Rabeprazole mitigates obesity-induced chronic inflammation and insulin resistance associated with increased M2-type macrophage polarization.

Macrophage polarization is closely associated with obesity-induced chronic inflammation and insulin resistance. Proton pump inhibitor Rabeprazole has long been used to treat gastritis and gastric ulcers. However, whether Rabeprazole plays a role in macrophage polarization during obesity is unknown. Here, we show that Rabeprazole suppresses M1-type macrophage-mediated inflammation, leads to increased M2-type macrophages and alters the polarization status from M1 to M2 in vitro. Mechanistically, Rabe-regulated macrophage polarization is associated with inhibition of NF-κB and activation of STAT6 signaling pathways. Furthermore, Rabeprazole induces M2-type adipose tissue macrophages and alleviates chronic inflammation, improving glucose tolerance and insulin sensitivity in high-fat diet-fed mice. In addition, Rabeprazole increases CD206+ M2-type liver macrophages and relieves liver inflammation, alleviating liver injury and lipid accumulation. Thus, our findings show that Rabeprazole effectively regulates macrophage polarization and controls obesity-associated chronic inflammation and insulin resistance, thus providing a potential therapeutic strategy against obesity-associated metabolic diseases.

Proton pump inhibitors enhance macropinocytosis-mediated extracellular vesicle endocytosis by inducing membrane v-ATPase assembly.

Besides participating in diverse pathological and physiological processes, extracellular vesicles (EVs) are also excellent drug-delivery vehicles. However, clinical drugs modulating EV levels are still lacking. Here, we show that proton pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis-mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI-induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI-induced macropinocytosis also increases doxorubicin and antisense oligonucleotides of microRNA-155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug-loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v-ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v-ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.

A neural network-assisted 3D theoretical thermoelastic solution for laminated liquid crystal elastomer plate used in restoring cardiac mechanical function.

Some atrial contractile assist devices applied on the heart surface can be regarded as a laminated Liquid crystal elastomer (LCE) plate under steady temperature loads and a contact mechanical force. An exact solution for the deformation of the laminated LCE plate under combined thermal and mechanical loads is derived by solving the three-dimensional (3D) equilibrium equations including heat conduction and thermoelastic theory. The validity of mathematical formula and computer programming is proved by convergence and comparison examples with finite element method (FEM). In order to simplify the complex calculation of exact solution, a back propagation neural network (BPNN) is further trained with a database containing 9504 sets of thermo-mechanical load conditions and their corresponding deformation which is solved by the exact solutions. Then the deformations of LCE plate subject to combined thermo-mechanical load can be predicted by this BP neural network instead of complex numerical calculation. Moreover, it is also applied to inverse the contact mechanical force at the bottom surface of LCE plate with a given deformation and temperature conditions. The results show that: (1) The results from the exact theoretical solution are in consistence with that from FEM but have a higher computational efficiency and stability; (2) The deformation of the laminated plate is more sensitive to the layered thickness of LCE than the variation of the temperature; (3) 3-D elasticity solutions of a laminated LCE plate under the combined thermos-mechanical load can be effectively predicted by a trained BP neural network.

Prediction of mechanical solutions for a laminated LCEs system fusing an analytical model and neural networks.

This paper presents a convenient and efficient method to predict the mechanical solutions of a laminated Liquid Crystal Elastomers (LCEs) system subjected to combined thermo-mechanical load, based on a back propagation (BP) neural network which is trained by machine learning from a database established by analytical solutions. Firstly, the general solutions of temperature, displacement, and stress of any single layer in the LCEs system are obtained by solving the two-dimensional (2D) governing equations of both heat conduction and thermoelasticity. Then, the unknown coefficients in above general solutions are determined by a transfer-matrix method based on the continuity condition at the interface of adjacent layers and the combined thermo-mechanical loads condition at the surface of the LCEs system. The formula derivation and calculator program are verified through convergence studies and comparisons with FEM results. Finally, a database with displacements of LCEs system in a temperature field subjected to 561 sets of mechanical loads is established based on the presented analytical model. The BP neural network based on above database is further applied to establish the relationship between deformation and mechanical load to predict the elastic deformation of the LCEs system in a temperature field subjected to a mechanical load. Moreover, the BP network can also inverse the coefficients of mechanical load which induces the specific deformation in a temperature field. The numerical examples show that: (1) The deformation of a laminated LCEs system due to thermal load is limited within the range of human temperature changes from 36 °C to 40 °C. (2) The thickness of the LCE is a sensitive parameter on the deformation at the bottom surface of the system. (3) The accuracy of predicted displacements induced by the thermo-mechanical load and the inversed mechanical load based on deformation of the LCEs system in a temperature field using BP neural network reaches 99.6% and 98.5% respectively.

Dynamic prediction of optical and chromatic performances for a light-emitting diode array based on a thermal-electrical-spectral model.

Light-emitting diode (LED) arrays have attracted increased attention in the area of high power intelligent automotive headlamps because of their superiority in disposing of the power limit of an individual LED package and controllably luminous intensity and illumination pattern. The optical and chromatic performances of an LED array do not equal to the sum of individual LED packages' performances, as the thermal interactions between individual LED packages can't be ignored in the actual application. This paper presents a thermal-electrical-spectral (TES) model to dynamically predict the optical and chromatic performances of the LED array. The thermal-electrical (TE) model considering the thermal coupling effect in the LED array is firstly proposed to predict the case temperature of each individual LED package, and the Spectral power distributions (SPDs) of individual LED package is then decomposed by the extended Asym2sig model to extract the spectral characteristic parameters. Finally, the experimental measurements of the designed LED arrays operated under usage conditions are used to verify the TES model. Some validation case studies show that the prediction accuracy of the proposed TES model, which is expressed as a quadratic polynomial function of current and case temperature, can be achieved higher than 95%. Therefore, it can be concluded that this TES model offers a convenient method with high accuracy to dynamically predict the optical and chromatic performances of LED arrays at real usages.

The barley miR393 has multiple roles in regulation of seedling growth, stomatal density, and drought stress tolerance.

microRNA393 (miR393) and its target module have been implicated as comprising a conserved mechanism to regulate developmental processes and plant growth in response to environmental signals through the auxin signaling pathway. Our previous work identified miR393 and its two targets in barley. In this study, we further investigated the expression pattern of miR393 and its biological functions in seedling growth and drought tolerance. We showed that the miR393 overexpressing line (OE) exhibited increased stomatal density with decreased guard cell length, while the miR393 knockdown line (MIM) displayed the opposite phenotype, which might be due to the effects of miR393 on AUXIN RESPONSE FACTOR5 (ARF5) and three stomatal development-related genes, such as EPIDERMAL PATTERNING FACTOR1 (EPF1), SPEECHLESS (SPCH), and MUTE. In addition, the MIM line conferred enhanced drought tolerance, with alleviated leaf chlorosis and lipid peroxidation after 22 days drought treatment. In contrast, the OE line was more sensitive to drought stress and accumulated more malondialdehyde and hydrogen peroxide than the wild type. Furthermore, polyethylene glycol (PEG) treatment-induced abscisic acid (ABA) accumulation in leaves was suppressed in the OE line, indicating that miR393 might regulate drought stress response and tolerance through its interaction with ABA biosynthesis. Overall, these data suggest that miR393 might be a potential target for manipulation of stomatal density and improvement of drought tolerance in barley.

Epigenetic regulation of miR396 expression by SWR1-C and the effect of miR396 on leaf growth and developmental phase transition in Arabidopsis.

In this study, we investigated the regulatory function of miR396 in the phase transition in Arabidopsis thaliana. Using AtMIR396a/b knockout mutants generated through clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-directed genome editing, we showed that miR396 negatively regulates the leaf size and vegetative phase transition, and the first leaf with abaxial trichomes appeared earlier in the mir396ab double mutant than in the wild type (WT) and was significantly delayed in miR396 overexpression lines. Moreover, mir396ab exhibited early flowering, whereas 35S:MIR396a/b and cib4-1 delayed flowering, and the flowering time was negatively correlated with FT gene expression. Furthermore, in arp6 and pie1 mutants, which are deficient in the ATP-dependent chromatin remodeling complex (SWR1-C), miR396 expression was significantly repressed. Compared with the WT, reduced H2A.Z deposit and stronger relative nucleosome occupancy in the promoter region of MIR396a was found in the arp6 mutant, indicating that SWR1-C contributes to the transcriptional activation of MIR396a via nucleosome dynamics. In addition, miR396 displayed specific spatio-temporal expression patterns in the leaf, which was altered in arp6 and pie1, and therefore affected the transcript levels of CIB4 and FT in these mutants. We propose that miR396 is not only a marker of cell differentiation, but also an age signal for leaf development and phase change. Meanwhile, SWR1-C-mediated epigenetic regulation contributes to the age-dependent enhancement of miR396 expression and differential miR396 accumulation among leaves.

A barley homolog of yeast ATG6 is involved in multiple abiotic stress responses and stress resistance regulation.

Autophagy is a highly conserved degradation pathway among eukaryote cells, which can recycle damaged or unwanted cell materials upon encountering stress conditions. As a key component of the Class III PI3K kinase complex, ATG6/Beclin-1 is essential for autophagosome formation. In this study, we isolated a putative HvATG6 gene in barley genome. The protein encoded by HvATG6 shares high sequence identity to ATG6 orthologs in rice and wheat, and has a typical autophagy-specific domain containing segments of repeated ß-sheet-α-helix. The expression of HvATG6 protein restored the appearance of autophagosomes in yeast atg6 mutant, indicating that HvATG6 complements the deficiency of yeast ATG6 protein in autophagy. Punctate florescence signals, considered as the PAS for autophagosome initiation, were observed in the cytoplasm of cells when HvATG6-GFP fusion construct was transformed into barley protoplast. Furthermore, the expression of HvATG6 was upregulated by various abiotic stresses including dark, H2O2 treatment, nitrogen deficiency, high salinity, drought, low temperature and toxic aluminum. Knockdown of HvATG6 in barley leaves through barley strip mosaic virus (BSMV)-induced gene silencing led to accelerated yellowing under dark and H2O2 treatments. Based on the above findings, we propose that barley ATG6 plays the similar role as other plant ATG6 orthologs, and might be involved in stress-induced autophagy process.