Molecular targets and mechanisms of different aberrant alternative splicing in metastatic liver cancer.

Metastasis remains a major challenge in the successful management of malignant diseases. The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon, stomach, and pancreatic cancers, as well as melanoma, breast cancer, and sarcoma. As an important factor that influences the development of metastatic liver cancer, alternative splicing drives the diversity of RNA transcripts and protein subtypes, which may provide potential to broaden the target space. In particular, the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence, progression, aggressiveness, and drug resistance of cancers caused by the selective splicing of specific genes. This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer. It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes, abnormal splicing, and the contribution of hypoxia to these changes during metastasis.

Knockdown of the glutamate-gated chloride channel gene decreases emamectin benzoate susceptibility in the fall armyworm, Spodoptera frugiperda.

Emamectin benzoate (EB), a derivative of avermectin, is the primary insecticide used to control the fall armyworm (FAW) in China. However, the specific molecular targets of EB against FAW remain unclear. In this study, we cloned the glutamate-gated chloride channel (GluCl) gene, which is known to be a primary molecular target for avermectin. We first investigated the transcript levels of SfGluCl in FAW and found that the expression level of SfGluCl in the head and nerve cord was significantly higher than that in other tissues. Furthermore, we found that the expression level of SfGluCl was significantly higher in eggs than that in other developmental stages, including larvae, pupae, and adults. Additionally, we identified three variable splice forms of SfGluCl in exons 3 and 9 and found that their splice frequencies remained unaffected by treatment with the LC50 of EB. RNAi mediated knockdown of SfGluCl showed a significant reduction of 42% and 65% after 48 and 72 h of dsRNA feeding, respectively. Importantly, knockdown of SfGluCl sifgnificantly reduced LC50 and LC90 EB treatment induced mortality of FAW larvae by 15% and 44%, respectively, compared to the control group feeding by dsEGFP. In contrast, there were no significant changes in the mortality of FAW larvae treated with the control insecticides chlorantraniliprole and spinetoram. Finally, molecular docking simulations revealed that EB bound to the large amino-terminal extracellular domain of SfGluCl by forming five hydrogen bonds, two alkyl hydrophobic interactions and one salt bridge. These findings strongly suggest that GluCl may serve as one of the molecular targets of EB in FAW, shedding light on the mode of action of this important insecticide.

The oncogenic role of MUC12 in RCC progression depends on c-Jun/TGF-ß signalling.

Renal cell carcinoma (RCC) is a common kidney cancer worldwide. Even though current treatments show promising therapeutic effectiveness, metastatic RCC still has limited therapeutic options so that novel treatments were urgently needed. Here, we identified that MUC12 was overexpressed in RCC patients and served as poor prognostic factor for RCC progression. Overexpression of MUC12 increased RCC cell growth and cell invasion while deficiency of MUC12 exerted opposite effects on RCC cells. Mechanistic dissection demonstrated that MUC12-mediated RCC cell growth and cell invasion were dependent of TGF-ß1 signalling because they could be blocked in the presence of TGF-ß1 inhibitor. Moreover, the regulation of TGF-ß1 by MUC12 relied on the transactivation of c-Jun. MUC12 promoted the recruitment of c-Jun on the promoter of TGF-ß1, leading to its transcription. Importantly, knockdown of c-Jun also attenuated MUC12-mediated TGF-ß1 induction and RCC cell invasion. In summary, our study defines the role of MUC12 in RCC progression and provides rational to develop novel targeted therapy to battle against RCC.

Synthesis and potent inhibitory activities of carboxybenzyl-substituted 8-(3-(R)-aminopiperidin-1-yl)-7-(2-chloro/cyanobenzyl)-3-methyl-3,7-dihydro-purine-2,6-diones as dipeptidyl peptidase IV (DPP-IV) inhibitors.

Fourteen 3-methyl-3,7-dihydro-purine-2,6-dione derivatives 1-14 bearing carboxybenzyl and 2-chloro/cyanobenzyl groups at the N-1 and N-7 positions, respectively, were synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitors. These compounds were characterized on the basis of NMR ((1)H and (13)C) and ESI MS data. In vitro bioassay indicates that most of these compounds showed moderate to good inhibitory activities against DPP-IV. Among them, compound 13 (IC50=36 nM) exhibited comparable activity with a positive control, Sitagliptin (IC50=16 nM). In addition, the structure-activity relationship of these compounds is also briefly discussed.

[Lumbar intervertebral disc protrusion treated with Santong tuina therapy: a multi-central randomized controlled trial].

OBJECTIVE: To observe the difference in the efficacy on lumbar intervertebral disc protrusion (LIDP) between Santong tuina therapy and conventional tuina therapy. METHODS: Multi-central, random and controlled clinical trial was carried out. One hundred and twenty cases of LIDP were randomized into an observation group and a control group, 60 cases in each one. In observation group, Santong tuina therapy was used. In control group, conventional tuina therapy was adopted. The clinical efficacy was observed in two groups, and lumbar vertebral function was scaled before and after treatment in two groups. RESULTS: The total effective rate was 95.0% (57/60) in observation group and was 96.7% (58/60) in control group, without significant statistical difference in comparison (P > 0.05). The cured and markedly effective rate was 81.7% (49/60) in observation group and was 63.3% (38/60) in control group, indicating significant statistical difference in comparison (P < 0.05). The self-comparison of lumbar vertebral function before and after treatment presented statistical significance in either observation group (12.25 +/- 3.15, 25.56 +/- 5.27) or control group (13.32 +/- 3.26, 20.46 +/- 4.25, both P < 0.05); additionally, there was significant difference in the comparison between groups after treatment (P < 0.05). The therapy adopted in observation group improved lumbar vertebral function much significantly. CONCLUSION: In the treatment of LIDP, Santong tuina therapy achieves much better clinical efficacy as compared with conventional tuina therapy.