Cytisine attenuates bone loss of ovariectomy mouse by preventing RANKL‐induced osteoclastogenesis

Postmenopausal Osteoporosis (PMOP) is oestrogen withdrawal characterized of much production and activation by osteoclast in the elderly female. Cytisine is a quinolizidine alkaloid that comes from seeds or other plants of the Leguminosae (Fabaceae) family. Cytisine has been shown several potential pharmacological functions. However, its effects on PMOP remain unknown. This study designed to explore whether Cytisine is able to suppress RANKL‐induced osteoclastogenesis and prevent the bone loss induced by oestrogen deficiency in ovariectomized (OVX) mice. In this study, we investigated the effect of Cytisine on RAW 264.7 cells and bone marrow monocytes (BMMs) derived osteoclast culture system in vitro and observed the effect of Cytisine on ovariectomized (OVX) mice model to imitate postmenopausal osteoporosis in vivo. We found that Cytisine inhibited F‐actin ring formation and tartrate‐resistant acid phosphatase (TRAP) staining in dose‐dependent ways, as well as bone resorption by pit formation assays. For molecular mechanism, Cytisine suppressed RANK‐related trigger RANKL by phosphorylation JNK/ERK/p38‐MAPK, IκBα/p65‐NF‐κB, and PI3K/AKT axis and significantly inhibited these signalling pathways. However, the suppression of PI3K‐AKT‐NFATc1 axis was rescued by AKT activator SC79. Meanwhile, Cytisine inhibited RANKL‐induced RANK‐TRAF6 association and RANKL‐related gene and protein markers such as NFATc1, Cathepsin K, MMP‐9 and TRAP. Our study indicated that Cytisine could suppress bone loss in OVX mouse through inhibited osteoclastogenesis. All data provide the evidence that Cytisine may be a promising agent in the treatment of osteoclast‐related diseases such as osteoporosis.     

Neobavaisoflavone inhibits osteoclastogenesis through blocking RANKL signalling‐mediated TRAF6 and c‐Src recruitment and NF‐κB,MAPK and Akt pathways

Psoralea corylifolia (P corylifolia) has been popularly applied in traditional Chinese medicine decoction for treating osteoporosis and promoting fracture healing since centuries ago. However, the bioactive natural components remain unknown. In this study, applying comprehensive two‐dimensional cell membrane chromatographic/C18 column/time‐of‐flight mass spectrometry (2D CMC/C18 column/TOFMS) system, neobavaisoflavone (NBIF), for the first time, was identified for the bioaffinity with RAW 264.7 cells membranes from the extracts of P corylifolia. Here, we revealed that NBIF inhibited RANKL‐mediated osteoclastogenesis in bone marrow monocytes (BMMCs) and RAW264.7 cells dose dependently at the early stage. Moreover, NBIF inhibited osteoclasts function demonstrated by actin ring formation assay and pit‐formation assay. With regard to the underlying molecular mechanism, co‐immunoprecipitation showed that both the interactions of RANK with TRAF6 and with c‐Src were disrupted. In addition, NBIF inhibited the phosphorylation of P50, P65, IκB in NF‐κB pathway, ERK, JNK, P38 in MAPKs pathway, AKT in Akt pathway, accompanied with a blockade of calcium oscillation and inactivation of nuclear translocation of nuclear factor of activated T cells cytoplasmic 1 (NFATc1). In vivo, NBIF inhibited osteoclastogenesis, promoted osteogenesis and ameliorated bone loss in ovariectomized mice. In summary, P corylifolia‐derived NBIF inhibited RANKL‐mediated osteoclastogenesis by suppressing the recruitment of TRAF6 and c‐Src to RANK, inactivating NF‐κB, MAPKs, and Akt signalling pathways and inhibiting calcium oscillation and NFATc1 translocation. NBIF might serve as a promising candidate for the treatment of osteoclast‐associated osteopenic diseases.     

Exosome derived from CD137‐modified endothelial cells regulates the Th17 responses in atherosclerosis

The role of exosomes derived from endothelial cells (ECs) in the progression of atherosclerosis (AS) and inflammation remains largely unexplored. We aimed to investigate whether exosome derived from CD137‐modified ECs (CD137‐Exo) played a major role in AS and to elucidate the potential mechanism underlying the inflammatory effect. Exosomes derived from mouse brain microvascular ECs treated with agonist anti‐CD137 antibody were used to explore the effect of CD137 signalling in AS and inflammation in vitro and vivo. CD137‐Exo efficiently induced the progression of AS in ApoE^?/? mice. CD137‐Exo increased the proportion of Th17 cells both in vitro and vivo. The IL‐6 contained in CD137‐Exo which is regulated by Akt and NF‐КB pathway was verified to activate Th17 cell differentiation. IL‐17 increased apoptosis, inhibited cell viability and improved lactate dehydrogenase (LDH) release in ECs subjected to inflammation induced by lipopolysaccharide (LPS). The expression of soluble intercellular adhesion molecule1 (sICAM‐1), monocyte chemoattractant protein‐1 (MCP‐1) and E‐selectin in the supernatants of ECs after IL‐17 treatment was dramatically increased. CD137‐Exo promoted the progression of AS and Th17 cell differentiation via NF‐КB pathway mediated IL‐6 expression. This finding provided a potential method to prevent local and peripheral inflammation in AS.     

Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway

Microtubule actin cross‐linking factor 1 (Macf1) is a spectraplakin family member known to regulate cytoskeletal dynamics, cell migration, neuronal growth and cell signal transduction. We previously demonstrated that knockdown of Macf1 inhibited the differentiation of MC3T3‐E1 cell line. However, whether Macf1 could regulate bone formation in vivo is unclear. To study the function and mechanism of Macf1 in bone formation and osteogenic differentiation, we established osteoblast‐specific Osterix (Osx) promoter‐driven Macf1 conditional knockout mice (Macf1^f/fOsx‐Cre). The Macf1^f/fOsx‐Cre mice displayed delayed ossification and decreased bone mass. Morphological and mechanical studies showed deteriorated trabecular microarchitecture and impaired biomechanical strength of femur in Macf1^f/fOsx‐Cre mice. In addition, the differentiation of primary osteoblasts isolated from calvaria was inhibited in Macf1^f/fOsx‐Cre mice. Deficiency of Macf1 in primary osteoblasts inhibited the expression of osteogenic marker genes (Col1, Runx2 and Alp) and the number of mineralized nodules. Furthermore, deficiency of Macf1 attenuated Bmp2/Smad/Runx2 signalling in primary osteoblasts of Macf1^f/fOsx‐Cre mice. Together, these results indicated that Macf1 plays a significant role in bone formation and osteoblast differentiation by regulating Bmp2/Smad/Runx2 pathway, suggesting that Macf1 might be a therapeutic target for bone disease.     

Reduction of SOST gene promotes bone formation through the Wnt/β-catenin signalling pathway and compensates particle-induced osteolysis

The increase in bone resorption and/or the inhibition of bone regeneration caused by wear particles are the main causes of periprosthetic osteolysis. The SOST gene and Sclerostin, a protein synthesized by the SOST gene, are the characteristic marker of osteocytes and regulate bone formation and resorption. We aimed to verify whether the SOST gene was involved in osteolysis induced by titanium (Ti) particles and to investigate the effects of SOST reduction on osteolysis. The results showed osteolysis on the skull surface with an increase of sclerostin levels after treated with Ti particles. Similarly, sclerostin expression in MLO-Y4 osteocytes increased when treated with Ti particles in vitro. After reduction of SOST, local bone mineral density and bone volume increased, while number of lytic pores on the skull surface decreased and the erodibility of the skull surface was compensated. Histological analyses revealed that SOST reduction increased significantly alkaline phosphatase- (ALP) and osterix-positive expression on the skull surface which promoted bone formation. ALP activity and mineralization of MC3T3-E1 cells also increased in vitro when SOST was silenced, even if treated with Ti particles. In addition, Ti particles decreased β-catenin expression with an increase in sclerostin levels, in vivo and in vitro. Inversely, reduction of SOST expression increased β-catenin expression. In summary, our results suggested that reduction of SOST gene can activate the Wnt/β-catenin signalling pathway, promoting bone formation and compensated for bone loss induced by Ti particles. Thus, this study provided new perspectives in understanding the mechanisms of periprosthetic osteolysis.     

Effect of c‐Ski on atrial remodelling in a rapid atrial pacing canine model

Atrial fibrosis is an important factor in the initiation and maintenance of atrial fibrillation (AF); therefore, understanding the pathogenesis of atrial fibrosis may reveal promising therapeutic targets for AF. In this study, we successfully established a rapid atrial pacing canine model and found that the inducibility and duration of AF were significantly reduced by the overexpression of c‐Ski, suggesting that this approach may have therapeutic effects. c‐Ski was found to be down‐regulated in the atrial tissues of the rapid atrial pacing canine model. We artificially up‐regulated c‐Ski expression with a c‐Ski–overexpressing adenovirus. Haematoxylin and eosin, Masson's trichrome and picrosirius red staining showed that c‐Ski overexpression alleviated atrial fibrosis. Furthermore, we found that the expression levels of collagen III and α‐SMA were higher in the groups of dogs subjected to right‐atrial pacing, and this increase was attenuated by c‐Ski overexpression. In addition, c‐Ski overexpression decreased the phosphorylation of smad2, smad3 and p38 MAPK (p38α and p38β) as well as the expression of TGF‐β1 in atrial tissues, as shown by a comparison of the right‐atrial pacing + c‐Ski‐overexpression group to the control group with right‐atrial pacing only. These results suggest that c‐Ski overexpression improves atrial remodelling in a rapid atrial pacing canine model by suppressing TGF‐β1–Smad signalling and p38 MAPK activation.     

Phosphorene as Cathode Material for High‐Voltage,Anti‐Self‐Discharge Zinc Ion Hybrid Capacitors

Output voltage and self‐discharge rate are two important performance indices for supercapacitors, which have long been overlooked, though these play a very significant role in their practical application. Here, a zinc anode is used to construct a zinc ion hybrid capacitor. Expanded operating voltage of the hybrid capacitor is obtained with novel electrolytes. In addition, significantly improved anti‐self‐discharge ability is achieved. The phosphorene‐based zinc ion capacitor exploiting a “water in salt” electrolyte with a working potential can reach 2.2 V, delivering 214.3 F g^?1 after 5000 cycles. The operating voltage is further extended to 2.5 V through the use of an organic solvent as the electrolyte; the solvent is prepared by adding 0.2 m ZnCl₂ into the tetraethylammonium tetrafluoroborate in propylene carbonate (Et₄NBF₄/PC) solvent, and it exhibits 105.9 F g^?1 even after 9500 cycles. More importantly, the phosphorene‐based capacitors possess excellent anti‐self‐discharge performance. The capacitors retain 76.16% of capacitance after resting for 300 h. The practical application of the zinc ion capacitor is demonstrated through a flexible paper‐based printed microcapacitor. It is believed that the developed zinc ion capacitor can effectively resolve the severe self‐discharge problem of supercapacitors. Moreover, high‐voltage zinc ion capacitors provide more opportunities for the application of supercapacitors.     

In Situ Electrochemical Synthesis of MXenes without Acid/Alkali Usage in/for an Aqueous Zinc Ion Battery

The traditional method to fabricate a MXene based energy storage device starts from etching MAX phase particles with dangerous acid/alkali etchants to MXenes, followed by device assembly. This is a multistep protocol and is not environmentally friendly. Herein, an all‐in‐one protocol is proposed to integrate synthesis and battery fabrication of MXene. By choosing a special F‐rich electrolyte, MAX V₂AlC is directly exfoliated inside a battery and the obtained V₂CT_X MXene is in situ used to achieve an excellent battery performance. This is a one‐step process with all reactions inside the cell, avoiding any contamination to external environments. Through the lifetime, the device experiences three stages of exfoliation, electrode oxidation, and redox of V₂O₅. While the electrode is changing, the device can always be used as a battery and the performance is continuously enhanced. The resulting aqueous zinc ion battery achieves outstanding cycling stability (4000 cycles) and rate performance (97.5 mAh g^?1 at 64 A g^?1), distinct from all reported aqueous MXene‐based counterparts with pseudo‐capacitive properties, and outperforming most vanadium‐based zinc ion batteries with high capacity. This work sheds light on the green synthesis of MXenes, provides an all‐in‐one protocol for MXene devices, and extends MXenes’ application in the aqueous energy storage field.     

乌司他丁对非停跳冠脉搭桥术患者的心肺保护作用研究

目的:探讨乌司他丁对非停跳冠脉搭桥术患者的心肺保护作用。方法:选取2017年12月-2019年4月我院收治的非停跳冠脉搭桥术患者76例,根据使用的药物不同分为两组,对照组应用常规方法,研究组应用乌司他丁,在麻醉之后切皮之前为T1,旁路血管开放时时间点为T2,手术结束为T3,手术之后的8 h为T4。比较两组治疗前后的心肺功能指标、动脉血气分析及血浆炎症因子、氧合指数术后恢复。结果:和T1进行对比时,两组T3、T4中的气道阻力(Air way Resistance,Raw)、呼吸指数(Respiratory Index,RI)、肺泡-动脉血氧分压差P(A-a)DO2均有所升高,在T2、T4中(PVR)有所升高,在T2、T3、T4中肺顺应性(Compliance of Lung,CL)有所降低。和对照组进行对比时,研究组在T3、T4中肺循环阻力(pulmonary vascular resistance, PVR)、RI、P(A-a)DO2有所降低,在T2、T3、T4中通气死腔百分比(VD/VT)有所降低(P0.05),在T2中CL有所升高(P0.05);治疗前,两组BNP、TNF-α、IL-6、IL-8无统计学意义(P0.05),治疗后BNP、肿瘤坏死因子(tumor necrosis factor-α,TNF-α)、白细胞介素-6 (Interleukin-6,IL-6)、白细胞介素-8 (Interleukin-8,IL-8)在T1、T2、T3、T4中低于对照组(P0.05),肌钙蛋白(cardiac troponin,cTnI)在T1中和对照组没有明显差异(P0.05),T2、T3、T4中研究组明显低于对照组(P0.05),研究组氧合指数高于对照组(P0.05);研究组T1、T2、T3、T4时平均动脉压(mean artery pressure,MBP)均高于对照组(P0.05),T1、T2、T3、T4时心率均低于对照组(P0.05);研究组ICU停留时间、ICU带气管插管时间、ICU机械通气时间、肺部并发症均低于对照组(P0.05)。结论:乌司他丁用于非停跳冠脉搭桥术的效果较好,可以保护患者的心肺功能。