MiR‐802 causes nephropathy by suppressing NF‐κB‐repressing factor in obese mice and human

Obesity is associated with significant microvascular complications including renal injuries and may induce end‐stage renal disease. Emerging studies have demonstrated microRNAs (miRNAs) are potential mediators in the pathophysiological process of nephropathy. The present study aimed to investigate the role of miR‐802 in obesity‐related nephropathy and potential molecular mechanisms. Through utilizing obese mouse model and human subjects, we explored the therapeutic benefits and clinical application of miR‐802 in protecting against nephropathy. Renal miR‐802 level was positively correlated with functional parameters, including blood urea nitrogen and creatinine in obese mice. Specific silencing of renal miR‐802 improved high fat diet (HFD)‐induced renal dysfunction, structural disorders and fibrosis. The up‐regulated inflammatory response and infiltrated macrophages were also significantly decreased in miR‐802 inhibitor‐treated obese mice. Mechanistically, miR‐802 directly bond to 3?‐UTR of NF‐κB‐repressing factor (NRF) and suppressed its expression. In clinical study, the circulating miR‐802 level was significantly increased in obese subjects, and positively correlated with plasma creatinine level but negatively correlated with creatinine clearance. Taken together, our findings provided evidence that miR‐802/NRF signalling was an important pathway in mediating obesity‐related nephropathy. It is a possible useful clinical approach of treating miR‐802 inhibitor to combat nephropathy.     

Deletion of pancreatic β‐cell adenosine kinase improves glucose homeostasis in young mice and ameliorates streptozotocin‐induced hyperglycaemia

Severe reduction in the β‐cell number (collectively known as the β‐cell mass) contributes to the development of both type 1 and type 2 diabetes. Recent pharmacological studies have suggested that increased pancreatic β‐cell proliferation could be due to specific inhibition of adenosine kinase (ADK). However, genetic evidence for the function of pancreatic β‐cell ADK under physiological conditions or in a pathological context is still lacking. In this study, we crossed mice carrying LoxP‐flanked Adk gene with Ins2‐Cre mice to acquire pancreatic β ‐cell ADK deficiency (Ins2‐Cre^±Adk^fl/fl) mice. Our results revealed that Ins2‐Cre^+/‐Adk^fl/fl mice showed improved glucose metabolism and β‐cell mass in younger mice, but showed normal activity in adult mice. Moreover, Ins2‐Cre^±Adk^fl/fl mice were more resistant to streptozotocin (STZ) induced hyperglycaemia and pancreatic β‐cell damage in adult mice. In conclusion, we found that ADK negatively regulates β‐cell replication in young mice as well as under pathological conditions, such as STZ induced pancreatic β‐cell damage. Our study provided genetic evidence that specific inhibition of pancreatic β‐cell ADK has potential for anti‐diabetic therapy.     

Berberine attenuates XRCC1‐mediated base excision repair and sensitizes breast cancer cells to the chemotherapeutic drugs

Berberine (BBR) is a natural isoquinoline alkaloid, which is used in traditional medicine for its anti‐microbial, anti‐protozoal, anti‐diarrhoeal activities. Berberine interacts with DNA and displays anti‐cancer activities, yet its effects on cellular DNA repair and on synthetic treatments with chemotherapeutic drugs remain unclear. In this study, we investigated the effects of BBR on DNA repair and on sensitization of breast cancer cells to different types of DNA damage anti‐tumoural drugs. We found BBR arrested cells in the cell cycle S phase and induced DNA breaks. Cell growth analysis showed BBR sensitized MDA‐MB‐231 cells to cisplatin, camptothecin and methyl methanesulfonate; however, BBR had no synergistic effects with hydroxurea and olaparib. These results suggest BBR only affects specific DNA repair pathways. Western blot showed BBR down‐regulated XRCC1 expressions, and the rescued XRCC1 recovered the resistance of cancer cells to BBR. Therefore, we conclude that BBR interferes with XRCC1‐mediated base excision repair to sensitize cancer cells to chemotherapeutic drugs. These finding can contribute to understanding the effects of BBR on cellular DNA repair and the clinical employment of BBR in treatment of breast cancer.     

Knockdown of Golgi phosphoprotein 73 blocks the trafficking of matrix metalloproteinase‐2 in hepatocellular carcinoma cells and inhibits cell invasion

Golgi phosphoprotein 73 (GP73) has been regarded as a novel serum biomarker for the diagnosis of hepatocellular carcinoma (HCC) in recent years. It has been reported that the upregulation of GP73 may promote the carcinogenesis and metastasis of HCC; however, the mechanisms remain poorly understood. In this study, GP73 correlates positively with matrix metalloproteinase‐2 (MMP‐2) in HCC‐related cells and tissues. Further studies indicate that the knockdown of GP73 blocks MMP‐2 trafficking and secretion, resulting in cell invasion inhibition. Additionally, the knockdown of GP73 induces the accumulation of intracellular MMP‐2, which inhibits the phosphorylation of Src at Y416 and triggers the inhibition of SAPK/JNK and p53‐p21 signalling pathways through a negative feedback loop. Finally, the transactivation of MMP2 was inhibited by the reduction in E2F1. This study reveals that GP73 plays functional roles in the trafficking and equilibrium of epithelial‐mesenchymal transition (EMT)‐related secretory proteins and that GP73 serves as a new potential target for combating the metastasis of HCC.     

MCLPMDA: A novel method for miRNA‐disease association prediction based on matrix completion and label propagation

MiRNAs are a class of small non‐coding RNAs that are involved in the development and progression of various complex diseases. Great efforts have been made to discover potential associations between miRNAs and diseases recently. As experimental methods are in general expensive and time‐consuming, a large number of computational models have been developed to effectively predict reliable disease‐related miRNAs. However, the inherent noise and incompleteness in the existing biological datasets have inevitably limited the prediction accuracy of current computational models. To solve this issue, in this paper, we propose a novel method for miRNA‐disease association prediction based on matrix completion and label propagation. Specifically, our method first reconstructs a new miRNA/disease similarity matrix by matrix completion algorithm based on known experimentally verified miRNA‐disease associations and then utilizes the label propagation algorithm to reliably predict disease‐related miRNAs. As a result, MCLPMDA achieved comparable performance under different evaluation metrics and was capable of discovering greater number of true miRNA‐disease associations. Moreover, case study conducted on Breast Neoplasms further confirmed the prediction reliability of the proposed method. Taken together, the experimental results clearly demonstrated that MCLPMDA can serve as an effective and reliable tool for miRNA‐disease association prediction.     

β‐arrestin 2 negatively regulates NOD2 signalling pathway through association with TRAF6 in microglia after cerebral ischaemia/reperfusion injury

We previously reported that nucleotide‐binding oligomerization domain‐containing protein (NOD) 2 was involved in the inflammatory responses to cerebral ischaemia/reperfusion (I/R) insult. However, the mechanism by which NOD2 participates in brain ischaemic injury and the regulation of NOD2 in the process are still obscure. Increased β‐arrestin 2 (ARRB2) expression was observed in microglia following cerebral I/R in wild‐type mice besides the up‐regulation of NOD2 and TRAF6. Stimulation of NOD2 by muramyl dipeptide (MDP) in BV2 cells induced the activation of NF‐κB by the phosphorylation of p65 subunit and the degradation of IκBα. Meanwhile, the protein level of Cyclooxygenase‐2 (COX‐2), the protein expression and activity of MMP‐9 were significantly increased in BV2 cells after administration of MDP. Furthermore, overexpression of ARRB2 significantly suppressed the inflammation induced by MDP, silence of ARRB2 significantly enhanced the inflammation induced by MDP in BV2 cells. In addition, we observed endogenous interaction of TRAF6 and ARRB2 after stimulation of MDP or cerebral I/R insult, indicating ARRB2 negatively regulates NOD2‐triggered inflammatory signalling pathway by associating with TRAF6 in microglia after cerebral I/R injury. Finally, the in vivo study clearly confirmed that ARRB2 negatively regulated NOD2‐induced inflammatory response, as ARRB2 deficiency exacerbated stroke outcomes and aggravated the NF‐κB signalling pathway induced by NOD2 stimulation after cerebral I/R injury. These findings revealed ARRB2 negatively regulated NOD2 signalling pathway through the association with TRAF6 in cerebral I/R injury.     

BAG3‐positive pancreatic stellate cells promote migration and invasion of pancreatic ductal adenocarcinoma

BAG3 is constitutively expressed in multiple types of cancer cells and its high expression is associated with tumour progression and poor prognosis of PDAC . However, little is known about the role of BAG3 in the regulation of stromal microenvironment of PDAC. The current study demonstrated that beside PDAC tumour cells, BAG3 was also expressed in some activated stroma cells in PDAC tissue, as well as in activated PSCs. In addition, the current study demonstrated that BAG3 expression in PSCs was involved in maintenance of PSCs activation and promotion of PDACs invasion via releasing multiple cytokines. The current study demonstrated that BAG3‐positive PSCs promoted invasion of PDACs via IL‐8, MCP1, TGF‐β2 and IGFBP2 in a paracrine manner. Furthermore, BAG3 sustained PSCs activation through IL‐6, TGF‐β2 and IGFBP2 in an autocrine manner. Thereby, the current study provides a new insight into the involvement of BAG3 in remodelling of stromal microenvironment favourable for malignant progression of PDAC, indicating that BAG3 might serve as a potential target for anti‐fibrosis of PDAC.     

Design‐to‐Device Approach Affords Panchromatic Co‐Sensitized Solar Cells

Data‐driven materials discovery has become increasingly important in identifying materials that exhibit specific, desirable properties from a vast chemical search space. Synergic prediction and experimental validation are needed to accelerate scientific advances related to critical societal applications. A design‐to‐device study that uses high‐throughput screens with algorithmic encodings of structure–property relationships is reported to identify new materials with panchromatic optical absorption, whose photovoltaic device applications are then experimentally verified. The data‐mining methods source 9431 dye candidates, which are auto‐generated from the literature using a custom text‐mining tool. These candidates are sifted via a data‐mining workflow that is tailored to identify optimal combinations of organic dyes that have complementary optical absorption properties such that they can harvest all available sunlight when acting as co‐sensitizers for dye‐sensitized solar cells (DSSCs). Six promising dye combinations are shortlisted for device testing, whereupon one dye combination yields co‐sensitized DSSCs with power conversion efficiencies comparable to those of the high‐performance, organometallic dye, N719. These results demonstrate how data‐driven molecular engineering can accelerate materials discovery for panchromatic photovoltaic or other applications.