A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis.

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger mixed lineage kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for other diseases involving GI tract inflammation.

Interferon-mediated repression of miR-324-5p potentiates necroptosis to facilitate antiviral defense.

Mixed lineage kinase domain-like protein (MLKL) is the terminal effector of necroptosis, a form of regulated necrosis. Optimal activation of necroptosis, which eliminates infected cells, is critical for antiviral host defense. MicroRNAs (miRNAs) regulate the expression of genes involved in various biological and pathological processes. However, the roles of miRNAs in necroptosis-associated host defense remain largely unknown. We screened a library of miRNAs and identified miR-324-5p as the most effective suppressor of necroptosis. MiR-324-5p downregulates human MLKL expression by specifically targeting the 3'UTR in a seed region-independent manner. In response to interferons (IFNs), miR-324-5p is downregulated via the JAK/STAT signaling pathway, which removes the posttranscriptional suppression of MLKL mRNA and facilitates the activation of necroptosis. In influenza A virus (IAV)-infected human primary macrophages, IFNs are induced, leading to the downregulation of miR-324-5p. MiR-324-5p overexpression attenuates IAV-associated necroptosis and enhances viral replication, whereas deletion of miR-324-5p potentiates necroptosis and suppresses viral replication. Hence, miR-324-5p negatively regulates necroptosis by manipulating MLKL expression, and its downregulation by IFNs orchestrates optimal activation of necroptosis in host antiviral defense.

Design, synthesis, evaluation and optimization of potent IRAK4 inhibitors alleviating production of inflammatory cytokines in LPS-induced SIRS model.

Interleukin-1 receptor associated kinase-4 (IRAK4) has emerged as a therapeutic target for inflammatory and autoimmune diseases. Through reversing the amide of CA-4948 and computer aided structure-activity relationship (SAR) studies, a series of IRAK4 inhibitors with oxazolo[4,5-b]pyridine scaffold were identified. Compound 32 showed improved potency (IC50 = 43 nM) compared to CA-4948 (IC50 = 115 nM), but suffered from hERG inhibition (IC50 = 5.7 µM). Further optimization led to compound 42 with reduced inhibition of hERG (IC50 > 30 µM) and 13-fold higher activity (IC50 = 8.9 nM) than CA-4948. Importantly, compound 42 had favorable in vitro ADME and in vivo pharmacokinetic properties. Furthermore, compound 42 significantly reduced LPS-induced production of serum TNF-α and IL-6 cytokines in the mouse model. The overall profiles of compound 42 support it as a lead for the development of IRAK4 inhibitors for the treatment of inflammatory and autoimmune disorders.

Doxorubicin sensitizes cancer cells to Smac mimetic via synergistic activation of the CYLD/RIPK1/FADD/caspase-8-dependent apoptosis.

Smac/Diablo is a pro-apoptotic protein via interaction with inhibitors of apoptosis proteins (IAPs) to relieve their inhibition of caspases. Smac mimetic compounds (also known as antagonists of IAPs) mimic the function of Smac/Diablo and sensitize cancer cells to TNF-induced apoptosis. However, the majority of cancer cells are resistant to Smac mimetic alone. Doxorubicin is a widely used chemotherapeutic drug and causes adverse effect of cardiotoxicity in many patients. Therefore, it is important to find strategies of combined chemotherapy to increase chemosensitivity and reduce the adverse effects. Here, we report that doxorubicin synergizes with Smac mimetic to trigger TNF-mediated apoptosis, which is mechanistically distinct from doxorubicin-induced cell death. Doxorubicin sensitizes cancer cells including human pancreatic and colorectal cancer cells to Smac mimetic treatment. The combined treatment leads to synergistic induction of TNFα to initiate apoptosis through activating NF-κB and c-Jun signaling pathways. Knockdown of caspase-8 or knockout of FADD significantly blocked apoptosis synergistically induced by Smac mimetic and doxorubicin, but had no effect on cell death caused by doxorubicin alone. Moreover, Smac mimetic and doxorubicin-induced apoptosis requires receptor-interacting protein kinase 1 (RIPK1) and its deubiquitinating enzyme cylindromatosis (CYLD), not A20. These in vitro findings demonstrate that combination of Smac mimetic and doxorubicin synergistically triggers apoptosis through the TNF/CYLD/RIPK1/FADD/caspase-8 signaling pathway. Importantly, the combined treatment induced in vivo synergistic anti-tumor effects in the xenograft tumor model. Thus, the combined therapy using Smac mimetic and doxorubicin presents a promising apoptosis-inducing strategy with great potential for the development of anti-cancer therapy.

Antiviral activity of mitoxantrone dihydrochloride against human herpes simplex virus mediated by suppression of the viral immediate early genes.

BACKGROUND: HSV-1 is a common pathogen that infects 50-90% of the human population worldwide. HSV-1 causes numerous infection-related diseases, some of which are severely life-threatening. There are antiviral medications with activity against HSV-1. However, with the emergence of drug-resistant mutant strains of HSV-1, there is an urgent need to develop new effective anti-HSV-1 agents. METHODS: Therefore, we screened a chemical library of approximately 1500 compounds to identify inhibitors of HSV-1-induced toxicity for further drug development. Moreover, we performed several experiments, including western blot analysis, Q-PCR analysis and luciferase activity assay, to explore the antiviral mechanism of the candidates. RESULTS: Here, we identified a small molecule, mitoxantrone dihydrochloride, with potency against HSV-1-induced toxicity. Furthermore, the viral titers and expression levels of HSV-1 viral proteins were potently reduced by the presence of MD in many cell lines. Using Q-PCR analysis, we found that MD efficiently reduced the transcription of viral genes that are essential for DNA synthesis, namely, UL5, UL9, UL29, UL30, UL42 and UL52. Notably, MD also significantly inhibited the transcription of the immediate early genes ICP0, ICP22, ICP27 and ICP47, all of which are required for the expression of early and late viral gene products. Using immunofluorescence and western blot analysis, we found that the antiviral effect of MD was independent of the activation of the NF-κB and MAPK pathways. Furthermore, we found that the reduction in the transcription of viral immediate early genes was not related to the promoter activities of ICP0. CONCLUSIONS: Therefore, the identification of compound MD as an inhibitor of toxicity induced by HSV-1 highlights its potential use in the development of novel anti-HSV-1 drugs.

Herpes Simplex Virus 1 (HSV-1) and HSV-2 Mediate Species-Specific Modulations of Programmed Necrosis through the Viral Ribonucleotide Reductase Large Subunit R1.

UNLABELLED: Receptor-interacting protein kinase 3 (RIP3) and its substrate mixed-lineage kinase domain-like protein (MLKL) are core regulators of programmed necrosis. The elimination of pathogen-infected cells by programmed necrosis acts as an important host defense mechanism. Here, we report that human herpes simplex virus 1 (HSV-1) and HSV-2 had opposite impacts on programmed necrosis in human cells versus their impacts in mouse cells. Similar to HSV-1, HSV-2 infection triggered programmed necrosis in mouse cells. However, neither HSV-1 nor HSV-2 infection was able to induce programmed necrosis in human cells. Moreover, HSV-1 or HSV-2 infection in human cells blocked tumor necrosis factor (TNF)-induced necrosis by preventing the induction of an RIP1/RIP3 necrosome. The HSV ribonucleotide reductase large subunit R1 was sufficient to suppress TNF-induced necrosis, and its RIP homotypic interaction motif (RHIM) domain was required to disrupt the RIP1/RIP3 complex in human cells. Therefore, this study provides evidence that HSV has likely evolved strategies to evade the host defense mechanism of programmed necrosis in human cells. IMPORTANCE: This study demonstrated that infection with HSV-1 and HSV-2 blocked TNF-induced necrosis in human cells while these viruses directly activated programmed necrosis in mouse cells. Expression of HSV R1 suppressed TNF-induced necrosis of human cells. The RHIM domain of R1 was essential for its association with human RIP3 and RIP1, leading to disruption of the RIP1/RIP3 complex. This study provides new insights into the species-specific modulation of programmed necrosis by HSV.

Antiviral activity of PHA767491 against human herpes simplex virus in vitro and in vivo.

BACKGROUND: Herpes simplex virus (HSV) is a common human pathogen that causes a variety of diseases, including oral-labial, genital lesions and life-threatening encephalitis. The antiviral nucleoside analogues such as acyclovir are currently used in anti-HSV therapies; however, clinical overuse of these drugs has led to the emergence of drug-resistant viral strains. Hence, there is an urgent need to develop new anti-HSV agents. METHODS: To identify novel anti-HSV-1 compounds, we screened the LOPAC small scale library of 1280 bioactive compounds to identify inhibitors of HSV-1-induced necroptosis. Further experiments including western blot analysis, Q-PCR analysis and immunohistochemistry were performed to explore the antiviral mechanism of the compounds. RESULTS: Here, we identified PHA767491 as a new inhibitor of HSV. PHA767491 potently blocked the proliferation of HSV in cells, as well as HSV induced cell death. Further, we found that PHA767491 strongly inhibited HSV infection post viral entry. Moreover, PHA767491 reduced the expression of viral genes required for DNA synthesis including UL30/42 DNA polymerase and UL5/8/52 helicase-primase complex. The essential immediate early (IE) genes such as ICP4 and ICP27 are critical for the expression of the early and late genes. Of note, PHA767491 inhibited the expression of all IE genes of both HSV-1 and HSV-2. Importantly, PHA767491 reduced viral titers in the tissues from the mice infected with HSV-1. Consistently, immunohistochemistry analysis showed that PHA767491 dramatically attenuated expression of viral protein gB in the livers. CONCLUSIONS: Taken together, PHA767491 has potent anti-HSV activity by inhibiting viral replication both in vitro and in mouse model. Thus, PHA767491 could be a promising agent for the development of new anti-HSV therapy.

Direct activation of RIP3/MLKL-dependent necrosis by herpes simplex virus 1 (HSV-1) protein ICP6 triggers host antiviral defense.

The receptor-interacting kinase-3 (RIP3) and its downstream substrate mixed lineage kinase domain-like protein (MLKL) have emerged as the key cellular components in programmed necrotic cell death. Receptors for the cytokines of tumor necrosis factor (TNF) family and Toll-like receptors (TLR) 3 and 4 are able to activate RIP3 through receptor-interacting kinase-1 and Toll/IL-1 receptor domain-containing adapter inducing IFN-ß, respectively. This form of cell death has been implicated in the host-defense system. However, the molecular mechanisms that drive the activation of RIP3 by a variety of pathogens, other than the above-mentioned receptors, are largely unknown. Here, we report that human herpes simplex virus 1 (HSV-1) infection triggers RIP3-dependent necrosis. This process requires MLKL but is independent of TNF receptor, TLR3, cylindromatosis, and host RIP homotypic interaction motif-containing protein DNA-dependent activator of IFN regulatory factor. After HSV-1 infection, the viral ribonucleotide reductase large subunit (ICP6) interacts with RIP3. The formation of the ICP6-RIP3 complex requires the RHIM domains of both proteins. An HSV-1 ICP6 deletion mutant failed to cause effective necrosis of HSV-1-infected cells. Furthermore, ectopic expression of ICP6, but not RHIM mutant ICP6, directly activated RIP3/MLKL-mediated necrosis. Mice lacking RIP3 exhibited severely impaired control of HSV-1 replication and pathogenesis. Therefore, this study reveals a previously uncharacterized host antipathogen mechanism.

The interplay between human herpes simplex virus infection and the apoptosis and necroptosis cell death pathways.

Human herpes simplex virus (HSV) is a ubiquitous human pathogen that establishes a lifelong latent infection and is associated with mucocutaneous lesions. In multicellular organisms, cell death is a crucial host defense mechanism that eliminates pathogen-infected cells. Apoptosis is a well-defined form of programmed cell death executed by a group of cysteine proteases, called caspases. Studies have shown that HSV has evolved strategies to counteract caspase activation and apoptosis by encoding anti-apoptotic viral proteins such as gD, gJ, Us3, LAT, and the ribonucleotide reductase large subunit (R1). Recently, necroptosis has been identified as a regulated form of necrosis that can be invoked in the absence of caspase activity. Receptor-interacting kinase 3 (RIP3 or RIPK3) has emerged as a central signaling molecule in necroptosis; it is activated via interaction with other RIP homotypic interaction motif (RHIM)-containing proteins such as RIP1 (or RIPK1). There is increasing evidence that HSV R1 manipulates necroptosis via the RHIM-dependent inactivation or activation ofRIP3 in a species-specific manner. This review summarizes the current understanding of the interplay between HSV infection and cell death pathways, with an emphasis on apoptosis and necroptosis.

Engineering Triple-Phase Interfaces around the Anode toward Practical Alkali Metal-Air Batteries.

Alkali metal-air batteries (AMABs) promise ultrahigh gravimetric energy densities, while the inherent poor cycle stability hinders their practical application. To address this challenge, most previous efforts are devoted to advancing the air cathodes with high electrocatalytic activity. Recent studies have underlined the solid-liquid-gas triple-phase interface around the anode can play far more significant roles than previously acknowledged by the scientific community. Besides the bottlenecks of uncontrollable dendrite growth and gas evolution in conventional alkali metal batteries, the corrosive gases, intermediate oxygen species, and redox mediators in AMABs cause more severe anode corrosion and structural collapse, posing greater challenges to the stabilization of the anode triple-phase interface. This work aims to provide a timely perspective on the anode interface engineering for durable AMABs. Taking the Li-air battery as a typical example, this critical review shows the latest developed anode stabilization strategies, including formulating electrolytes to build protective interphases, fabricating advanced anodes to improve their anti-corrosion capability, and designing functional separator to shield the corrosive species. Finally, the remaining scientific and technical issues from the prospects of anode interface engineering are highlighted, particularly materials system engineering, for the practical use of AMABs.

Restructuring Electrolyte Solvation by a Versatile Diluent Toward Beyond 99.9% Coulombic Efficiency of Sodium Plating/Stripping at Ultralow Temperatures.

The reversible and durable operation of sodium metal batteries at low temperatures (LT) is essential for cold-climate applications but is plagued by dendritic Na plating and unstable solid-electrolyte interphase (SEI). Current Coulombic efficiencies of sodium plating/stripping at LT fall far below 99.9%, representing a significant performance gap yet to be filled. Here, the solvation structure of the conventional 1 m NaPF6 in diglyme electrolyte by facile cyclic ether (1,3-dioxolane, DOL) dilution is efficiently reconfigured. DOL diluents help shield the Na+-PF6 - Coulombic interaction and intermolecular forces of diglyme, leading to anomalously high Na+-ion conductivity. Besides, DOL participates in the solvation sheath and weakens the chelation of Na+ by diglyme for facilitated desolvation. More importantly, it promotes concentrated electron cloud distribution around PF6 - in the solvates and promotes their preferential decomposition. A desired inorganic-rich SEI is generated with compositional uniformity, high ionic conductivity, and high Young's modulus. Consequently, a record-high Coulombic efficiency over 99.9% is achieved at an ultralow temperature of -55 °C, and a 1 Ah capacity pouch cell of initial anode-free sodium metal battery retains 95% of the first discharge capacity over 100 cycles at -25 °C. This study thus provides new insights for formulating electrolytes toward increased Na reversibility at LT.

Porous Polymer Materials for CO2 Capture and Electrocatalytic Reduction.

Efficient capture of CO2 and its conversion into other high value-added compounds by electrochemical methods is an effective way to reduce excess CO2 in the atmosphere. Porous polymeric materials hold great promise for selective adsorption and electrocatalytic reduction of CO2 due to their high specific surface area, tunable porosity, structural diversity, and chemical stability. Here, we review recent research advances in this field, including design of porous organic polymers (POPs), porous coordination polymers (PCPs), covalent organic frameworks (COFs), and functional nitrogen-containing polymers for capture and electrocatalytic reduction of CO2. In addition, key issues and prospects for the optimal design of porous polymers for future development are elucidated. This review is expected to shed new light on the development of advanced porous polymer electrocatalysts for efficient CO2 reduction.

Synthesis and evaluation of dihydrofuro[2,3-b]pyridine derivatives as potent IRAK4 inhibitors.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key regulator to control downstream NF-κB and MAPK signals in the innate immune response and has been proposed as a therapeutic target for the treatment of inflammatory and autoimmune diseases. Herein, a series of IRAK4 inhibitors based on a dihydrofuro[2,3-b]pyridine scaffold was developed. Structural modifications of the screening hit 16 (IC50 = 243 nM) led to IRAK4 inhibitors with improved potency but high clearance (Cl) and poor oral bioavailability, as exemplified by compound 21 (IC50 = 6.2 nM, Cl = 43 ml/min/kg, F = 1.6%, LLE = 5.4). Structure modification aimed at improving LLE and reducing clearance identified compound 38. Compound 38 showed significantly improved clearance while maintained excellent biochemical potency against IRAK4 (IC50 = 7.3 nM, Cl = 12 ml/min/kg, F = 21%, LLE = 6.0). Importantly, compound 38 had favorable in vitro safety and ADME profiles. Furthermore, compound 38 reduced the in vitro production of pro-inflammatory cytokines in both mouse iBMDMs and human PBMCs and was orally efficacious in the inhibition of serum TNF-α secretion in LPS-induced mouse model. These findings suggested that compound 38 has development potential as an IRAK4 inhibitor for the treatment of inflammatory and autoimmune disorders.

Discovery of a novel RIPK2 inhibitor for the treatment of inflammatory bowel disease.

Nucleotide-binding oligomerization domain-containing protein 1 and 2 (NOD 1/2) are important cytosolic pattern recognition receptors that initiate host immune response. The dysregulation of NOD signaling is highly associated with inflammatory bowel disease (IBD) that needs novel treatment options. Receptor-interacting protein kinase 2 (RIPK2) is a critical mediator of NOD signaling and considered a promising therapeutic target for IBD treatment. However, there are currently no RIPK2 inhibitors available for clinical use. Here, we report the discovery and characterization of Zharp2-1 as a novel and potent RIPK2 inhibitor that effectively blocks RIPK2 kinase function and NOD-mediated NF-κB/MAPK activation in both human and mouse cell lines. Zharp2-1 exhibits significantly superior solubility compared to the non-prodrug form of the advanced RIPK2 inhibitor prodrug GSK2983559. The improved solubility combined with favorable in vitro metabolic stability translated to excellent in vivo pharmacokinetic profiles for Zharp2-1. In addition, Zharp2-1 demonstrates better effects than GSK2983559 in inhibiting the muramyl dipeptide (MDP)-induced production of pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs) and MDP-induced peritonitis in mice. Furthermore, Zharp2-1 markedly reduces Listeria monocytogenes infection-induced cytokines release in both human and mouse cells. Importantly, Zharp2-1 significantly ameliorates DNBS-induced colitis in rats and suppressed pro-inflammatory cytokine release in intestinal specimens from IBD patients. Collectively, our findings indicate that Zharp2-1 is a promising RIPK2 inhibitor with the potential to be further developed for IBD therapy.

Inhibition of lysosome-tethered Ragulator-Rag-3D complex restricts the replication of Enterovirus 71 and Coxsackie A16.

Enterovirus 71 (EV71) and Coxsackie A16 (CVA16) are two major causative agents of hand, foot, and mouth disease (HFMD) in young children. However, the mechanisms regulating the replication and pathogenesis of EV71/CVA16 remain incompletely understood. We performed a genome-wide CRISPR-Cas9 knockout screen and identified Ragulator as a mediator of EV71-induced apoptosis and pyroptosis. The Ragulator-Rag complex is required for EV71 and CVA16 replication. Upon infection, the Ragulator-Rag complex recruits viral 3D protein to the lysosomal surface through the interaction between 3D and RagB. Disruption of the lysosome-tethered Ragulator-Rag-3D complex significantly impairs the replication of EV71/CVA16. We discovered a novel EV71 inhibitor, ZHSI-1, which interacts with 3D and significantly reduces the lysosomal tethering of 3D. ZHSI-1 treatment significantly represses replication of EV71/CVA16 as well as virus-induced pyroptosis associated with viral pathogenesis. Importantly, ZHSI-1 treatment effectively protects against EV71 infection in neonatal and young mice. Thus, our study indicates that targeting lysosome-tethered Ragulator-Rag-3D may be an effective therapeutic strategy for HFMD.

Facile preparation of flexible binder-free graphene electrodes for high-performance supercapacitors.

A facile two-step strategy to prepare flexible graphene electrodes has been developed for supercapacitors using thermal reduction of graphene oxide (GO) and thermally reduced graphene oxide (TRGO) composite films. The tunable porous structure of the GO/TRGO film provided channels to release the high pressure generated by CO2 gas. The graphene electrode obtained from reduced-GO/TRGO (1 : 1 in mass ratio) film showed great flexibility and high film density (0.52 g cm-3). Using the EMI-BF4 electrolyte with a working voltage of 3.7 V, the as-fabricated free-standing reduced-GO/TRGO (1 : 1) film achieved a great gravimetric capacitance of 180 F g-1 (delivering a gravimetric energy density of 85.6 W h kg-1), a volumetric capacitance of 94 F cm-3 (delivering a volumetric energy density of 44.7 W h L-1), and a 92% retention after 10 000 charge/discharge cycles. In addition, the solid state flexible supercapacitor with the free-standing reduced-GO/TRGO (1 : 1) film as the electrodes and the EMI-BF4/poly (vinylidene fluoride hexafluopropylene) (PVDF-HFP) gel as the electrolyte also demonstrated a high gravimetric capacitance of 146 F g-1 with excellent mechanical flexibility, bending stability, and electrochemical stability. The strategy developed in this study provides great potentials for the synthesis of flexible graphene electrodes for supercapacitors.

A Diluted Electrolyte for Long-Life Sulfurized Polyacrylonitrile-Based Anode-Free Li-S Batteries.

Lithium-metal batteries have attracted extensive research attention because of their high energy densities. Developing appropriate electrolytes compatible with lithium-metal anodes is of great significance to facilitate their practical application. Currently used electrolytes still face challenges of high production costs and unsatisfactory Coulombic efficiencies of lithium plating/stripping. In this research, we have developed a diluted electrolyte which is compatible with both lithium-metal anode and sulfurized polyacrylonitrile cathode. It presents a very high Li plating/stripping Coulombic efficiency of 99.3% over prolonged cycling, and the as-assembled anode-free Li-S battery maintains 71.5% of the initial specific capacity after 200 cycles at 0.1 A g-1. This work could shed light on designing a low-cost and high-performance liquid electrolyte for next-generation high-energy batteries.

Functional Polymer Materials for Advanced Lithium Metal Batteries: A Review and Perspective.

Lithium metal batteries (LMBs) are promising next-generation battery technologies with high energy densities. However, lithium dendrite growth during charge/discharge results in severe safety issues and poor cycling performance, which hinders their wide applications. The rational design and application of functional polymer materials in LMBs are of crucial importance to boost their electrochemical performances, especially the cycling stability. In this review, recent advances of advanced polymer materials are examined for boosting the stability and cycle life of LMBs as different components including artificial solid electrolyte interface (SEI) and functional interlayers between the separator and lithium metal anode. Thereafter, the research progress in the design of advanced polymer electrolytes will be analyzed for LMBs. At last, the major challenges and key perspectives will be discussed for the future development of functional polymers in LMBs.

Effect of porous structural properties on lithium-ion and sodium-ion storage: illustrated by the example of a micro-mesoporous graphene1-x (MoS2) x anode.

In this work, we synthesized micro-mesoporous graphene1-x (MoS2) x with different compositional ratios via co-reduction of graphite oxide and exfoliated MoS2 platelets. We systematically studied the performance of the micro-mesoporous graphene1-x (MoS2) x as anodes in lithium-ion batteries and sodium-ion batteries. The results show that the specific surface areas of the composites decrease with introducing MoS2. The irreversible capacitance, which is related to the formation of solid electrolyte interphases, also decreases. Besides specific surface area, we found that micropores can benefit the lithiation and sodiation. We demonstrated that a specific charge capacity of 1319.02 mA h g-1 can be achieved at the 50th cycle for the graphene½(MoS2)½ anode in lithium-ion batteries. Possible relationships between such a high specific capacity and the micro-mesoporous structure of the graphene1-x (MoS2) x anode are discussed. This work may shed light on a general strategy for the structural design of electrode materials in lithium-ion batteries and sodium-ion batteries.

Optimization of microwave-assisted extraction followed by RP-HPLC for the simultaneous determination of oleanolic acid and ursolic acid in the fruits of Chaenomeles sinensis.

An optimized microwave-assisted extraction (MAE) method and an efficient HPLC analysis method were developed for fast extraction and simultaneous determination of oleanolic acid and ursolic acid in the fruit of Chaenomeles sinensis. The open vessel MAE process was optimized by using a central composite experimental design. The optimal conditions identified were microwave power 600 W, temperature 52 degrees C, solvent to material ratio 32 mL/g and extraction time 7 min. The results showed that MAE is a more rapid extraction method with higher yield and lower solvent consumption. The HPLC-photodiode array detection analysis method was validated to have good linearity, precision, reproduction and accuracy. Compared with conventional extraction and analysis methods, MAE-HPLC-photodiode array detection is a faster, convenient and appropriate method for determination of oleanolic acid and ursolic acid in the fruits of C. sinensis.