Stabilized Li-Rich Layered Oxide Cathode by a Spontaneously Formed Yb and Oxygen-Vacancy Rich Layer on the Surface.

Li-rich layered oxides (LLOs) are among the most promising cathode materials with high theoretical specific capacity (>250 mAh g-1 ). However, capacity decay and voltage hysteresis due tostructural degradation during cycling impede the commercial application of LLOs. Surface engineering and element doping are two methods widely applied tomitigate the structural degradation. Here, it is found that trace amount lanthanide element Yb doping can spontaneously form a surficial Yb-rich layer with high density of oxygen vacancy on the LLO-0.3% Yb (Li1.2 Mn0.54 Co0.13-x Ybx Ni0.13 O2 where x = 0.003) cathodes, which mitigating lattice oxygen loss and the non-preferred layered-to-spinel-to-rock salt tri-phase transition. Meanwhile, there are also some Yb ions doped into the lattice of LLO, which enhance the binding energy with oxygen and stabilize the lattice in grain interior during cycling. The dual effects of Yb doping greatly mitigate the structure degradation during cycling, and facilitate fast diffusion of lithium ions. As a result, the LLO-0.3% Yb sample achieves significantly improved cycling stability, with a capacity retention of 84.69% after 100 cycles at 0.2 C and 84.3% after 200 cycles at 1 C. These finding shighlight the promising rare element doping strategy that can have both surface engineering and doping effects in preparing LLO cathodes with high stability.

Blockade of ASIC1a inhibits acid-induced rat articular chondrocyte senescence through regulation of autophagy.

Acid-sensitive ion channel 1a (ASIC1a), which is abundant in chondrocytes, can sense changes in extracellular acidification. Our previous data demonstrated that ASIC1a is involved in acid-induced rat articular chondrocyte damage in osteoarthritis; however, its specific mechanisms remain unclear. The present study aims to explore the role of ASIC1a in rat articular chondrocyte senescence. RNA-seq transcriptome analysis identified senescence-associated secretory phenotype and matrix metalloproteinases genes were overexpressed by extracellular acidification (pH 6.0) in rat articular chondrocytes. An increase in senescence-associated ß-galactosidase and senescence-related markers p16, p21 and p53 was observed in the pH 6.0-treated group compared with the control group. Acid-induced senescence-related markers could be blocked by the ASIC1a-specific inhibitor psalmotoxin-1 in rat articular chondrocytes and human immortalized C28/I2 chondrocyte cell lines. Moreover, our results showed that extracellular acidification increased autophagosomes and the autophagy-related proteins LC3B-II and Beclin-1; these effects could also be reversed by psalmotoxin-1 treatment, indicating ASIC1a participated in acid-induced chondrocyte autophagy. Blocking ASIC1a-mediated autophagy with chloroquine also inhibited senescence-related markers, decreased ROS expression, and restored cell membrane potential induced by pH 6.0 treatment. Taken together, these findings suggested that ASIC1a may be involved in acid-induced rat articular chondrocyte senescence by activating autophagy, which provides a potential therapeutic strategy for the treatment of osteoarthritis.

Immunomodulatory functions of TRPM7 and its implications in autoimmune diseases.

An autoimmune disease is an inappropriate response to one's tissues due to a break in immune tolerance and exposure to self-antigens. It often leads to structural and functional damage to organs and systemic disorders. To date, there are no effective interventions to prevent the progression of autoimmune diseases. Hence, there is an urgent need for new treatment targets. TRPM7 is an enzyme-coupled, transient receptor ion channel of the subfamily M that plays a vital role in pathologic and physiologic conditions. While TRPM7 is constitutively activated under certain conditions, it can regulate cell migration, polarization, proliferation and cytokine secretion. However, a growing body of evidence highlights the critical role of TRPM7 in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and diabetes. Herein, we present (a) a review of the channel kinase properties of TRPM7 and its pharmacological properties, (b) discuss the role of TRPM7 in immune cells (neutrophils, macrophages, lymphocytes and mast cells) and its upstream immunoreactive substances, and (c) highlight TRPM7 as a potential therapeutic target for autoimmune diseases.

Systemic pharmacological verification of Baixianfeng decoction regulating TNF-PI3K-Akt-NF-κB pathway in treating rheumatoid arthritis.

Traditional Chinese medicine has a long history of treating complex diseases, especially for the conditioning of systemic diseases. It has been reported that Baixianfeng (BXF) decoction used to treat rheumatoid arthritis (RA) may be due to its systemic regulatory effect, but the specific mechanism still remains to be elucidated. The research philosophy and methods of systemic pharmacology were used to explore the mechanism of BXF decoction in treating RA in this study. TCMSP database was used to search the ingredients of BXF decoction and screen the ADME parameters. The parameter index was set as OB ≥ 30%, DL ≥ 0.18, HL ≥ 4 h. The targets of the screened compounds were searched and predicted by TCMSP and Target-Prediction platforms. The disease targets of RA were obtained through the DisGeNET, OMIM, and PharmGkb databases. A series of network construction and analysis relied on Cytoscape 3.2.1 software, and the DAVID database was used for pathway enrichment. The adjuvant arthritis rat model was used for the verification of animal experiments to verify the predicted pathway results in terms of pathological phenotype, inflammatory factors, and pathway protein expression. The results showed that the related targets of 81 active ingredients in the drug crossed 56 targets of RA, and these common targets were enriched in 83 significant pathways, among which the TNF signaling pathway had research significance. Animal experiments have proved that BXF decoction was effective in treating adjuvant arthritis rats. The drug relieved the pathological phenotype of rats in dose-dependent. It reduced the serum content of TNF-α and IL-1ß, and reduced the gene expression of TNF-α and IL-6 in spleen tissue. In the cartilage tissue protein of rats, it inhibited the degradation of collagen Ⅱ protein. Further, BXF decoction reduced the activation of p-PI3K, p-Akt, and p-P65 protein, and decreased the overexpression of apoptotic proteins such as cleaved-caspase8 and cleaved-caspase3 in cartilage tissue. Meanwhile, it inhibited the protein expression of MMP9, TNF-α, IL-6, and IL-1ß. In conclusion, this study successfully practiced the combination of systemic pharmacology and experimental verification, and clarified that BXF decoction inhibited the progression of adjuvant arthritis rats through the TNF-PI3K-Akt-NF-κB signal axis. It provides new evidence for the study of the mechanism of BXF decoction in treating RA.

Solid Solution of Bi and Sb for Robust Lithium Storage Enabled by Consecutive Alloying Reaction.

Materials with alloying reactions have significant potential as electrodes for lithium-ion batteries (LIBs) due to its high theoretical capacity and appropriate lithiation potentials. Nonetheless, their cycling performance is inferior due to violent volume expansion and severe pulverization of active materials. Herein, solid solution of Bi0.5 Sb0.5 encapsulated with carbon is discovered to enable consecutive alloying reactions with manageable volume change, suitable for developing LIBs with high capacity and robust cyclability. A Sb-rich shell and Bi-rich core structure is formed in cycling since the alloying reaction between Sb and Li occurs first, followed by the alloying reaction between Bi and Li. Such a consecutive alloying reaction obeying the thermodynamic path is experimentally realized by the carbon capsulation, which acts as a protecting solid layer to avoid polarized reactions occurred when exposed directly to liquid electrolyte. The LIBs using Bi0.5 Sb0.5 @carbon run on the consecutive alloying reactions exhibits high capacity, prolonged lifespan (489.4 mAh g-1 after 2000 cycles at 1 A g-1 ) and fast kinetic, while those using bare Bi0.5 Sb0.5 suffer from worsened kinetic and thus a poor cycling performance owning to the polarized reactions. The work paves a way of developing alloy electrodes for alkaline-ion rechargeable batteries with potential industry applications.

Blockade of TRPM7 Alleviates Chondrocyte Apoptosis and Articular Cartilage Damage in the Adjuvant Arthritis Rat Model Through Regulation of the Indian Hedgehog Signaling Pathway.

Articular cartilage damage with subsequent impairment of joint function is a common feature of articular diseases, in particular, rheumatoid arthritis and osteoarthritis. While articular cartilage injury mediated by chondrocyte apoptosis is a known major pathological feature of arthritis, the specific mechanisms remain unclear at present. Transient receptor potential melastatin-like seven channel (TRPM7) is reported to play an important regulatory role in apoptosis. This study focused on the effects of TRPM7 on arthritic chondrocyte injury and its underlying mechanisms of action. Sodium nitroprusside (SNP)-induced rat primary chondrocyte apoptosis and rat adjuvant arthritis (AA) were used as in vitro and in vivo models, respectively. Blockage of TRPM7 with 2-APB or specific siRNA resulted in increased chondrocyte viability and reduced toxicity of SNP. Moreover, treatment with 2-APB enhanced the Bcl-2/Bax ratio and reduced cleaved PARP and IL-6, MMP-13 and ADAMTS-5 expression in SNP-treated chondrocytes. Activation of Indian Hedgehog with purmorphamine reversed the protective effects of 2-APB on SNP-induced chondrocyte apoptosis. Blockage of TRPM7 with 2-APB relieved the clinical signs of AA in the rat model and reduced the arthritis score and paw swelling. Similar to findings in SNP-treated chondrocytes, 2-APB treatment increased the Bcl-2/Bax ratio and suppressed cleaved PARP, IL-6, MMP-13, ADAMTS-5, TRPM7, and Indian hedgehog expression in articular cartilage of AA rats. Our collective findings suggest that blockade of TRPM7 could effectively reduce chondrocyte apoptosis and articular cartilage damage in rats with adjuvant arthritis through regulation of the Indian Hedgehog signaling pathway.

Curcumin ameliorates IL-1ß-induced apoptosis by activating autophagy and inhibiting the NF-κB signaling pathway in rat primary articular chondrocytes.

Articular cartilage damage and chondrocyte apoptosis are common features of rheumatoid arthritis and osteoarthritis. Recently, curcumin has been reported to exhibit protective effects on degeneration in articular cartilage diseases. However, the effects and mechanisms of curcumin on articular chondrocyte injury remain to be elucidated. The aim of the present study is to investigate the chondroprotective mechanisms of curcumin on interleukin-1ß (IL-1ß)-induced chondrocyte apoptosis in vitro. The results revealed that IL-1ß decreased cell viability and induced apoptosis in primary articular chondrocytes. Curcumin pretreatment reduced IL-1ß-induced articular chondrocyte apoptosis. In addition, treatment with curcumin increased autophagy in articular chondrocytes and protected against IL-1ß-induced apoptosis. The curcumin-mediated protection against IL-1ß induced apoptosis was abolished when cells were treated with the autophagy inhibitor 3-methyladenine or transfected with Beclin-1 small interfering RNA. Furthermore, IL-1ß stimulation significantly increased the phosphorylation levels of nuclear factor (NF)-κB p65 and glycogen synthase kinase-3ß, and decreased the phosphorylation levels of ß-catenin in articular chondrocytes, and these alterations to the phosphorylation levels were partly reversed by treatment with curcumin. Dual-luciferase and electrophoretic mobility shift assays demonstrated that IL-1ß increased NF-κB p65 promoter activity in chondrocytes, and this was also reversed by curcumin. Pretreatment with the NF-κB inhibitor pyrrolidine dithiocarbamate enhanced the protective effects of curcumin on chondrocyte apoptosis, but Wnt/ß-catenin inhibitor, XAV-939, did not exhibit this effect. Molecular docking and dynamic simulation studies results showed that curcumin could bound to RelA (p65) protein. These results indicate that curcumin may suppress IL-1ß-induced chondrocyte apoptosis through activating autophagy and restraining NF-κB signaling pathway.

Nerve growth factor promotes ASIC1a expression via the NF-κB pathway and enhances acid-induced chondrocyte apoptosis.

Nerve growth factor (NGF) is a neurotrophic factor that is thought to have a broad role in the nervous system and tumors, and has recently been described as a mediator of inflammation. It is not clear whether or not NGF participates in apoptosis of articular chondrocytes. In this study, we determined if NGF affects ASIC1a expression and NF-κB P65 activation in rat chondrocytes, and measured the effectiveness of NGF on apoptotic protein expression in acid-induced chondrocytes. NGF was shown to up-regulate the level of ASIC1a in a dose- and time-dependent fashion. Simultaneously, NGF activated NF-κB P65 in chondrocytes. Additionally, the elevated ASIC1a expression induced by NGF was eliminated by the NF-κB inhibitor (PDTC) in chondrocytes. Moreover, NGF reduced cell viability and induced LDH release under the premise of acid-induced articular chondrocytes. Furthermore, NGF could enhance cleaved-caspase 9 and cleaved-PARP expression in acid-pretreated chondrocytes, and which could be inhibited by using psalmotoxin 1(PcTX1) or PDTC. Together, these results indicated that NGF may up-regulate ASIC1a expression through the NF-κB signaling pathway, and further promote acid-induced apoptosis of chondrocytes.

17ß-estradiol attenuates rat articular chondrocyte injury by targeting ASIC1a-mediated apoptosis.

Epidemiological evidence suggests that the etiology and pathogenesis of rheumatoid arthritis (RA) are closely associated with estrogen metabolism and deficiency. Estrogen protects against articular damage. Estradiol replacement therapy ameliorates local inflammation and knee joint swelling in ovariectomized models of RA. The mechanistic basis for the protective role of 17ß-estradiol (17ß-E2) is poorly understood. Acid-sensing ion channel 1a (ASIC1a), a sodium-permeable channel, plays a pivotal role in acid-induced articular chondrocyte injury. The aims of this study were to evaluate the role of 17ß-E2 in acid-induced chondrocyte injury and to determine the effect of 17ß-E2 on the level and activity of ASIC1a protein. Results showed that pretreatment with 17ß-E2 attenuated acid-induced damage, suppressed apoptosis, and restored mitochondrial function. Further, 17ß-E2 was shown to reduce protein levels of ASIC1a through the ERα receptor, to protect chondrocytes from acid-induced apoptosis, and to induce ASIC1a protein degradation through the autophagy-lysosomal pathway. Taken together, these results show that the use of 17ß-E2 may be a novel strategy for the treatment of RA by reducing cartilage destruction through down-regulation of ASIC1a protein levels.