Growing evidence suggests that long non‐coding RNAs (lncRNAs) are associated with carcinogenesis. LncRNA small nucleolar RNA host gene 3 (SNHG3) is up‐regulated in various cancers and positively associated with poor prognosis of these cancers. However, the precise role of lncRNA SNHG3 in bladder cancer (Bca) remains unclear. In our research, we first reported that lncRNA SNHG3 was up‐regulated in bladder cancer tissues and positively related to poor clinical prognosis. Moreover, knockdown of lncRNA SNHG3 significantly suppressed the proliferation, migration, invasion and EMT process of Bca cells in vitro and vivo. Mechanistically, we revealed that suppression of SNHG3 evidently enhanced miR‐515‐5p expression and decreased GINS2 expression at posttranscriptional levels. Moreover, SNHG3 positively regulated GINS2 expression by sponging miR‐515‐5p under a competing endogenous RNA (ceRNA) mechanism. To sum up, our study suggested lncRNA SNHG3 acted as a microRNA sponge and an oncogenic role in the progression of bladder cancer.

New Delhi metallo-β-lactamase-1 (NDM-1) has emerged as a major global threat to human health for its rapid rate of dissemination and ability to make pathogenic microbes resistant to almost all known β-lactam antibiotics. In addition, effective NDM-1 inhibitors have not been identified to date. In spite of the plethora of structural and kinetic data available, the accurate molecular characteristics of and details on the enzymatic reaction of NDM-1 hydrolyzing β-lactam antibiotics remain incompletely understood. In this study, a combined computational approach including molecular docking, molecular dynamics simulations and quantum mechanics/molecular mechanics calculations was performed to characterize the catalytic mechanism of meropenem catalyzed by NDM-1. The quantum mechanics/molecular mechanics results indicate that the ionized D124 is beneficial to the cleavage of the C-N bond within the β-lactam ring. Meanwhile, it is energetically favorable to form an intermediate if no water molecule coordinates to Zn2. Moreover, according to the molecular dynamics results, the conserved residue K211 plays a pivotal role in substrate binding and catalysis, which is quite consistent with previous mutagenesis data. Our study provides detailed insights into the catalytic mechanism of NDM-1 hydrolyzing meropenem β-lactam antibiotics and offers clues for the discovery of new antibiotics against NDM-1 positive strains in clinical studies.

Opiates have long been used as analgesics to relieve pain associated with various medical conditions. μ-opioid receptor (MOR) is the main member of the opioid receptor super-family and the excitation or overexpression of MOR promotes the proliferation of many kinds of tumor cells. It was found in our previous studies that MOR was highly expressed in the tissue and cells of human liver cancer. However, the impact of MOR on the progress of human liver cancer remains unknown. The purpose of this study is to investigate the impact of MOR downregulation on the progress of human liver cancer and the mechanisms involved. RNA interfering or specific inhibitor was administered to downregulate the MOR in human hepato-cellular carcinoma cells and it was found that the proliferation of hepatocellular carcinoma cells was significantly inhibited with the increase of the apoptotic rate, while the cell cycle was blocked in G0/G1 phase and the tumor growth in the mice was retarded. In addition, downregulation of MOR resulted in the increase of phosphorylation of the MKK7 expression and JNK activation. On the contrary, blockade of MKK7 pathway can reverse the antitumor role of MOR. In summary, downregulation of MOR is able to inhibit both in vivo and in vitro human liver cancer progress and it shows potential to be used in cancer therapy.

DNA methyltransferases play crucial roles in establishing and maintenance of DNA methylation, which is an important epigenetic mark. Flipping the target cytosine out of the DNA helical stack and into the active site of protein provides DNA methyltransferases with an opportunity to access and modify the genetic information hidden in DNA. To investigate the conversion process of base flipping in the HhaI methyltransferase (M.HhaI), we performed different molecular simulation approaches on M.HhaI-DNA-S-adenosylhomocysteine ternary complex. The results demonstrate that the nonspecific binding of DNA to M.HhaI is initially induced by electrostatic interactions. Differences in chemical environment between the major and minor grooves determine the orientation of DNA. Gln237 at the target recognition loop recognizes the GCGC base pair from the major groove side by hydrogen bonds. In addition, catalytic loop motion is a key factor during this process. Our study indicates that base flipping is likely to be an “induced-fit” process. This study provides a solid foundation for future studies on the discovery and development of mechanism-based DNA methyltransferases regulators.

Background: High levels of the post-translational modification O-GlcNAcylation (O-GlcNAc) are found in multiple cancers, including bladder cancer. Autophagy, which can be induced by stress from post-translational modifications, plays a critical role in maintaining cellular homeostasis and regulating tumorigenesis. The impact of O-GlcNAcylation on autophagy in bladder cancer remains unclear. Here, we evaluate the change in autophagic activity in response to O-GlcNAcylation and explore the potential mechanisms. Methods: O-GlcNAcylation levels in bladder cancer cells were altered through pharmacological or genetic manipulations: treating with 6-diazo-5-oxo-norleucine (DON) or thiamet-G (TG) or up-and downregulation of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA). Autophagy was determined using fluorescence microscopy and western blotting. Co-immunoprecipitation (Co-IP) assays were performed to evaluate whether the autophagy regulator AMP-activated protein kinase (AMPK) was O-GlcNAc modified. Results: Cellular autophagic flux was strikingly enhanced as a result of O-GlcNAcylation suppression, whereas it decreased at high O-GlcNAcylation levels. Phosphorylation of AMPK increased after the suppression of O-GlcNAcylation. We found that O-GlcNAcylation of AMPK suppressed the activity of this regulator, thereby inhibiting ULK1 activity and autophagy. Conclusion: We characterized a new function of O-GlcNAcylation in the suppression of autophagy via regulation of AMPK.

Constipation, a gastrointestinal function disorder, is one of the side effects of paclitaxel (PTX) chemotherapy. Shenhuang plaster (SHP) application on the Shenque acupoint promotes gut motility in clinical settings. In this study, we elucidated the ingredients in SHP and evaluated its effects on PTX-induced constipation using a tumour-bearing mouse model. SHP was prepared using the traditional Chinese plaster preparation method. The ingredients were analysed using UPLC-MS/MS and identified via screening in a standard drug database. The gastrointestinal transit was evaluated by the movement of a fluorescein-labelled dextran in the gastrointestinal tract. A histological study of the mucosa was carried out after haematoxylin and eosin staining. mRNA expression was assessed using real-time RT-PCR, and the foetal microbiota composition was elucidated through 16 s rDNA sequencing and BLAST analysis. Our results indicate that the application of SHP attenuated weight gain inhibition by PTX; however, no inhibitory effect was observed on tumour growth. PTX-induced sluggish intestine, villus, and mucosal base layer damage were significantly improved following the application of SHP. Further, SHP enhanced the stimulation efficiency of PTX on TLR4 and its downstream cytokines, as well as on IL-1β in intestinal cells. SHP combined with PTX reshaped the microbiota, which showed beneficial effects on health. Hence, these results provide evidence that SHP alleviates PTX-induced constipation and intestinal morphological damage but augments the effects of PTX on the expression of cytokines in the TLR4 pathway and IL-1β. Therefore, we propose that SHP stimulates the host immune response to eradicate cancer cells.

Objectives: Asthma is a chronic airway inflammatory disease, which is characterized by airway remodeling, hyperreactivity and shortness of breath. Paeoniflorin is one of the major active ingredients in Chinese peony, which exerts anti-inflammatory and immune-regulatory effects in multiple diseases. However, it remains unclear whether paeoniflorin treatment can suppress allergic asthma.Methods: In this study, we evaluated the effect of paeoniflorin on lung function and airway inflammation in asthmatic mice. These asthmatic Balb/c mice were first sensitized and constructed through ovalbumin (OVA) motivation. Subsequently, we determined the mechanism of action of paeoniflorin in treating allergic asthma through integrated transcriptomic and metabolomic data sets.Results: Our results demonstrated that many genes and metabolites were regulated in the paeoniflorin-treated mice. Moreover, the potential target proteins of paeoniflorin played important roles in fatty acid metabolism, inflammatory response, oxidative stress and local adhesion.Conclusion: Paeoniflorin has a beneficial effect on asthma, which may be achieved through regulating fatty acid metabolism, inflammatory response and the adhesion pathway at system level.

Cannabinoid receptor 2 (CNR2) is a major receptor in the endogenous cannabinoid system. In recent years, many studies have shown that the receptor is closely associated with schizophrenia. This study examined the relationship between CNR2 gene polymorphisms (rs2501432C/T, rs2229579C/T, rs2501401G/A) and schizophrenia. Three hundred sixteen schizophrenia patients and 334 healthy subjects were recruited as case and control groups, respectively. For rs2501432, the CT/TT genotype frequencies in the dominant model, TT genotype frequencies in the additive model, and T allele frequencies of the case group were lower than the control (P < 0.05), and the CT and TT genotypes and T allele frequencies of the male case group were significantly lower than the control (P < 0.05). For rs2229579, the T allele frequencies of the case group were higher than the control (P < 0.05). The T-C-G haplotype in the case group had a significantly lower frequency compared with the controls, but the T-T-A haplotype frequencies were higher in the case group than in the controls (P < 0.05). Our results suggest that the T allele of rs2501432 may be a protective factor, particularly in males, but the T allele of rs2229579 may be a risk factor for schizophrenia. T-C-G may be a protective haplotype for schizophrenia, but not the T-T-A haplotype.