALD. In the AOT test, FPHAP at the maximum administration dosage (480 g/kg, calculated based on the quantity of crude material) did not induce obvious abnormality and death of mice, and had no significant influence on body weight, as well as the relative organ weight, showing that the maximum tolerated dose (MTD) of FPHAP was 480 g/kg on Kunming mice. In the anti-acute ALD study, FPHAP significantly reduced the levels of AST, ALT, LDH, ROS, MDA, TNF-α, IL-1ß, IL-18, and IL-6, alleviated the morphology of liver injury, increased the levels of SOD and GSH, up-regulated the expressions of Nrf-2, HO-1 and NQO1, and reduced apoptosis of liver cells in acute ALD mice, indicating that FPHAP could significantly alleviate acute ALD by suppressing oxidative stress, inflammation, and apoptosis. CONCLUSIONS: FPH could protect acute alcohol-induced liver damage of mice by suppressing oxidative stress, inflammation, and apoptosis. Our study provides scientific evidence for the therapeutic effect of Ficus pandurata Hance in acute ALD mice and suggests its potential development in humans for liver protection, supporting its traditional application.

Design of Beam Shaping Assemblies for Accelerator-Based BNCT With Multi-Terminals.

To moderate fast neutrons produced by accelerator to appropriate therapeutic energies for boron neutron capture therapy (BNCT), beam shaping assembly (BSA) is required definitely. In this work, based on a model of 2.5 MeV/30 mA proton accelerator, the Monte Carlo simulation software MCNPX was employed to design multi-terminal BSAs. All parameters for both the thermal and epithermal neutron beams at the exit ports of the designed BSAs meet the treatment recommendation values proposed by the International Atomic Energy Agency (IAEA). The clinical parameters of the thermal and epithermal neutron beams were also calculated for clinical indication consideration.

Metamaterial assisted illumination nanoscopy via random super-resolution speckles.

Structured illumination microscopy (SIM) is one of the most powerful and versatile optical super-resolution techniques. Compared with other super-resolution methods, SIM has shown its unique advantages in wide-field imaging with high temporal resolution and low photon damage. However, traditional SIM only has about 2 times spatial resolution improvement compared to the diffraction limit. In this work, we propose and experimentally demonstrate an easily-implemented, low-cost method to extend the resolution of SIM, named speckle metamaterial-assisted illumination nanoscopy (speckle-MAIN). A metamaterial structure is introduced to generate speckle-like sub-diffraction-limit illumination patterns in the near field with improved spatial frequency. Such patterns, similar to traditional SIM, are then used to excite objects on top of the surface. We demonstrate that speckle-MAIN can bring the resolution down to 40 nm and beyond. Speckle-MAIN represents a new route for super-resolution, which may lead to important applications in bio-imaging and surface characterization.

Syringaresinol Protects against Type 1 Diabetic Cardiomyopathy by Alleviating Inflammation Responses, Cardiac Fibrosis, and Oxidative Stress.

SCOPE: Syringaresinol (SYR) is a phenolic compound, which could be found in various cereals and medicinal plants. It exerts both anti-inflammatory and antioxidant pharmacological properties. However, little is known about the effect of SYR on modulating diabetic cardiomyopathy. The present study aimed to investigate the pharmacodynamic effect of SYR on diabetic cardiomyopathy and the underlying molecular mechanism. METHODS AND RESULTS: In STZ-induced type 1 diabetic mice, orally administration with SYR in every other day for 8 weeks significantly improves cardiac dysfunction and preventes cardiac hypertrophy and fibrosis. The macrophage infiltration and oxidative stress biomarkers are also suppressed by SYR without affecting hyperglycemia and body weight. In neonatal cardiomyocytes, high glucose-induced cell apoptosis and fibrosis are potently decreased by SYR, and the inflammatory response and oxidant stress are also alleviated by SYR incubation. Mechanistically, SYR may exert protective effects by restoring suppression of antioxidant kelch-like ECH-associated protein 1 (Keap1)/nuclear factor-E2-related factor 2 (Nrf2) system and abnormal activation of transforming growth factor-ß (TGF-ß)/mothers against decapentaplegic homolog (Smad) signaling pathway in vitro and in vivo. CONCLUSION: The results indicated that SYR could be a potential therapeutic agent for the treatment of diabetic cardiomyopathy by inhibiting inflammation, fibrosis, and oxidative stress. The signaling pathway of Keap1/Nrf2 and TGF-ß/Smad could be used as therapeutic targets for diabetic complications.

Metamaterial-Assisted Photobleaching Microscopy with Nanometer Scale Axial Resolution.

The past two decades have witnessed a dramatic progress in the development of novel super-resolution fluorescence microscopy technologies. Here, we report a new fluorescence imaging method, called metamaterial-assisted photobleaching microscopy (MAPM), which possesses a nanometer-scale axial resolution and is suitable for broadband operation across the entire visible spectrum. The photobleaching kinetics of fluorophores can be greatly modified via a separation-dependent energy transfer process to a nearby metamaterial. The corresponding photobleaching rate is thus linked to the distance between the fluorophores and the metamaterial layer, leading to a reconstructed image with exceptionally high axial resolution. We apply the MAPM technology to image the HeLa cell membranes tagged with fluorescent proteins and demonstrate an axial resolution of ∼2.4 nm with multiple colors. MAPM utilizes a metamaterial-coated substrate to achieve super-resolution without altering anything else in a conventional microscope, representing a simple solution for fluorescence imaging at nanometer axial resolution.

Resveratrol prevents ISO-induced myocardial remodeling associated with regulating polarization of macrophages through VEGF-B/AMPK/NF-kB pathway.

Macrophage expansion and inflammatory responses are involved in induction of cardiac remodeling. Resveratrol has strong anti-inflammatory effects, however its effect on macrophage infiltration and polarization is unknown. This study aimed to investigate the anti-inflammatory effects of RSV on ISO-induced myocardial remodeling in mice and its regulatory role in macrophage polarization. BALB/c mice were orally administered with RSV (100 mg/kg) daily for one week, then were subcutaneously injected with ISO (50 mg/kg) daily for another week. ISO injections to mouse caused cardiac dysfunction evidenced by cardiac hypertrophy and cardiomyocyte fibrosis. Meanwhile, macrophage M1 polarization was found in ISO treated mice, which was evidenced by increased percentage of Ly6Clow macrophages in the heart, levels of M1 cytokines and expression of CD68, and decreased percentage of Ly6Chigh macrophage, levels of M2 cytokines and expression of CD206. All these changes in cardiac and macrophage M1 polarization were ameliorated when mice were pretreated with RSV. The effect of RSV on macrophage polarization was also tested in RAW264.7 cells. It was found that pre-treatment with RSV decreased the levels of M1 marker or proinflammatory cytokines, while increased the levels of M2 markers in ISO treated cells. In addition, it was found that RSV could upregulate the expression of VEGF-B and the activity of AMPK, while it downregulated the expression of phosphorylated NF-κB p65 both in RAW264.7 cells and in mice. Furthermore, pretreatment with VEGF-B siRNA greatly reversed changes in almost all above parameters evoked by RSV in RAW264.7 cells. Therefore, our findings suggest RSV has potential therapeutic effects in ISO-induced myocardial injury, which may be by inhibiting the M1 polarization of macrophages through VEGFB/AMPK/NF-кB pathway.

Optical edge detection based on high-efficiency dielectric metasurface.

Optical edge detection is a useful method for characterizing boundaries, which is also in the forefront of image processing for object detection. As the field of metamaterials and metasurface is growing fast in an effort to miniaturize optical devices at unprecedented scales, experimental realization of optical edge detection with metamaterials remains a challenge and lags behind theoretical proposals. Here, we propose a mechanism of edge detection based on a Pancharatnam-Berry-phase metasurface. We experimentally demonstrated broadband edge detection using designed dielectric metasurfaces with high optical efficiency. The metasurfaces were fabricated by scanning a focused laser beam inside glass substrate and can be easily integrated with traditional optical components. The proposed edge-detection mechanism may find important applications in image processing, high-contrast microscopy, and real-time object detection on compact optical platforms such as mobile phones and smart cameras.

Facile Synthesis of Stable and Highly Luminescent Methylammonium Lead Halide Nanocrystals for Efficient Light Emitting Devices.

Metal halide perovskites are promising candidates for use in light emitting diodes (LEDs), due to their potential for color tunable and high luminescence efficiency. While recent advances in perovskite-based light emitting diodes have resulted in external quantum efficiencies exceeding 12.4% for the green emitters, and infrared emitters based on 3 D/2D mixed dimensional perovskites have exceeded 20%, the external quantum efficiencies of the red and blue emitters still lag behind. A critical issue to date is creating highly emissive and stable perovskite emitters with the desirable emission band gap to achieve full-color displays and white LEDs. Herein, we report the preparation and characterization of a highly luminescent and stable suspension of cubic-shaped methylammonium lead triiodide (CH3NH3PbI3) perovskite nanocrystals, where we synthesize the nanocrystals via a ligand-assisted reprecipitation technique, using an acetonitrile/methylamine compound solvent system to solvate the ions and toluene as the antisolvent to induce crystallization. Through tuning the ratio of the ligands, the ligand to toluene ratio, and the temperature of the toluene, we obtain a solution of CH3NH3PbI3 nanocrystals with a photoluminescence quantum yield exceeding 93% and tunable emission between 660 and 705 nm. We also achieved red emission at 635 nm by blending the nanocrystals with bromide salt and obtained perovskite-based light emitting diodes with maximum electroluminescent external quantum efficiency of 2.75%.

A Strategy for Architecture Design of Crystalline Perovskite Light-Emitting Diodes with High Performance.

All present designs of perovskite light-emitting diodes (PeLEDs) stem from polymer light-emitting diodes (PLEDs) or perovskite solar cells. The optimal structure of PeLEDs can be predicted to differ from PLEDs due to the different fluorescence dynamics and crystallization between perovskite and polymer. Herein, a new design strategy and conception is introduced, "insulator-perovskite-insulator" (IPI) architecture tailored to PeLEDs. As examples of FAPbBr3 and MAPbBr3 , it is experimentally shown that the IPI structure effectively induces charge carriers into perovskite crystals, blocks leakage currents via pinholes in the perovskite film, and avoids exciton quenching simultaneously. Consequently, as for FAPbBr3 , a 30-fold enhancement in the current efficiency of IPI-structured PeLEDs compared to a control device with poly(3,4ethylenedioxythiophene):poly(styrene sulfonate) as hole-injection layer is achieved-from 0.64 to 20.3 cd A-1 -while the external quantum efficiency is increased from 0.174% to 5.53%. As the example of CsPbBr3 , compared with the control device, both current efficiency and lifetime of IPI-structured PeLEDs are improved from 1.42 and 4 h to 9.86 cd A-1 and 96 h. This IPI architecture represents a novel strategy for the design of light-emitting didoes based on various perovskites with high efficiencies and stabilities.

Tunable Near-Infrared Luminescence in Tin Halide Perovskite Devices.

Infrared emitters are reasonably rare in solution-processed materials. Recently, research into hybrid organo-lead halide perovskite, originally popular in photovoltaics,1-3 has gained traction in light-emitting diodes (LED) due to their low-cost solution processing and good performance.4-9 The lead-based electroluminescent materials show strong colorful emission in the visible region, but lack emissive variants further in the infrared. The concerns with the toxicity of lead may, additionally, limit their wide-scale applications. Here, we demonstrate tunable near-infrared electroluminescence from a lead-free organo-tin halide perovskite, using an ITO/PEDOT:PSS/CH3NH3Sn(Br1-xIx)3/F8/Ca/Ag device architecture. In our tin iodide (CH3NH3SnI3) LEDs, we achieved a 945 nm near-infrared emission with a radiance of 3.4 W sr(-1) m(-2) and a maximum external quantum efficiency of 0.72%, comparable with earlier lead-based devices. Increasing the bromide content in these tin perovskite devices widens the semiconductor bandgap and leads to shorter wavelength emissions, tunable down to 667 nm. These near-infrared LEDs could find useful applications in a range of optical communication, sensing and medical device applications.