Ferulic acid (FA) has potential therapeutic effects in multiple diseases including cardiovascular diseases. However, the effect and molecular basis of FA in heart failure (HF) has not been thoroughly ...elucidated. Herein, we investigated the roles and mechanisms of FA in HF in isoproterenol (ISO)-induced HF rat model. Results found that FA ameliorated cardiac dysfunction, alleviated oxidative stress, reduced cell/myocardium injury-related enzyme plasma level, inhibited cardiocyte apoptosis in ISO-induced HF rat models. Moreover, FA reduced the co-localization of Keap1 and nuclear factor-E2-related factor 2 (Nrf2) in heart tissues of ISO-induced HF rats, and FA alleviated the inhibitory effects of ISO on expressions of p-Nrf2, heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (NQO1). Additionally, Nrf2 signaling pathway inhibitor ML385 showed adverse effects. FA weakened the effects of ML385 in ISO-induced HF rat models. Collectively, FA ameliorated HF by decreasing oxidative stress and inhibiting cardiocyte apoptosis via activating Nrf2 pathway in ISO-induced HF rats. Our data elucidated the underling molecular mechanism and provided a novel insight into the cardioprotective function of FA, thus suggested the therapeutic potential of FA in HF treatment.
Metabolite lactic acid has always been regarded as a metabolic by-product rather than a bioactive molecule. Recently, this view has changed since it was discovered that lactic acid can be used as a ...signal molecule and has novel signal transduction functions both intracellular and extracellular, which can regulate key functions in the immune system. In recent years, more and more evidence has shown that lactic acid is closely related to the metabolism and polarization of macrophages. During inflammation, lactic acid is a regulator of macrophage metabolism, and it can prevent excessive inflammatory responses; In malignant tumors, lactic acid produced by tumor tissues promotes the polarization of tumor-associated macrophages, which in turn promotes tumor progression. In this review, we examined the relationship between lactic acid and macrophage metabolism. We further discussed how lactic acid plays a role in maintaining the homeostasis of macrophages, as well as the biology of macrophage polarization and the M1/M2 imbalance in human diseases. Potential methods to target lactic acid in the treatment of inflammation and cancer will also be discussed so as to provide new strategies for the treatment of diseases.
The sp2‐hybridized nanocarbon (e.g., carbon nanotubes (CNTs) and graphene) exhibits extraordinary mechanical strength and electrical conductivity but limited external accessible surface area and a ...small amount of pores, while nanostructured porous carbon affords a huge surface area and abundant pore structures but very poor electrical conductance. Herein the rational hybridization of the sp2 nanocarbon and nanostructured porous carbon into hierarchical all‐carbon nanoarchitectures is demonstrated, with full inherited advantages of the component materials. The sp2 graphene/CNT interlinked networks give the composites good electrical conductivity and a robust framework, while the meso‐/microporous carbon and the interlamellar compartment between the opposite graphene accommodate sulfur and polysulfides. The strong confinement induced by micro‐/mesopores of all‐carbon nanoarchitectures renders the transformation of S8 crystal into amorphous cyclo‐S8 molecular clusters, restraining the shuttle phenomenon for high capacity retention of a lithium‐sulfur cell. Therefore, the composite cathode with an ultrahigh specific capacity of 1121 mAh g−1 at 0.5 C, a favorable high‐rate capability of 809 mAh g−1 at 10 C, a very low capacity decay of 0.12% per cycle, and an impressive cycling stability of 877 mAh g−1 after 150 cycles at 1 C. As sulfur loading increases from 50 wt% to 77 wt%, high capacities of 970, 914, and 613 mAh g−1 are still available at current densities of 0.5, 1, and 5 C, respectively. Based on the total mass of packaged devices, gravimetric energy density of GSH@APC‐S//Li cell is expected to be 400 Wh kg−1 at a power density of 10 000 W kg−1, matching the level of engine driven systems.
3D interconnected graphene/CNT networks are coated with porous carbon. The sp2 graphene/CNT interlinked network gives the composites good electrical conductivity and a robust framework, while the meso‐/microporous carbon and the interlamellar compartment between the opposite graphene accommodate sulfur and polysulfides, provide accessibility for liquid electrolyte to active materials, and restrain the shuttle phenomenon.
All‐solid‐state (ASS) lithium metal batteries (LMBs) are considered the most promising next‐generation batteries due to their superior safety and high projected energy density. To access the ...practically desired high energy density of ASS LMBs, an ultrathin solid‐state electrolyte (SSE) film with fast ion‐transport capability presents as an irreplaceable component to reduce the proportion of inactive materials in ASS batteries. In this contribution, an ultrathin (60 µm), flexible, and free‐standing argyrodite (Li6PS5Cl) SSE film is designed through a self‐limited strategy. A chemically compatible cellulose membrane is employed as the self‐limiting skeleton that not only defined the thinness of the sulfide SSE film but also strengthened its mechanical properties. The ionic conductivity of the SSE film reaches up to 6.3 × 10−3 S cm−1 at room temperature, enabling rapid lithium‐ion transportation. The self‐limited SSE thin films are evaluated in various ASS LMBs with different types of cathode (sulfur and lithium titanate) and anode materials (lithium and lithium‐indium alloy) at both mold‐cell and pouch‐cell levels, demonstrating a stable performance and high‐rate capability. This study provides a general strategy for the rational design of an SSE thin film towards high‐energy‐density ASS batteries.
An ultrathin, flexible, and free‐standing argyrodite solid‐state electrolyte film is designed through a self‐limited strategy. The ionic conductivity of the SSE film reaches up to 6.3 × 10−3 S cm−1 at room temperature, enabling rapid lithium‐ion transportation in all‐solid‐state batteries.
The construction of multi‐stereocenters by a transition metal‐catalyzed cross‐coupling reaction is a major challenge. The catalytic desymmetric functionalization of unactivated alkenes remains ...largely unexplored. Herein, we disclose ‐a desymmetric dicarbofunctionalization of 1,6‐dienes via a nickel‐catalyzed reductive cross‐coupling reaction. The leverage of the underdeveloped chiral 8‐Quinox enables the Ni‐catalyzed desymmetric carbamoylalkylation of both unactivated mono‐ and disubstituted alkenes to form pyrrolidinone bearing two nonadjacent stereogenic centers in high enantio‐ and stereoselectivitives with broad functional‐group tolerance. The synthetic application of pyrrolidinones allows the rapid access to complex chiral fused‐heterocycles.
The desymmetric dicarbofunctionalization of unactivated alkenes by a nickel‐catalyzed reductive cross‐coupling reaction has been developed to access pyrrolidinones bearing multi‐stereocenters with broad functional‐group tolerance. The utilization of the 8‐Quinox ligand is crucial for maintaining high enantio‐ and stereoselectivities.
In this study, we determined and genetically characterized three fowl adenoviruses isolated from chickens with inclusion body hepatitis (IBH) and hydropericardium syndrome (HPS) in China and assessed ...their pathogenicity. The full genome of HBQ12, BJH13 and JSJ13 was found to be 44,081, 43,966 and 43,756 nucleotides long, respectively. Sequence alignment and phylogenetic analysis revealed that strain HBQ12 and BJH13 were clustered together belonging to fowl adenoviruses D species and serotyped as FAdV-11, whereas strain JSJ13 was classified into fowl adenoviruses C species and serotyped as FAdV-4. To our knowledge, this is the first report of FAdV-4 strain circulating in China. The pathogenicity test showed that mortality for chickens infected with HBQ12 and JSJ13 within 21 days post infection (dpi) was 8.6% and 28.6%, respectively. Necropsy displayed mild or severe hepatitis and hydropericardium at 3 and 5 dpi as well as dead chickens. Viral DNA was detected in almost all tissues sampled from dead chickens. These results revealed that fowl adenovirus strains HBQ12 and JSJ13 are capable of causing IBH and HPS in chickens, indicating that preventive measures against FAdV infection on poultry farms should be implemented in China.
Emerging evidence suggests that epithelial‐mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is ...crucial for improving treatment of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play important roles in HCC; however, the mechanisms by which miRNAs target the EMT and their therapeutic potential remains largely unknown. To better explore the roles of miRNAs in the EMT process, we established an EMT model in HCC cells by transforming growth factor beta 1 treatment and found that several tumor‐related miRNAs were significantly decreased. Among these miRNAs, miR‐125b expression was most strongly suppressed. We also found down‐regulation of miR‐125b in most HCC cells and clinical specimens, which correlated with cellular differentiation in HCC patients. We then demonstrated that miR‐125b overexpression attenuated EMT phenotype in HCC cancer cells, whereas knockdown of miR‐125b promoted the EMT phenotype in vitro and in vivo. Moreover, we found that miR‐125b attenuated EMT‐associated traits, including chemoresistance, migration, and stemness in HCC cells, and negatively correlated with EMT and cancer stem cell (CSC) marker expressions in HCC specimens. miR‐125b overexpression could inhibit CSC generation and decrease tumor incidence in the mouse xenograft model. Mechanistically, our data revealed that miR‐125b suppressed EMT and EMT‐associated traits of HCC cells by targeting small mothers against decapentaplegic (SMAD)2 and 4. Most important, the therapeutic delivery of synthetic miR‐125b mimics decreased the target molecule of CSC and inhibited metastasis in the mice model. These findings suggest a potential therapeutic treatment of miR‐125b for liver cancer. Conclusion: miR‐125b exerts inhibitory effects on EMT and EMT‐associated traits in HCC by SMAD2 and 4. Ectopic expression of miR‐125b provides a promising strategy to treat HCC. (Hepatology 2015;62:801–815)
Accumulating evidence suggests that Ras GTPase‐activating protein SH3 domain‐binding protein 1 (G3BP1) is very crucial to regulate tumorigenesis and metastasis. Recently, many research works have ...suggested that G3BP1 is overexpressed in many human cancers including esophageal cancer. Nevertheless, the functional roles of G3BP1 in esophageal cancer are still unknown. Here, the results suggested that silencing of G3BP1 inhibited proliferation, migration, and invasion of esophageal cancer cells, whereas overexpression of G3BP1 led to opposite effects on the growth and metastasis. Surprisingly, G3BP1‐depletion had no effect on cell death but caused the arrest of cell cycle in the G0/G1 phase and increased the levels of p53 and p21. In addition, loss of G3BP1 led to a significant elevation of E‐cadherin and decrease of N‐cadherin, Vimentin, Snail, MMP‐9, and MMP‐2. Mechanistically, loss of G3BP1 dramatically suppressed Wnt‐stimulated T‐cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor activity and downregulated its target genes including c‐Myc, Axin2, and cyclin D1. Moreover, knockdown of G3BP1 downregulated the expression levels of p‐PI3K, p‐AKT, and p‐GSK‐3β, but the total PI3K, AKT, and GSK‐3β were not changed. Furthermore, our data proved that the promoting effects of G3BP1‐overexpression on cell proliferation, migration, and invasion could be rescued by PI3K inhibitor LY294002 treatment. Collectively, our results here elucidate that G3BP1‐depletion suppresses proliferation, migration, and invasion capabilities of esophageal cancer cells via the inactivation of Wnt/β‐catenin and PI3K/AKT signaling pathways. Furthermore, our findings imply that G3BP1 can participate in the regulation of esophageal cancer progression, and will be taken as a promising target to treat esophageal cancer.
In our study, we investigated the effects of GTPase‐activating protein SH3 domain‐binding protein 1‐depletion (G3BP1) on cell proliferation, cell cycle, cell death, migration, and invasion of esophageal cancer cells. Our results demonstrated that knockdown of G3BP1 gave rise to inhibition of esophageal cancer cell proliferation, migration, invasion, epithelial‐mesenchymal transition, and cell cycle arrest in the G0/G1 phase through suppressing Wnt/β‐catenin and PI3K/AKT signaling pathways, whereas overexpression of G3BP1 led to opposite the effects on proliferation, migration, and invasion. Our data suggest that G3BP1 plays a crucial role in esophageal cancer progression, and may be a novel prognostic marker and potential therapeutic target for esophageal cancer.
Long noncoding RNAs (lncRNAs) are emerging as important regulators of multiple cellular processes such as cell invasion, growth, apoptosis and differentiation. LncRNAs can function as competing ...endogenous RNAs (ceRNAs) which sponge and sequester microRNA (miRNA) to regulate specific targets. Previously, we found that the target genes of several miRNAs, including FADD, Fas, Casp and Bax, are related to neuronal apoptosis and form a regulatory network. Among several factors, microRNA‐296‐5p expression was found to be negatively correlated with caspase activity and apoptosis. Here, we aimed to investigate the role of miR‐296‐5p in neuroblastoma (NB) cells. By performing quantitative real‐time PCR (qRT‐PCR), western blot and flow cytometry assays we analysed the expression of apoptotic markers in NB cells transfected with miR‐296‐5p mimics or inhibitor. Pathway‐specific PCR array allowed us to identify the target genes of miR‐296‐5p. Using LncBase online tool, we predicted lncRNA KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) as an upstream regulator of miR‐296‐5p. The binding of KCNQ1OT1 and miR‐296‐5p was validated via RNA immunoprecipitation and Biotin pull‐down assays. We also demonstrate that miR‐296‐5p suppresses apoptosis of NB cells in vitro and in vivo. Mechanistically, miR‐296‐5p directly bound the 3′UTR of Bax mRNA, thus repressing Bax at the mRNA and protein level. Moreover, through bioinformatic analysis and molecular experiments, we showed that KCNQ1OT1 sponged miR‐296‐5p and impaired its effect on NB cell apoptosis. In summary, KCNQ1OT1 is a potent promoting factor of cell apoptosis, which acts by sponging miR‐296‐5p and upregulating Bax. Our findings identify a regulatory axis of cell fate in NB cells.
Increasing evidence shows that long noncoding RNAs (lncRNAs) can function as competing endogenous RNAs by sponging microRNAs in a sequence‐specific manner and impairing their functions of binding and suppressing target mRNAs. Through bioinformatic analysis and subsequent molecular experiments, we implied that lncRNA KCNQ1 opposite strand/antisense transcript 1 promotes Bax expression and neuroblastoma cells apoptosis by direct binding with miR‐296‐5p.
Self-healing capability helps biological systems to maintain their survivability and extend their lifespan. Similarly, self-healing is also beneficial to next-generation secondary batteries because ...high-capacity electrode materials, especially the cathodes such as oxygen or sulfur, suffer from shortened cycle lives resulting from irreversible and unstable phase transfer. Herein, by mimicking a biological self-healing process, fibrinolysis, we introduced an extrinsic healing agent, polysulfide, to enable the stable operation of sulfur microparticle (SMiP) cathodes. An optimized capacity (∼3.7 mAh cm–2) with almost no decay after 2000 cycles at a high sulfur loading of 5.6 mg(S) cm–2 was attained. The inert SMiP is activated by the solubilization effect of polysulfides whereas the unstable phase transfer is mediated by mitigated spatial heterogeneity of polysulfides, which induces uniform nucleation and growth of solid compounds. The comprehensive understanding of the healing process, as well as of the spatial heterogeneity, could further guide the design of novel healing agents (e.g., lithium iodine) toward high-performance rechargeable batteries.
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