Activation of TAS2R4 signaling attenuates podocyte injury induced by high glucose.

Bitter taste receptors (TAS2Rs) Tas2r108 gene possesses a high abundance in mouse kidney; however, the biological functions of Tas2r108 encoded receptor TAS2Rs member 4 (TAS2R4) are still unknown. In the present study, we found that mouse TAS2R4 (mTAS2R4) signaling was inactivated in chronic high glucose-stimulated mouse podocyte cell line MPC, evidenced by the decreased protein expressions of mTAS2R4 and phospholipase C ß2 (PLCß2), a key downstream molecule of mTAS2R4 signaling. Nonetheless, agonism of mTAS2R4 by quinine recovered mTAS2R4 and PLCß2 levels, and increased podocyte cell viability as well as protein expressions of ZO-1 and nephrin, biomarkers of podocyte slit diaphragm, in high glucose-cultured MPC cells. However, blockage of mTAS2R4 signaling with mTAS2R4 blockers γ-aminobutyric acid and abscisic acid, a Gßγ inhibitor Gallein, or a PLCß2 inhibitor U73122 all abolished the effects of quinine on NLRP3 inflammasome and p-NF-κB p65 as well as the functional podocyte proteins in MPC cells in a high glucose condition. Furthermore, knockdown of mTAS2R4 with lentivirus-carrying Tas2r108 shRNA also ablated the effect of quinine on the key molecules of the above inflammatory signalings and podocyte functions in high glucose-cultured MPC cells. In summary, we demonstrated that activation of TAS2R4 signaling alleviated the podocyte injury caused by chronic high glucose, and inhibition of NF-κB p65 and NLRP3 inflammasome mediated the protective effects of TAS2R4 activation on podocytes. Moreover, activation of TAS2R4 signaling could be an important strategy for prevention and treatment of diabetic kidney disease.

In Situ Hydrogel Modulates cDC1-Based Antigen Presentation and Cancer Stemness to Enhance Cancer Vaccine Efficiency.

Effective presentation of antigens by dendritic cells (DC) is essential for achieving a robust cytotoxic T lymphocytes (CTLs) response, in which cDC1 is the key DC subtype for high-performance activation of CTLs. However, low cDC1 proportion, complex process, and high cost severely hindered cDC1 generation and application. Herein, the study proposes an in situ cDC1 recruitment and activation strategy with simultaneous inhibiting cancer stemness for inducing robust CTL responses and enhancing the anti-tumor effect. Fms-like tyrosine kinase 3 ligand (FLT3L), Poly I:C, and Nap-CUM (NCUM), playing the role of cDC1 recruitment, cDC1 activation, inducing antigen release and decreasing tumor cell stemness, respectively, are co-encapsulated in an in situ hydrogel vaccine (FP/NCUM-Gel). FP/NCUM-Gel is gelated in situ after intra-tumoral injection. With the near-infrared irradiation, tumor cell immunogenic cell death occurred, tumor antigens and immunogenic signals are released in situ. cDC1 is recruited to tumor tissue and activated for antigen cross-presentation, followed by migrating to lymph nodes and activating CTLs. Furthermore, tumor cell stemness are inhibited by napabucasin, which can help CTLs to achieve comprehensive tumor killing. Collectively, the proposed strategy of cDC1 in situ recruitment and activation combined with stemness inhibition provides great immune response and anti-tumor potential, providing new ideas for clinical tumor vaccine design.

Macrophage-camouflaged epigenetic nanoinducers enhance chemoimmunotherapy in triple negative breast cancer.

Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer (TNBC), but the clinical outcomes remain unsatisfied. Abnormal epigenetic regulation is associated with acquired drug resistance and T cell exhaustion, which is a critical factor for the poor response to chemoimmunotherapy in TNBC. Herein, macrophage-camouflaged nanoinducers co-loaded with paclitaxel (PTX) and decitabine (DAC) (P/D-mMSNs) were prepared in combination with PD-1 blockade therapy, hoping to improve the efficacy of chemoimmunotherapy through the demethylation of tumor tissue. Camouflage of macrophage vesicle confers P/D-mMSNs with tumor-homing properties. First, DAC can achieve demethylation of tumor tissue and enhance the sensitivity of tumor cells to PTX. Subsequently, PTX induces immunogenic death of tumor cells, promotes phagocytosis of dead cells by dendritic cells, and recruits cytotoxic T cells to infiltrate tumors. Finally, DAC reverses T cell depletion and facilitates immune checkpoint blockade therapy. P/D-mMSNs may be a promising candidate for future drug delivery design and cancer combination therapy in TNBC.

Iterative learning control with high-order internal model for first-order hyperbolic systems.

This paper studies the iterative learning control (ILC) algorithm for first-order hyperbolic systems. Unlike most of the ILC literature of distributed parameter systems, in the iteration domain, that require identical desired trajectories. Here the desired trajectories are iteratively varying and described by a high-order internal model (HOIM). The HOIM-based P-type ILC design is firstly introduced in this paper to the first-order hyperbolic systems, which enable the systems to achieve the perfect tracking for the iteration-varying desired trajectories on L2 space. Meanwhile, the convergence theorem of the proposed algorithm is established for first-order time-delay hyperbolic systems. Finally, simulation results testify the validity of the algorithm.

Lack of miRNA-17 family mediates high glucose-induced PAR-1 upregulation in glomerular mesangial cells.

Upregulation of thrombin receptor protease-activated receptor 1 (PAR-1) is verified to contribute to chronic kidney diseases, including diabetic nephropathy; however, the mechanisms are still unclear. In this study, we investigated the effect of PAR-1 on high glucose-induced proliferation of human glomerular mesangial cells (HMCs), and explored the mechanism of PAR-1 upregulation from alteration of microRNAs. We found that high glucose stimulated proliferation of the mesangial cells whereas PAR-1 inhibition with vorapaxar attenuated the cell proliferation. Moreover, high glucose upregulated PAR-1 in mRNA level and protein expression while did not affect the enzymatic activity of thrombin in HMCs after 48 h culture. Then high glucose induced PAR-1 elevation was likely due to the alteration of the transcription or post-transcriptional processing. It was found that miR-17 family members including miR-17-5p, -20a-5p, and -93-5p were significantly decreased among the eight detected microRNAs only in high glucose-cultured HMCs, but miR-129-5p, miR-181a-5p, and miR-181b-5p were markedly downregulated in both high glucose-cultured HMCs and equivalent osmotic press control compared with normal glucose culture. So miR-20a was selected to confirm the role of miR-17 family on PAR-1 upregulation, finding that miR-20a-5p overexpression reversed the upregulation of PAR-1 in mRNA and protein levels induced by high glucose in HMCs. In summary, our finding indicated that PAR-1 upregulation mediated proliferation of glomerular mesangial cells induced by high glucose, and deficiency of miR-17 family resulted in PAR-1 upregulation.

High glucose upregulates PAR-1 in SH-SY5Y cells via deficiency of miR-20a and miR-190a.

Thrombin activity enhancement and its receptor protease-activated receptor 1 (PAR-1) activation play vital roles in neurologic deficits in the central nervous system. Our recent study showed that PAR-1 upregulation stimulated by chronic high glucose (HG) caused central neuron injury through neuroinflammation; however, the molecular mechanisms are far from clear. In the present study, we found that HG resulted in neuronal injury of SH-SY5Y cells as evidenced by decreased cell viability and increased lactate dehydrogenase release and elevated the mRNA level of PAR-1. Moreover, we predicted and determined several potential microRNAs (miRs) combining with the 3'-UTR of PAR-1 mRNA, finding that miR-20a-5p, miR-93-5p, and miR-190a-5p were significantly decreased in HG-cultured SH-SY5Y cells compared with control. Further, SH-SY5Y cells stably transfected with miR-20a-5p or miR-190a-5p mimic were established, and overexpression efficiency were confirmed. It was found that miR-20a-5p or miR-190a-5p overexpression markedly decreased PAR-1 mRNA level and protein expression in SH-SY5Y cells cultured with HG and normal glucose, indicating that miR-20a or miR-19a deficiency contributed to HG-induced PAR-1 upregulation. Together, our findings demonstrated that PAR-1 upregulation mediated HG-induced neuronal damage in central neurons, which was achieved through miR-20a or miR-190a deficiency.

Piperine, as a TAS2R14 agonist, stimulates the secretion of glucagon-like peptide-1 in the human enteroendocrine cell line Caco-2.

Piperine is reported to ameliorate common metabolic diseases, however, its molecular mechanism is still unclear. In the present study, we examined whether piperine could stimulate glucagon-like peptide-1 (GLP-1) secretion in a human enteroendocrine cell line, Caco-2, and explored the potential mechanisms from the activation of human bitter taste receptors (TAS2Rs). It was found that TAS2R14 was highly expressed in Caco-2 cells, far more than TAS2R4 and TAS2R10. Piperine and flufenamic acid (FA, a known TAS2R14 agonist) markedly increased intracellular calcium mobilization and significantly enhanced the GLP-1 secretion, accompanied by elevated levels of proglucagon mRNA in Caco-2 cells compared with the control. Moreover, piperine and FA activated TAS2R14 signaling as evidenced by the increased mRNA and protein levels of TAS2R14, and the protein expression of its downstream key molecules including phospholipase C ß2 (PLCß2) and a transient receptor potential channel melastatin 5 (TRPM5). On the other hand, a G protein ßγ subunit inhibitor Gallein or a PLC inhibitor U73122 alleviated piperine-stimulated GLP-1 secretion in Caco-2 cells. In the meantime, a flavanone hesperetin significantly attenuated piperine and FA induced the intracellular calcium mobilization and GLP-1 secretion. Furthermore, TAS2R14 knockdown reversed the piperine-triggered up-regulation of PLCß2 and TRPM5 as well as increased the GLP-1 secretion in Caco-2 cells by TAS2R14 shRNA transfection. In summary, our findings demonstrated that piperine promoted the GLP-1 secretion from enteroendocrine cells through the activation of TAS2R14 signaling. Moreover, TAS2R14 was likely a target of piperine in the alleviation of metabolic diseases.

Plasmonic Chiral Metamaterials with Sub-10 nm Nanogaps.

Sub-10 nm nanogaps are enantioselectively fabricated between two nanocrescents based on nanoskiving and show tailored circular dichroism (CD) activity. The mirror symmetry of the nanostructure is broken by subsequent deposition with different azimuthal angles. Strong plasmonic coupling is excited in the gaps and at the tips, leading to the CD activity. The dissymmetry g-factor of the chiral nanogaps with 5 nm gap-width is -0.055, which is 2.5 times stronger than that of the 10 nm gap-width. Moreover, the surface-enhanced Raman scattering (SERS) performance of l/d-cysteine absorbed on chiral nanogaps manifests as the emergence of enantiospecific Raman peaks and the appearance of distinct changes in SERS intensities, which affirms that chiral nanogaps can recognize specific cysteine enantiomers via standard Raman spectroscopy in the absence of circularly polarized light source and a chiral label molecule. The sub-10 nm chiral nanogaps with tailored chiroptical responses show great potential in a class of chiral applications, such as chiral sensing, polarization converters, label-free chiral recognition, and asymmetric catalysis.

Sarsasapogenin attenuates Alzheimer-like encephalopathy in diabetes.

BACKGROUND: A crosstalk exists between diabetes and Alzheimer's disease (AD), and diabetic encephalopathy displays AD-like disorders. Sarsasapogenin (Sar) has strong anti-inflammatory efficacy, showing neuroprotection and memory-enhancement effects. PURPOSE: This study aims to verify the ameliorative effects of Sar on diabetic encephalopathy in vivo and in vitro, and to clarify the mechanisms from attenuation of AD-like pathology. METHODS: Streptozotocin-induced type 1 diabetic rats and high glucose-cultured SH-SY5Y cells were used in this study. After Sar treatment (20 and 60 mg/kg) for consecutive 9 weeks, Morris water maze and novel object recognition tasks were performed. Hematoxylin-eosin staining was used for examining loss of neurons in CA1 area and ki67 expression for reflecting neurogenesis in DG area of hippocampus. Aß production pathway and tau phosphorylation kinase cascade were examined in these two models. RESULTS: Sar improved learning and memory ability, loss of neurons and reduction of neurogenesis in the hippocampus of diabetic rats. Moreover, Sar suppressed Aß overproduction due to up-regulation of BACE1 in protein and mRNA and tau hyperphosphorylation from inactivation of AKT/GSK-3ß cascade in the hippocampus and cerebral cortex of diabetic rats and high glucose-cultured SH-SY5Y cells, and PPARγ antagonism abolished the effects of Sar on key molecules in the two pathways. Additionally, it was found that high glucose-stimulated Aß overproduction was prior to tau hyperphosphorylation in neurons. CONCLUSION: Sar alleviated diabetic encephalopathy, which was obtained through inhibitions of Aß overproduction and tau hyperphosphorylation mediated by the activation of PPARγ signaling. Hence, Sar is a good candidate compound for AD-like disorders.

An in situ SERS study of plasmonic nanochemistry based on bifunctional "hedgehog-like" arrays.

An in situ SERS (surface-enhanced Raman scattering) study of plasmonic nanochemistry is realized on hierarchical Ag nanocone arrays ("hedgehog-like" arrays, denoted as HLAs) without any conventional catalyst. Ag nanocones are designed on 3D polystyrene (PS) microsphere arrays to provide a high density of hot spots within the laser-illumination area. Both experiments and numerical simulations demonstrate that the remarkable SERS and plasmonic catalytic performance of HLAs arise from the improved utilization rate of irradiation light in the third dimension and the tip enhancement effect of the nanocone arrays. On further combining their inherent SERS and catalytic properties, the in situ SERS study of plasmon-induced photocatalytic degradation reactions is realized. In this paper, not only the decomposition of methylene blue (MB) molecules is observed, but also the detailed molecular mechanisms of the reactions are revealed. Based on the bifunctional properties of the membrane-material interface, the HLAs are believed to be promising candidates in SERS and in situ SERS studies.

3D zig-zag nanogaps based on nanoskiving for plasmonic nanofocusing.

We combine anisotropic wet etching and nanoskiving to create a novel three-dimensional (3D) nanoantenna for plasmonic nanofocusing, vertically aligned zig-zag nanogaps, constituted of nanogaps with defined angles. Instead of conventional lithography, we used the thickness of a self-assembled monolayer (SAM) to define nanogaps with high throughput, and anisotropic etching of Si V-grooves to naturally define ultra-sharp tips. Both nanogaps and sharp tips can synergistically squeeze the electro-magnetic (EM) field and excite 3D nanofocusing, enabling great potential applications in chemical sensing and plasmonic devices. The dependence of the EM field enhancement on structural features is systematically investigated and optimized. We found that the field enhancement and confinement are stronger at the tipped-nanogap compared to what standalone tips or nanogaps produce. The intensity of surface-enhanced Raman spectroscopy (SERS) recorded on the 70.5° tipped-nanogaps is 45 times higher than that recorded with linear nanogaps and 5 times higher than that recorded with tip-only nanowires, which is attributed to the integration of the tip and gap in plasmonic nanostructures. This proposed nanofabrication technique and the resulting structures equipped with a strongly enhanced EM field will promote broad applications for nanophotonics and surface-enhanced spectroscopy.

Broad-Range Electrically Tunable Plasmonic Resonances of a Multilayer Coaxial Nanohole Array with an Electroactive Polymer Wrapper.

Plasmonic assemblies featuring high sensitivity that can be readily shifted by external fields are the key for sensitive and versatile sensing devices. In this paper, a novel fast-responsive plasmonic nanocomposite composed of a multilayer nanohole array and a responsive electrochromic polymer is proposed with the plasmonic mode appearance vigorously cycled upon orthogonal electrical stimuli. In this nanocomposite, the coaxially stacked plasmonic nanohole arrays can induce multiple intense Fano resonances, which result from the crosstalk between a broad surface plasmon resonance (SPR) and the designed discrete transmission peaks with ultrahigh sensitivity; the polymer wrapper could provide the sensitive nanohole array with real-time-varied surroundings of refractive indices upon electrical stimuli. Therefore, a pronounced pure electroplasmonic shift up to 72 nm is obtained, which is the largest pure electrotuning SPR range to our knowledge. The stacked nanohole arrays here are also directly used as a working electrode, and they ensure sufficient contact between the working electrode (plasmonic structure) and the electroactive polymer, thus providing considerably improved response speed (within 1 s) for real-time sensing and switching.

Perforating domed plasmonic films for broadband and omnidirectional antireflection.

Domed Ag nano-hole/disk array films exhibit a reflectivity of less than 0.7% over a wide spectral range (400-1000 nm) and even lower values down to 0.05% with an oblique incidence angle; this unique optical response is attributed to three key factors: diffractive scattering loss on nanostructures, localized plasmonic absorption and curved surface (domed units).