An Ultrathin Composite Polymer Electrolyte Dual-Reinforced by a Polymer of Intrinsic Microporosity (PIM-1) and Poly(tetrafluoroethylene) (PTFE) Porous Membrane.

The performances of solid-state polymer electrolytes are urgently required to be further improved for high energy density lithium metal batteries. Herein, a highly reinforced ultrathin composite polymer electrolyte (PLPP) is successfully fabricated in a large scale by densely filling the well-dispersed mixture of polyethylene oxide (PEO), Li-salt (LiTFSI) and a polymer of intrinsic microporosity (PIM-1) into porous poly(tetrafluoroethylene) (PTFE) matrix. Based on the macro-plus-micro synergistic enhancement of the PTFE with excellent mechanical properties and the soluble PIM-1 with suitable functional groups, the PLPP electrolyte exhibits excellent properties including mechanical stress, thermal stability, lithium-ion transference number, voltage window and ionic conductivity, which are all superior to the typical PEO/LiTFSI electrolytes. As a result, the Li/PLPP/Li symmetric cell can stably cycle for > 2000 h, and the LiFePO4/PLPP/Li full cell exhibits excellent rate performance (>10 C) and high cycling stability with an initial capacity of 158.8 mAh g-1 and a capacity retention of 78.8% after 300 cycles. In addition, the excellent mechanical properties as well as the wide voltage window reasonably result in the stable operation of full cells with either high-loading cathode up to 28.1 mg cm-2 or high voltage cathode with high energy density.

Structural optimizations on the 7H-pyrrolo[2,3-d]pyrimidine scaffold to develop highly selective, safe and potent JAK3 inhibitors for the treatment of Rheumatoid arthritis.

Janus Kinase 3 (JAK3) is important for the signaling transduction of cytokines in immune cells and is identified as potential target for treatment of rheumatoid arthritis (RA). Recently, we designed and synthesized two JAK3 inhibitors J1b and J1f, which featured with high selectivity but mild bioactivity. Therefore, in present study the structure was optimized to increase the potency. As shown in the results, most of the compounds synthesized showed stronger inhibitory activities against JAK3 in contrast to the lead compounds, among which 9a was the most promising candidate because it had the most potent effect in ameliorating carrageenan-induced inflammation of mice and exhibited low acute in vivo toxicity (MTD > 2 g/kg). Further analysis revealed that 9a was highly selective to JAK3 (IC50 = 0.29 nM) with only minimal effect on other JAK members (>3300-fold) and those kinases bearing a thiol in a position analogous to that of Cys909 in JAK3 (>150-fold). Meanwhile, the selectivity of JAK3 was also confirmed by PBMC stimulation assay, in which 9a irreversibly bound to JAK3 and robustly inhibited the signaling transduction with mild suppression on other JAKs. Moreover, it was showed that 9a could remarkably inhibited the proliferation of lymphocytes in response to concanavalin A and significantly mitigate disease severity in collagen induced arthritis. Therefore, present data indicate that compound 9a is a selective JAK3 inhibitor and could be a promising candidate for clinical treatment of RA.

Design and synthesis of highly selective Janus kinase 3 covalent inhibitors for the treatment of rheumatoid arthritis.

Selective inhibition of Janus kinase 3 (JAK3) is a promising strategy for the treatment of autoimmune diseases. Based on the discovery of a hydrophobic pocket unutilized between the lead compound RB1 and the JAK3 protein, a series of covalent JAK3 inhibitors were prepared by introducing various aromatic fragments to RB1. Among them, J1b (JAK3 IC50 = 7.2 nM, other JAKs IC50 > 1000 nM) stood out because of its low toxicity (MTD > 2 g/kg) and superior anti-inflammatory activity in Institute of Cancer Research mice. Moreover, the acceptable bioavailability (F% = 31.69%) ensured that J1b displayed excellent immune regulation in collagen-induced arthritis mice, whose joints in the high-dose group were almost recovered to a normal state. Given its clear kinase selectivity (Bmx IC50 = 539.9 nM, other Cys909 kinases IC50 > 1000 nM), J1b was nominated as a highly selective JAK3 covalent inhibitor, which could be used to safely treat arthritis and other autoimmune diseases.

Dimensionality reduction induced synergetic optimization of the thermoelectric properties in Bi2Si2X6 (X = Se, Te) monolayers.

Different from three-dimensional bulk compounds, two-dimensional monolayer compounds exhibit much better thermoelectric performance on account of the quantum confinement and interface effect. Here, we present a systematic study on the electronic and thermal transport properties of bulk and monolayer Bi2Si2X6 (X = Se, Te) through theoretical calculations using density functional theory based on first-principles and Boltzmann transport theory. Monolayer Bi2Si2X6 are chemically, mechanically and thermodynamically stable semiconductors with suitable band gaps, and they have lower lattice thermal conductivity (κL) in the a/b direction than their bulk counterparts. The calculated κL of monolayer Bi2Si2Se6 (Bi2Si2Te6) is as low as 0.72 (0.95) W m-1 K-1 at 700 K. Moreover, monolayer Bi2Si2X6 exhibit a higher Seebeck coefficient compared with bulk Bi2Si2X6 owing to the sharper peaks in the electronic density of states (DOS). This results in a significant increase in power factor by dimensionality reduction. Combined with the synergetically suppressed thermal conductivity, the maximum ZT values for monolayer Bi2Si2Se6 and Bi2Si2Te6 are significantly enhanced up to 5.03 and 2.87 with p-type doping at 700 K, which are more than 2 times that of the corresponding bulk compounds. These results demonstrate the superb thermoelectric performance of monolayer Bi2Si2X6 for promising thermoelectric conversion applications.

miR-31-5p modulates cell progression in lung adenocarcinoma through TNS1/p53 axis.

OBJECTIVE: To clarify the modulatory mechanism of miR-31-5p in lung adenocarcinoma (LUAD) progression in vivo and in vitro. METHODS: The Cancer Genome Atlas (TCGA) database was employed to access LUAD-related miRNA and mRNA expression data. Downstream targets of miR-31-5p were predicted by public databases. The interaction between miR-31-5p and TNS1 was determined by dual-luciferase reporter assay. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to measure miR-31-5p and TNS1 expression levels in LUAD cells. Western blot was introduced to test protein expression levels of TNS1, p53, and apoptosis-related proteins. In-vitro functional assays were conducted to evaluate the biological effects of miR-31-5p on cell proliferation, colony formation, migration, and apoptosis. In-vivo tumor xenograft experiment was applied to examine the effects of miR-31-5p on LUAD tumor growth, followed by immunochemistry assays for assessing TNS1 and p53 expression levels in the tumor tissue. RESULTS: miR-31-5p was prominently upregulated in LUAD tissue and was identified to present a similar trend in LUAD cell lines H1299, H23, and A549. miR-31-5p overexpression exerted an active role in cell proliferation and migration, but it suppressed cell apoptosis. Additionally, a reverse correlation between miR-31-5p and TNS1 regarding the expression level was identified, and TNS1 was verified to be a direct target of miR-31-5p. Besides, it was further validated by the rescue experiments that the tumor-promoting effects of miR-31-5p on LUAD cell functions were attenuated by TNS1 overexpression to some extent. The results based on the tumor xenograft experiment revealed that LUAD cell growth could be facilitated by miR-31-5p via the TNS1/p53 axis. CONCLUSION: miR-31-5p facilitates LUAD cell progression mediated by the TNS1/p53 axis.

Theoretical Study of Small Molecules Adsorption on Pristine and Transition Metal Doped GeSe Monolayer for Gas Sensing Application.

By using first-principles calculations, the sensing properties of pristine and transition metal (TM) atoms (Ti, V, and Co) embedded germanium selenide (GeSe) monolayer toward small gas molecules (H2, NH3, CO, O2, SO2, NO, and NO2) were investigated. The adsorption energies, electronic structure, optical properties, and recovery time of the adsorption systems were calculated and analyzed in detail. The results indicate that TM doped GeSe has stronger interaction with gas molecules compared with the pristine GeSe monolayer. Especially for Ti- and V-GeSe monolayer, the absolute value of adsorption energies are up to 2 eV for O2, NO, and NO2. The doping with TM atoms also changes the charge transfer and electronic structures of adsorption systems. Combined with the result of the calculated optical properties and recovery time, it can be concluded that Ti-GeSe monolayer has great potential for NH3 detection, while Co-GeSe monolayer can be very promising SO2 gas sensors.

Connexin32 ameliorates epithelial-to-mesenchymal-transition in diabetic renal tubular via inhibiting NOX4.

Renal tubulointerstitial fibrosis (RIF), characterized by epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells (TECs), is the main cause of diabetic renal fibrosis. Oxidative stress plays a pivotal role in the development of diabetic RIF. Connexin32 (Cx32), prominently expressed in renal TECs, has emerged as an important player in the regulation of oxidative stress. However, the role of Cx32 in diabetic RIF has not been explored yet. Here, we showed that adenovirus-mediated Cx32 overexpression suppressed EMT to ameliorate RIF and renal function in STZ-induced diabetic mice, while knockout (KO) of Cx32 exacerbated RIF in diabetic mice. Moreover, overexpression of Cx32 inhibited EMT and the production of extra cellular matrix (ECM) in high glucose (HG) induced NRK-52E cells, whereas knockdown of Cx32 showed the opposite effects. Furthermore, we showed that NOX4, the main source of ROS in renal tubular, was down-regulated by Cx32. Mechanistically, Cx32 down-regulated the expression of PKC alpha in a carboxyl-terminal-dependent manner, thereby inhibiting the phosphorylation at Thr147 of p22phox triggered by PKC alpha, which ultimately repressed the formation of the p22phox-NOX4 complex to reduce the protein level of NOX4. Thus, we establish Cx32 as a novel target and confirm the protection mechanism in RIF.

ß-Ga2O3: a potential high-temperature thermoelectric material.

The thermoelectric properties of intrinsic n-type ß-Ga2O3 are evaluated by first-principles calculations combined with Boltzmann transport theory and relaxation time approximation. The electron mobility is predicted by considering polar optical phonon scattering in ß-Ga2O3. A temperature power law of T-0.67 is obtained for the intrinsic electron mobility. Due to the ultra-wide band gap of 4.7-4.9 eV, ß-Ga2O3 has a large Seebeck coefficient. As a result, a maximum power factor of 3.1 × 10-3 W m-1 K-2 is obtained at 1600 K. A clear anisotropy in lattice thermal conductivity is observed, with the highest thermal conductivity of 23.1 W m-1 K-1 at 300 K along the [010] direction, and a lower value of 13.2 and 12.2 W m-1 K-1 along the [001] and [100] directions, respectively. A high ZT value of 1.07 at 1600 K can be obtained at the optimal carrier concentration of 2.4 × 1019 cm-3, which is superior to that of most other oxides such as ZnO. In addition, the lattice thermal conductivity can be reduced by precisely adjusting the grain size, and the lattice thermal conductivity at 300 K (1600 K) can be reduced by 73% (39%) when the grain size is decreased to 10 nm. The excellent thermoelectric properties of ß-Ga2O3 have promoted its potential application in the field of high temperature thermoelectric conversion.

Polarization-sensitive switchable display through critical coupling between graphene and a quasi-BIC.

Enhanced light-matter interaction of a local field is of prime importance in optics as it can improve the performance of nanophotonic devices. Such enhancement can be achieved by utilizing the optical bound states in the continuum (BICs). In this study, a dielectric metasurface is proposed that could enhance the light-matter interactions in graphene. A symmetry-protected BIC was observed in such a metasurface, which could transform into a quasi-BIC with a high quality (Q-) factor when the in-plane symmetry is broken. As the graphene monolayer was introduced into the system, its absorption was enhanced by the quasi-BIC resonance. By optimizing the graphene Fermi energy and the asymmetry parameter of the metasurface to satisfy the critical-coupling condition, a tunable absorber could be achieved. The absorbing intensity could be efficiently modulated by varying the polarization direction of the incident light, the maximum difference of which was up to 95.4%. Also, further investigation showed that such a feature indicates potential application in digital switches and image displays, which could be switched by incident polarization only, and therefore without dependence on an additional structural change.

Interfacial Engineering of Bi19Br3S27 Nanowires Promotes Metallic Photocatalytic CO2 Reduction Activity under Near-Infrared Light Irradiation.

Developing highly efficient photocatalysts to utilize solar radiation for converting CO2 into solar fuels is of great importance for energy sustainability and carbon neutralization. Herein, through an alkali-etching-introduced interface reconstruction strategy, a nanowire photocatalyst denoted as V-Bi19Br3S27, with rich Br and S dual-vacancies and surface Bi-O bonding introduced significant near-infrared (NIR) light response, has been developed. The as-obtained V-Bi19Br3S27 nanowires exhibit a highly efficient metallic photocatalytic reduction property for converting CO2 into CH3OH when excited solely under NIR light irradiation. Free of any cocatalyst and sacrificial agent, metallic defective V-Bi19Br3S27 shows 2.3-fold higher CH3OH generation than Bi19Br3S27 nanowires. The detailed interfacial structure evolution and reaction mechanism have been carefully illustrated down to the atomic scale. This work provides a unique interfacial engineering strategy for developing high-performance sulfur-based NIR photocatalysts for photon reducing CO2 into alcohol for achieving high-value solar fuel chemicals, which paves the way for efficiently using the solar radiation energy extending to the NIR range to achieve the carbon neutralization goal.

Significant improvement in thermoelectric performance of SnSe/SnS via nano-heterostructures.

In this work, we study theoretically the electronic and phonon transport properties of heterojunction SnSe/SnS, bilayer SnSe and SnS. The energy filtering effect caused by the nano heterostructure in SnSe/SnS induces an increase in the Seebeck coefficient, causing a large power factor. We calculate the phonon relaxation time and lattice thermal conductivity κL for the three structures; the heterogeneous nanostructure could effectively reduce κL due to the enhanced phonon boundary scattering at interfaces. The average κL notably reduces from around 3.3 (3.2) W m-1 K-1 for bilayer SnSe (SnS) to nearly 2.2 W m-1 K-1 for SnSe/SnS at 300 K. As a result, the average ZT (ZTave in b and c directions) reaches 1.63 with temperature range around 300-800 K, which is improved by 63% (25%) compared with that of bilayer SnSe (SnS). Our theoretical results show that the heterogeneous nanostructure is an innovative approach for improving the Seebeck coefficient and significantly reducing κL, effectively enhancing thermoelectric properties.

Role of ultramicropores in the remarkable gas storage in hypercrosslinked polystyrene networks studied by positron annihilation.

In this paper, hypercrosslinked polystyrene (HCLPS) networks were synthesized by radical bulk polymerization and Friedel-Crafts alkylation reactions using vinylbenzyl-co-divinylbenzene chloride (VBC-DVB) as the precursors. A series of HCLPS was prepared with varying content of DVB from 0 to 10% in the precursor. Both N2 adsorption and positron annihilation measurements reveal micropores in the HCLPS. Especially, the existence of ultramicropores with a size in the range of 0.63-0.7 nm is confirmed by positron lifetime measurements. With increasing DVB content from 0 to 10%, the number of ultramicropores shows a gradual increase. Both the H2 and CO2 adsorption capacity increase monotonously with the increase of the DVB content. With 10% DVB in the HCLPS, the H2 storage increases to 10.3 mmol g-1 (2.05 wt%) at 77 K and 1 bar and the CO2 capture reaches 2.81 mmol g-1 (12.4 wt%) at 273 K and 1 bar. The remarkable gas storage ability is ascribed to the existence of the ultramicropores, which result in a stronger affinity to the gas molecules. By using positrons as a new probe for the pores, our results provide convincing evidence of the role of ultramicropores in the gas adsorption performance in microporous organic polymers.

CCDC102B functions in centrosome linker assembly and centrosome cohesion.

The proteinaceous centrosome linker is an important structure that allows the centrosome to function as a single microtubule-organizing center (MTOC) in interphase cells. However, the assembly mechanism of the centrosome linker components remains largely unknown. In this study, we identify CCDC102B as a new centrosome linker protein that is required for maintaining centrosome cohesion. CCDC102B is recruited to the centrosome by C-Nap1 (also known as CEP250) and interacts with the centrosome linker components rootletin and LRRC45. CCDC102B decorates and facilitates the formation of rootletin filaments. Furthermore, CCDC102B is phosphorylated by Nek2A (an isoform encoded by NEK2) and is disassociated from the centrosome at the onset of mitosis. Together, our findings reveal a molecular role for CCDC102B in centrosome cohesion and centrosome linker assembly.This article has an associated First Person interview with the first authors of the paper.

Optical Fermi level-tuned plasmonic coupling in a grating-assisted graphene nanoribbon system.

A novel graphene-based grating-coupled metamaterial structure is proposed, and the optical response of this structure can be obviously controlled by the Fermi level, which is theoretically regulated by the electric field of an applied voltage. The upper graphene monolayer can be intensely excited with the aid of periodic grating and thus it can be considered a bright mode. Meanwhile, the lower graphene monolayer cannot be directly excited, but it could be indirectly activated by the help of bright mode. The plasmonic polaritons resulting from the light-graphene interaction resonance can lead to a destructive interference effect, leading to a plasmonic induced transparency. This structure has a simple construction and retains the integrity of graphene. In the meantime, it can achieve a good tuning effect by adjusting the voltage regulation of microstructure array and it can obtain an outstanding reflection efficiency. Thus, this graphene-based metamaterial structure with these properties is very suitable for the plasmonic optical reflector. In contacting with the characteristics of material, the group delay of this device can reach to 0.3ps, which can well match the slow light performance. Therefore, the device is expected to make some contribution in optical reflection and slow light devices.

Gentiopicroside activates the bile acid receptor Gpbar1 (TGR5) to repress NF-kappaB pathway and ameliorate diabetic nephropathy.

Our previous studies indicated that the G-protein-coupled bile acid receptor, Gpbar1 (TGR5), inhibits inflammation by inhibiting the NF-κB signalling pathway, eventually attenuating diabetic nephropathy (DN). Gentiopicroside (GPS), the main active secoiridoid glycoside of Gentiana manshurica Kitagawa, has been demonstrated to inhibit inflammation in various diseases via inhibiting the inflammatory signalling pathways. However, whether GPS inhibits the NF-κB signalling pathway by activating TGR5 and regulates the pathological progression of diabetic renal fibrosis requires further investigation. In this study, we found that GPS significantly reversed the downregulation of TGR5 and inhibited the overproduction of fibronectin (FN), transforming growth factor ß1 (TGF-ß1), intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in glomerular mesangial cells (GMCs) exposed to high glucose (HG). Additionally, GPS prevented the phosphorylation and degradation of IκBα, and subsequently inhibited the activation of the NF-κB signalling pathway. Further investigation found that GPS enhanced the stabilization of IκBα by promoting the interaction of ß-arrestin2 with IκBα via TGR5 activation, which contributed to the inhibition of NF-κB signalling pathway. Importantly, the depletion of TGR5 blocked the inhibition of the NF-κB signalling pathway and reversed the downregulation of FN, ICAM-1, VCAM-1 and TGF-ß1 by GPS in HG-induced GMCs. Moreover, GPS increased the TGR5 protein levels and promoted the interaction between IκBα and ß-arrestin2, thereby inhibiting the reduction of IκBα and blocked NF-κB p65 nuclear translocation in the kidneys of STZ-induced diabetic mice. Collectively, these data suggested that GPS regulates the TGR5-ß-arrestin2-NF-κB signalling pathway to prevent inflammation in the kidneys of diabetic mice, and ultimately ameliorates the pathological progression of diabetic renal fibrosis.

Strongly coupled evenly divided disks: a new compact and tunable platform for plasmonic Fano resonances.

Plasmonic artificial molecules are promising platforms for linear and nonlinear optical modulation at various regimes including the visible, infrared and terahertz bands. Fano resonances in plasmonic artificial structures are widely used for controlling spectral lineshapes and tailoring of near-field and far-field optical response. Generation of a strong Fano resonance usually relies on strong plasmon coupling in densely packed plasmonic structures. Challenges in reproducible fabrication using conventional lithography significantly hinders the exploration of novel plasmonic nanostructures for strong Fano resonance. In this work, we propose a new class of plasmonic molecules with symmetric structure for Fano resonances, named evenly divided disk, which shows a strong Fano resonance due to the interference between a subradiant anti-bonding mode and a superradiant bonding mode. We successfully fabricated evenly divided disk structures with high reproducibility and with sub-20 nm gaps, using our recently developed sketch and peel lithography technique. The experimental spectra agree well with the calculated response, indicating the robustness of the Fano resonance for the evenly divided disk geometry. Control experiments reveal that the strength of the Fano resonance gradually increases when increasing the number of split parts on the disk from three to eight individual segments. The Fano-resonant plasmonic molecules that can also be reliably defined by our unique fabrication approach open up new avenues for application and provide insight into the design of artificial molecules for controlling light-matter interactions.

High thermoelectric performance of topological half-Heusler compound LaPtBi achieved by hydrostatic pressure.

The topological phase transition and thermoelectric performance of LaPtBi under hydrostatic pressure up to 34.6 GPa have been systematically investigated using first-principles calculations based on density functional theory. The results indicate that the band structure can be tuned by applying hydrostatic pressure. As the energy band gap is opened under the hydrostatic pressure, a topological phase transition occurs in this material, changing from a topologically nontrivial semimetal to a trivial semiconductor. In addition, the hydrostatic pressure also has a remarkable effect on the thermoelectric properties of the topological half-Heusler compound LaPtBi. Though the lattice thermal conductivity shows a continuous increase with increasing hydrostatic pressure, the power factor is greatly enhanced due to the increase of the Seebeck coefficient. As a result, a maximum ZT value of 1.74 at 1000 K is achieved in n-type LaPtBi under pressure of 21.0 GPa. It is obvious that the thermoelectric figure of merit of LaPtBi is far beyond that of state-of-the-art half-Heusler thermoelectric materials, such as ZrNiSn, FeNbSb and TiCoSb. The realization of high thermoelectric performance in the half-Heusler compound LaPtBi under hydrostatic pressure could provide a new way to further explore other topological thermoelectric materials.

Microscopic origin of the extremely low thermal conductivity and outstanding thermoelectric performance of BiSbX3 (X = S, Se) revealed by first-principles study.

In this paper, we performed comprehensive investigations of both the thermal and electrical transport properties of BiSbSe3 and BiSbS3 by using first-principles calculations and Boltzmann transport theory. Due to the repulsion between the lone-pair electrons of Sb and the p orbital of Se(S), both BiSbSe3 and BiSbS3 show strong anharmonicity with Grüneisen parameters of 1.90 and 1.79, respectively. As a result, these two materials possess extremely low lattice thermal conductivities. Meanwhile, both BiSbSe3 and BiSbS3 exhibit similar anisotropic thermal transport behaviors, which is due to the smaller phonon group velocities along the a axis. The predicted highest ZT values at 750 K are 2.9 for n-type BiSbSe3 and 1.2 for p-type BiSbS3. Our calculations provide insights into the origin of the extremely low thermal conductivity in BiSbSe3 and BiSbS3, which is meaningful for exploiting high performance thermoelectric materials with low thermal conductivity.

PAQR3 regulates phosphorylation of FoxO1 in insulin-resistant HepG2 cells via NF-κB signaling pathway.

Insulin resistance is a significant feature of type 2 diabetes mellitus and glucose and lipid metabolism disorders. Activation of NF-κB signaling pathway plays an important role in the formation of insulin resistance. FoxO1 plays a major role in regulating glucose and lipid metabolism, as well as insulin signaling pathway. Previous studies have shown that Progestin and AdipoQ Receptor 3 (PAQR3) suppresses the activity of PI3K/Akt, which is an upstream pathway of FoxO1, and additionally promotes the pathological process of diabetic renal inflammatory fibrosis via activating NF-κB pathway. On this basis, it has caused us great concern whether NF-κB is involved in PAQR3 regulation of FoxO1 under insulin resistance. In this study, we aimed to investigate whether PAQR3 regulates phosphorylation of FoxO1 via NF-κB pathway in palmitic acid (PA)-induced insulin-resistant HepG2 cells, thereby causing glucose and lipid metabolism disorders. We found that PA stimulation and PAQR3 overexpression decreased the phosphorylation of FoxO1 and the expressions of glucokinase (GCK) and low density lipoprotein receptor (LDLR), in addition, promoted the nuclear accumulation of NF-κB. Inhibition of NF-κB pathway increased the phosphorylation of FoxO1 and the expressions of GCK and LDLR which were downregulated by PA stimulation and PAQR3 overexpression. Taken together, in PA-induced insulin-resistant HepG2 cells, PAQR3 might regulate the phosphorylation of FoxO1 and the expressions of GCK and LDLR through NF-κB pathway, thereby regulating the glucose and lipid metabolism disorders induced by insulin resistance.

Polydatin attenuates renal fibrosis in diabetic mice through regulating the Cx32-Nox4 signaling pathway.

We previously found that polydatin could attenuate renal oxidative stress in diabetic mice and improve renal fibrosis. Recent evidence shows that NADPH oxidase 4 (Nox4)-derived reactive oxygen species (ROS) contribute to inflammatory and fibrotic processes in diabetic kidneys. In this study we investigated whether polydatin attenuated renal fibrosis by regulating Nox4 in vitro and in vivo. In high glucose-treated rat glomerular mesangial cells, polydatin significantly decreased the protein levels of Nox4 by promoting its K48-linked polyubiquitination, thus inhibited the production of ROS, and eventually decreasing the expression of fibronectin (FN) and intercellular adhesion molecule-1 (ICAM-1), the main factors that exacerbate diabetic renal fibrosis. Overexpression of Nox4 abolished the inhibitory effects of polydatin on FN and ICAM-1 expression. In addition, the expression of Connexin32 (Cx32) was significantly decreased, which was restored by polydatin treatment. Cx32 interacted with Nox4 and reduced its protein levels. Knockdown of Cx32 abolished the inhibitory effects of polydatin on the expression of FN and ICAM-1. In the kidneys of streptozocin-induced diabetic mice, administration of polydatin (100 mg·kg-1·d-1, ig, 6 days a week for 12 weeks) increased Cx32 expression and reduced Nox4 expression, decreased renal oxidative stress levels and the expression of fibrotic factors, eventually attenuating renal injury and fibrosis. In conclusion, polydatin promotes K48-linked polyubiquitination and degradation of Nox4 by restoring Cx32 expression, thereby decreasing renal oxidative stress levels and ultimately ameliorating the pathological progress of diabetic renal fibrosis. Thus, polydatin reduces renal oxidative stress levels and attenuates diabetic renal fibrosis through regulating the Cx32-Nox4 signaling pathway.