Melatonin protects vertebral endplate chondrocytes against apoptosis and calcification via the Sirt1‐autophagy pathway

Melatonin is reportedly associated with intervertebral disc degeneration (IDD). Endplate cartilage is vitally important to intervertebral discs in physiological and pathological conditions. However, the effects and mechanism of melatonin on endplate chondrocytes (EPCs) are still unclear. Herein, we studied the effects of melatonin on EPC apoptosis and calcification and elucidated the underlying mechanism. Our study revealed that melatonin treatment decreases the incidence of apoptosis and inhibits EPC calcification in a dose‐dependent manner. We also found that melatonin upregulates Sirt1 expression and activity and promotes autophagy in EPCs. Autophagy inhibition by 3‐methyladenine reversed the protective effect of melatonin on apoptosis and calcification, while the Sirt1 inhibitor EX‐527 suppressed melatonin‐induced autophagy and the protective effects of melatonin against apoptosis and calcification, indicating that the beneficial effects of melatonin in EPCs are mediated through the Sirt1‐autophagy pathway. Furthermore, melatonin may ameliorate IDD in vivo in rats. Collectively, this study revealed that melatonin reduces EPC apoptosis and calcification and that the underlying mechanism may be related to Sirt1‐autophagy pathway regulation, which may help us better understand the association between melatonin and IDD.     

Inhibition of circular RNA CDR1as increases chemosensitivity of 5‐FU‐resistant BC cells through up‐regulating miR‐7

This study aims to explore the mechanism of Circular RNA CDR1as implicating in regulating 5‐fluorouracil (5‐FU) chemosensitivity in breast cancer (BC) by competitively inhibiting miR‐7 to regulate CCNE1. Expressions of CDR1as and miR‐7 in 5‐FU‐resistant BC cells were determined by RT‐PCR. CCK‐8, colony formation assay and flow cytometry were applied to measure half maximal inhibitory concentration (IC50), 5‐Fu chemosensitivity and cell apoptosis. Western blot was used to detect the expressions of apoptosis‐related factors. CDR1as was elevated while miR‐7 was inhibited in 5‐FU‐resistant BC cells. Cells transfected with si‐CDR1as or miR‐7 mimic had decreased IC50 and colony formation rate, increased expressions of Bax/Bcl2 and cleaved‐Caspase‐3/Caspase‐3, indicating inhibition of CDR1as and overexpression of miR‐7 enhances the chemosensitity of 5‐FU‐resistant BC cells. Targetscan software indicates a binding site of CDR1as and miR‐7 and that CCNE1 is a target gene of miR‐7. miR‐7 can gather CDR1as in BC cells and can inhibit CCNE1. In comparison to si‐CDR1as group, CCNE1 was increased and chemosensitivity to 5‐Fu was suppressed in si‐CDR1as + miR‐7 inhibitor group. When compared with miR‐7 mimic group, CDR1as + miR‐7 mimic group had increased CCNE1 and decreased chemosensitivity to 5‐Fu. Nude mouse model of BC demonstrated that the growth of xenotransplanted tumour in si‐CDR1as + miR‐7 inhibitor group was faster than that in si‐CDR1as group. The tumour growth in CDR1as + miR‐7 mimic group was faster than that in miR‐7 mimic group. CDR1as may regulate chemosensitivity of 5‐FU‐resistant BC cells by inhibiting miR‐7 to regulate CCNE1.     

LncRNA DUXAP9‐206 directly binds with Cbl‐b to augment EGFR signaling and promotes non‐small cell lung cancer progression

Long noncoding RNAs (lncRNAs) are involved in the pathology of various tumours, including non‐small cell lung cancer (NSCLC). However, the underlying molecular mechanisms of their specific association with NSCLC have not been fully elucidated. Here, we report that a cytoplasmic lncRNA, DUXAP9‐206 is overexpressed in NSCLC cells and closely related to NSCLC clinical features and poor patient survival. We reveal that DUXAP9‐206 induced NSCLC cell proliferation and metastasis by directly interacting with Cbl‐b, an E3 ubiquitin ligase, and reducing the degradation of epidermal growth factor receptor (EGFR) and thereby augmenting EGFR signaling in NSCLC. Notably, correlations between DUXAP9‐206 and activated EGFR signaling were also validated in NSCLC patient specimens. Collectively, our findings reveal the novel molecular mechanisms of DUXAP9‐206 in mediating the progression of NSCLC and DUXAP9‐206 may serve as a potential target for NSCLC therapy.     

Absence of estrogen receptor beta leads to abnormal adipogenesis during early tendon healing by an up‐regulation of PPARγ signalling

Achilles tendon injury is one of the challenges of sports medicine, the aetiology of which remains unknown. For a long time, estrogen receptor β (ERβ) has been known as a regulating factor of the metabolism in many connective tissues, such as bone, muscle and cartilage, but little is known about its role in tendon. Recent studies have implicated ERβ as involved in the process of tendon healing. Tendon‐derived stem cells (TDSCs) are getting more and more attention in tendon physiological and pathological process. In this study, we investigated how ERβ played a role in Achilles tendon healing. Achilles tendon injury model was established to analyse how ERβ affected on healing process in vivo. Cell proliferation assay, Western blots, qRT‐PCR and immunocytochemistry were performed to investigate the effect of ERβ on TDSCs. Here, we showed that ERβ deletion in mice resulted in inferior gross appearance, histological scores and, most importantly, increased accumulation of adipocytes during the early tendon healing which involved activation of peroxisome proliferator‐activated receptor γ (PPARγ) signalling. Furthermore, in vitro results of ours confirmed that the abnormity might be the result of abnormal TDSC adipogenic differentiation which could be partially reversed by the treatment of ERβ agonist LY3201. These data revealed a role of ERβ in Achilles tendon healing for the first time, thereby providing a new target for clinical treatment of Achilles tendon injury.     

Immunogenic cell death in cancer therapy: Present and emerging inducers

In the tumour microenvironment (TME), immunogenic cell death (ICD) plays a major role in stimulating the dysfunctional antitumour immune system. Chronic exposure of damage‐associated molecular patterns (DAMPs) attracts receptors and ligands on dendritic cells (DCs) and activates immature DCs to transition to a mature phenotype, which promotes the processing of phagocytic cargo in DCs and accelerates the engulfment of antigenic components by DCs. Consequently, via antigen presentation, DCs stimulate specific T cell responses that kill more cancer cells. The induction of ICD eventually results in long‐lasting protective antitumour immunity. Through the exploration of ICD inducers, recent studies have shown that there are many novel modalities with the ability to induce immunogenic cancer cell death. In this review, we mainly discussed and summarized the emerging methods for inducing immunogenic cancer cell death. Concepts and molecular mechanisms relevant to antitumour effects of ICD are also briefly discussed.     

One‐Step Controllable Synthesis of Catalytic Ni4Mo/MoOx/Cu Nanointerfaces for Highly Efficient Water Reduction

Currently, in addition to the electroactive non‐noble metal water‐splitting electrocatalysts, a scalable synthetic route and simple activity enhancement strategy is also urgently needed. In particular, the well‐controlled synthesis of the well‐recognized metal–metal nanointer face in a single step remains a key challenge. Here, the synthesis of Cu‐supported Ni₄Mo nanodots on MoO_x nanosheets (Ni₄Mo/MoO_x) with controllable Ni₄Mo particle size and d‐band structure is reported via a facile one‐step electrodeposition process. Density functional theory (DFT) calculations reveal that the active open‐shell effect from Ni‐3d‐band optimizes the electronic configuration. The Cu‐substrate enables the surface Ni–Mo alloy dots to be more electron‐rich, forming a local connected electron‐rich network, which boosts the charge transfer for effective binding of O‐related species and proton–electron charge exchange in the hydrogen evolution reaction. The Cu‐supported Ni₄Mo/MoO_x shows an ultralow overpotential of 16 mV at a current density of 10 mA cm^?2 in 1 m KOH, demonstrating the smallest overpotential, at loadings as low as 0.27 mg cm^?2, among all non‐noble metal catalysts reported to date. Moreover, an overpotential of 105 mV allows it to achieve a current density of 250 mA cm^?2 in 70 °C 30% KOH, a remarkable performance for alkaline hydrogen evolution with competitive potential for applications.     

Design,Synthesis and in Vitro Tumor Cytotoxicity Evaluation of 3,5‐Diamino‐N‐substituted Benzamide Derivatives as Novel GSK‐3β Small Molecule Inhibitors

Glycogen synthase kinase‐3 (GSK‐3) plays an important regulatory role in various signaling pathways; such as PI3 K/AKT, which is closely related to the occurrence and development of tumors. At present, the most reported active GSK‐3 inhibitors have the same structure: lactam ring or amide structure. To find out the GSK‐3β small molecule inhibitor with novel, safe, efficient and more uncomplicated synthesis method, we analyzed in‐depth reported crystal‐binding patterns of GSK‐3β small molecule inhibitor with GSK‐3β protein, and designed and synthesized 17 non‐reported 3,5‐diamino‐N‐substituted benzamide compounds. Their structures were confirmed by ¹H‐NMR, ¹³C‐NMR, and HR‐MS. The preliminary screening of tumor cytotoxicity of compounds in vitro was detected by MTT, and their structure–activity relationships were illustrated. The results have shown that 3,5‐diamino‐N‐[3‐(trifluoromethyl)phenyl]benzamide ( 4d ) exhibited significant tumor cytotoxicity against human colon cancer cells (HCT‐116) with IC₅₀ of 8.3 μm and showed commendable selectivity to GSK‐3β. In addition, Compound 4d induced apoptosis to some extent and possessed modest PK properties.     

Co–B Nanoflakes as Multifunctional Bridges in ZnCo2O4 Micro‐/Nanospheres for Superior Lithium Storage with Boosted Kinetics and Stability

Transition metal oxides hold great promise as high‐energy anodes in next‐generation lithium‐ion batteries. However, owing to the inherent limitations of low electronic/ionic conductivities and dramatic volume change during charge/discharge, it is still challenging to fabricate practically viable compacted and thick TMO anodes with satisfactory electrochemical performance. Herein, with mesoporous cobalt–boride nanoflakes serving as multifunctional bridges in ZnCo₂O₄ micro‐/nanospheres, a compacted ZnCo₂O₄/Co–B hybrid structure is constructed. Co–B nanoflakes not only bridge ZnCo₂O₄ nanoparticles and function as anchors for ZnCo₂O₄ micro‐/nanospheres to suppress the severe volume fluctuation, they also work as effective electron conduction bridges to promote fast electron transportation. More importantly, they serve as Li⁺ transfer bridges to provide significantly boosted Li⁺ diffusivity, evidenced from both experimental kinetics analysis and density functional theory calculations. The mesopores within Co–B nanoflakes help overcome the large Li⁺ diffusion barriers across 2D interfaces. As a result, the ZnCo₂O₄/Co–B electrode delivers high gravimetric/volumetric/areal capacities of 995 mAh g^?1/1450 mAh cm^?3/5.10 mAh cm^?2, respectively, with robust rate capability and long‐term cyclability. The distinct interfacial design strategy provides a new direction for designing compacted conversion‐type anodes with superior lithium storage kinetics and stability for practical applications.     

Na3V2(PO4)3 as the Sole Solid Energy Storage Material for Redox Flow Sodium‐Ion Battery

Redox flow batteries have considerable advantages of system scalability and operation flexibility over other battery technologies, which makes them promising for large‐scale energy storage application. However, they suffer from low energy density and consequently relatively high cost for a nominal energy output. Redox targeting–based flow batteries are employed by incorporating solid energy storage materials in the tank and present energy density far beyond the solubility limit of the electrolytes. The success of this concept relies on paring suitable redox mediators with solid materials for facilitated reaction kinetics and lean electrolyte composition. Here, a redox targeting‐based flow battery system using the NASICON‐type Na₃V₂(PO₄)₃ as a capacity booster for both the catholyte and anolyte is reported. With 10‐methylphenothiazine as the cathodic redox mediator and 9‐fluorenone as anodic redox mediator, an all‐organic single molecule redox targeting–based flow battery is developed. The anodic and cathodic capacity are 3 and 17 times higher than the solubility limit of respective electrolyte, with which a full cell can achieve an energy density up to 88 Wh L^?1. The reaction mechanism is scrutinized by operando and in‐situ X‐ray and UV–vis absorption spectroscopy. The reaction kinetics are analysed in terms of Butler–Volmer formalism.     

Polarization-Independent Narrowband Near-Perfect Absorption Based on One-Dimension Embedded Aluminum Grating

Plasmonics - In the past, the polarization-insensitive absorption is realized mainly employing the two-dimensional periodic structure of fourfold rotational symmetry, which greatly increases the...