The novel antitumor compound clinopodiside A induces cytotoxicity via autophagy mediated by the signaling of BLK and RasGRP2 in T24 bladder cancer cells.

In the study, we investigated the anti-cancer effect of clinopodiside A and the underlying mechanisms using T24 bladder cancer cells as an experimental model. We found that the compound inhibited the growth of the bladder cancer cells in vitro and in vivo in a in a concentration- and dose-dependent manner, respectively, which showed a combinational effect when used together with cisplatin. In the bladder cancer cells, clinopodiside A caused autophagy, which was mediated by the signaling of BLK and RasGRP2, independently. Inhibition of the autophagy by chemical inhibitor 3-methyladenine or by the inhibition of the signaling molecules attenuated the cytotoxicity of clinopodiside A. Further analyses showed that clinopodiside A acted in synergism with cisplatin which itself could trigger both autophagy and apoptosis, which occurred with concomitant enhancements in autophagy and the cisplatin-evoked apoptosis. In conclusion, our results suggest that clinopodiside A inhibits the growth of the bladder cancer cells via BLK- and RasGRP2-mediated autophagy. The synergistic effect between clinopodiside A and cisplatin is attributed to the increases in autophagy and autophagy-promoted apoptosis. Clinopodiside A is a promising investigational drug for the treatment of cancer, at least blabber, which can be used alone or in combination with clinical drug(s).

The prevalence and characteristics of alexithymia in patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Alexithymia is common in patients with type 2 diabetes mellitus (T2DM). Although the estimated prevalence of alexithymia in patients with T2DM is widely reported, these results have not been synthesized. AIM: To systematically assess the prevalence and characteristics of alexithymia in patients with T2DM. METHODS: We searched for relevant publications in PubMed, Embase, Web of Science, China Knowledge Resource Integrated Database, Wanfang Database, Chinese Biomedical Database, and Weipu Database. The prevalence of alexithymia, the mean scores, and standard deviations of the total scale of the 20-item Toronto Alexithymia Scale (TAS-20) were pooled using random effects meta-analysis in Stata 13.0, with studies stratified by study location in this meta-analysis. RESULTS: This meta-analysis included thirteen articles. Pooled prevalence of alexithymia (TAS-20 total scores ≥61) were 43.0% (95%CI 35.0-51.0%), and the prevalence of alexithymia was higher in China (45.0%, 95%CI 36.0-54.0%) compared with non-China (41.0%, 95%CI 29.0-54.0%). The pooled mean score for the TAS-20 total scale was 57.70 (95% CI 55.25-60.15). Leave-one-out analysis showed that none of the studies significantly impacted the overall pooled results. CONCLUSIONS: This meta-analysis indicated a high prevalence of alexithymia in patients with T2DM. Thus, clinicians need to be aware of and assess appropriately for alexithymia in patients with T2DM.

The binding between NPM and H2B proteins signals for the diabetes-associated centrosome amplification.

Diabetes not only increases the risk for cancer but also promotes cancer metastasis. Centrosome amplification (CA) is sufficient to initiate tumorigenesis and can enhance the invasion potential of cancer cells. We have reported that diabetes can induce CA, with diabetic pathophysiological factors as the triggers, which involves the signaling of nucleophosmin (NPM). Thus, CA can serve as a candidate biological link between diabetes and cancer. In the present study, we attempted to identify the NPM binding partners and investigated whether the binding between NPM and its partner mediated the CA. We confirmed that high glucose, insulin, and palmitic acid cancer could elicit CA in the HCT16 colon cancer cells and found that the experimental treatment increased the binding between NPM and H2B, but not between p-NPM and H2B. The molecular docking analysis supported the fact that NPM and H2B could bind to each other through various amino acid residues. The treatment also increased the colocalization of NPM and H2B in the cytosol. Importantly, disruption of the NPM1-H2B complex by individual knockdown of the protein level of NPM or H2B led to the inhibition of the treatment-evoked CA. In conclusion, our results suggest that the binding between NPM and H2B proteins signals for the CA by high glucose, insulin, and palmitic acid.

A computational method to predict topologically associating domain boundaries combining histone Marks and sequence information.

BACKGROUND: The three-dimensional (3D) structure of chromatins plays significant roles during cell differentiation and development. Hi-C and other 3C-based technologies allow us to look deep into the chromatin architectures. Many studies have suggested that topologically associating domains (TAD), as the structure and functional unit, are conserved across different organs. However, our understanding about the underlying mechanism of the TAD boundary formation is still limited. RESULTS: We developed a computational method, TAD-Lactuca, to infer this structure by taking the contextual information of the epigenetic modification signals and the primary DNA sequence information on the genome. TAD-Lactuca is found stable in the case of multi-resolutions and different datasets. It could achieve high accuracy and even outperforms the state-of-art methods when the sequence patterns were incorporated. Moreover, several transcript factor binding motifs, besides the well-known CCCTC-binding factor (CTCF) motif, were found significantly enriched on the boundaries. CONCLUSIONS: We provided a low cost, effective method to predict TAD boundaries. Above results suggested the incorporation of sequence features could significantly improve the performance. The sequence motif enrichment analysis indicates several gene regulation motifs around the boundaries, which is consistent with TADs may serve as the functional units of gene regulation and implies the sequence patterns would be important in chromatin folding.

[The role of interleukin-1ß on the pulmonary fibrosis in mice exposed to crystalline silica].

OBJECTIVE: This study was designed to evaluate the role of interleukin (IL)-1ß in the development of fibrosis in mice exposed to silica. METHODS: The total of 96 Male C57BL/6 mice were divided into four groups. (1) blank control group, (2) PBS group in which mice were instilled with PBS only, (3) silica + IL-1ß mAb group in which mice were instilled with 2.5 mg silica dust and 40 µg anti-IL-1ß mAb, (4) silica group in which mice were instilled with 2.5 mg silica dust and 40 µg IgG. The final volume of suspension or PBS instilled into the mouse was 50 µl. At 7, 28 and 84 days after treatment, 8 mice were sacrificed in each group. Then BALF was collected for the count of inflammatory cells and cytokines determination. The lung tissues were collected for the detecting of mRNA levels of fibrogenic molecules. RESULTS: The collagen deposition induced by silica in the lung tissues was partly inhibited by anti-IL-1ß. A intensely pulmonary cytokines such as IL-1ß, TNF-α, MCP-1 were induced by crystalline silica exposure, and partly inhibited by anti-IL-1ß. The levels of TGF-ß and fibronectin in silica exposed mice were significantly elevated than those in control mice at days 28 and 84 after treatment (P < 0.01). And the mRNA levels of TGF-ß, collagen I and fibronectin were significantly decreased in silica+IL-1ß mAb group when compared with those in silica group at days 7, 28 and 84 (P < 0.01). There was a significant decrease of the ratios of IFN-γ/IL-4 in both silica+anti-IL-1ß mAb and silica groups when compared with those in control mice at the above three time points (P < 0.01). However, the IFN-γ/IL-4 ratios in silica+anti-IL-1ß group were significantly higher than those in silica group at 7, 28 and 84 days (P < 0.05 or P < 0.01). CONCLUSION: IL-1ß may promote the pulmonary fibrosis in mice exposed to silica.