The Natural Compound Dehydrocrenatidine Attenuates Nicotine-Induced Stemness and Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma by Regulating a7nAChR-Jak2 Signaling Pathways.

BACKGROUND: Exposure to nicotine has been observed associated with tumor progression, metastasis, and therapy resistance of many cancers. Hepatocellular carcinoma (HCC) is one major cancer related to the liver and the most difficult to treat malignancies worldwide. The underlying mechanism of nicotine in the stimulation of HCC tumorigenesis is still not studied well. METHODS: Classically, nicotine binds to nicotinic acetylcholine receptors (nAChRs) and induces many downstream cancer-associated signaling pathways. Big data analysis is used to explore the importance of a7nAChR-Jak2 axis in the progression of hepatocellular carcinoma. Bioinformatic analysis was performed to determine gene associated with a7nAChR-Jak2 axis of HCC patients. Biological importance of a7nAChR-Jak2 axis was investigated in vitro (Hun7 and HepG2 cell lines), and athymic nude mouse models bearing HepG2-HCC cells xenografts were established in vivo. RESULT: We found that nicotine exposure stimulated the HCC tumorigenicity by inducing the expression of one of the key nAChRs subunit that is α7nAChR as well as the expression of Janus kinase (JAK)-2. In both the in vitro and in vivo studies, the reduced overexpression of α7nAChR and increased sensitization of HCC towards treatment is observed with dehydrocrenatidine (DHCT), a novel and potent JAK family kinase inhibitor. Interestingly, DHCT treatment results in the reduction of the epithelial-mesenchymal transition process which leads to a significant reduction of clonogenicity, migratory, and invasive ability of HCC cells. Moreover, DHCT treatment also inhibits the cancer stem cell phenotype by inhibiting the tumor-sphere formation and reducing the number of ALDH1+ cells population in nicotine-stimulated HCC cells. CONCLUSIONS: Taken together, the presented results indicate the positive effect of inhibition of nicotine induced overexpression of α7nAChR and JAK2, unique to HCC. Thus, these findings suggest the nicotine effect on HCC progression via α7nAChR-mediated JAK2 signaling pathways, and DHCT treatment enhances the therapeutic potential of HCC patients via overcoming/reversing the effect of nicotine in HCC patients.

Surgical treatment of midclavicular fractures in the elderly: a comparison of locking and nonlocking plates.

Operative treatment of midclavicular fractures in patients older than 60 years poses an increased risk of fixation failure. Although plating of midclavicular fractures in the elderly is still a popular fixation method, osteopenic bone may result in plate loosening and fixation failure. The purpose of this study is to prospectively evaluate and compare the clinical outcomes of midclavicular fractures in patients older than 60 years who are treated with either a locking compression plate or nonlocking plate. Sixty-four elderly patients with midclavicular fractures were surgically treated with either a locking compression plate or nonlocking plate, which included dynamic compression plates and reconstruction plates. The locking compression plate group included 29 patients with an average age of 69.1 years. The nonlocking plate group included 35 patients with an average age of 66.3 years. Both groups were similar for age, gender, injury mechanism, fracture patterns, and confounding medical condition (P>.5). However, the locking compression plate group had lower complication rates compared to the nonlocking plate group (P=.087). In addition, the locking compression plate group had higher rates of return to work and exercise (P=.02, P=.016, respectively). If surgery of elderly patients with midclavicular fractures is indicated, internal fixation with a locking compression plate is preferable to a nonlocking plate.

alpha-melanocyte-stimulating hormone gene transfer attenuates inflammation after bile duct ligation in the rat.

Cholestasis occurs in a wide variety of human liver diseases, and hepatocellular injury is an invariant feature of cholestasis causing liver dysfunction and inflammation, promoting fibrogenesis, and ultimately leading to liver failure. alpha-Melanocyte-stimulating hormone (alpha-MSH) is a potent anti-inflammatory agent in many models of inflammation, suggesting that it inhibits a critical step common to different forms of inflammation. The aim of this study was to investigate whether the gene transfer of alpha-MSH could attenuate hepatic inflammation after bile duct ligation in the rat. Studies were performed in bile duct-ligated (BDL) rats. Hydrodynamic-based gene transfection with alpha-MSH plasmid via rapid tail vein injection was performed 30 min after ligation of bile duct. The endpoints were studied as markers of inflammation 7 days after bile duct ligation. alpha-MSH expression in liver via a single administration of naked plasmid was demonstrated. Liver inflammation index, including neutrophil infiltration and serum alanine aminotransferase, were significantly reduced in alpha-MSH gene transfer rats. Markers for liver inflammation, including expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and inducible NO synthase (iNOS) mRNA, as assessed by real-time PCR, were also attenuated by alpha-MSH gene therapy. Expression of iNOS protein in liver diminished after alpha-MSH gene transfer. Consistent with these data, hepatic stellate cells (HSC) and Kupffer cells were markedly inhibited in alpha-MSH gene-treated rats. Our findings show that gene transfer of alpha-MSH could attenuate hepatic inflammation after bile duct ligation in the rat.