Downregulation of AC092894.1 promotes oxaliplatin resistance in colorectal cancer via the USP3/AR/RASGRP3 axis.

BACKGROUND: Oxaliplatin resistance is a complex process and has been one of the most disadvantageous factors and indeed a confrontation in the procedure of colorectal cancer. Recently, long non-coding RNAs (lncRNAs) have emerged as novel molecules for the treatment of chemoresistance, but the specific molecular mechanisms mediated by them are poorly understood. METHODS: The lncRNAs associated with oxaliplatin resistance were screened by microarray. lncRNA effects on oxaliplatin chemoresistance were then verified by gain- and loss-of-function experiments. Finally, the potential mechanism of AC092894.1 was explored by RNA pull-down, RIP, and Co-IP experiments. RESULTS: AC092894.1 representation has been demonstrated to be drastically downregulated throughout oxaliplatin-induced drug-resistant CRC cells. In vivo and in vitro experiments revealed that AC092894.1 functions to reverse chemoresistance. Studies on the mechanism suggested that AC092894.1 served as a scaffold molecule that mediated the de-ubiquitination of AR through USP3, thereby increasing the transcription of RASGRP3. Finally, sustained activation of the MAPK signaling pathway induced apoptosis in CRC cells. CONCLUSIONS: In conclusion, this study identified AC092894.1 as a suppressor of CRC chemoresistance and revealed the idea that targeting the AC092894.1/USP3/AR/RASGRP3 signaling axis is a novel option for the treatment of oxaliplatin resistance.

LPS inhibits TRIM65 expression in macrophages and C57BL/6J mouse by activating the ERK1/2 signaling pathway.

Activated macrophages serve a key role in various inflammatory diseases, such as atherosclerosis and septic shock. Tripartite motif-containing protein 65 (TRIM65) has been previously reported to participate in tumor progression and lung inflammation. However, the molecular mechanisms that controls its expression under inflammatory conditions and its consequences in activated macrophages remain poorly understood. The present study first collected the tissues of C57BL/6J mice, smooth muscle cells, macrophages and endothelial cells to determine the expression and distribution of TRIM65 by reverse transcription-quantitative (RT-q) PCR and western blotting. Mouse and human macrophages were treated with LPS and C57BL/6J mice were intraperitoneally injected with LPS followed by isolation of spleen, lung, aorta and bone marrow. Following treatment, TRIM65 mRNA and protein level was examined by RT-qPCR and western blotting. The results showed that TRIM65 was highly expressed in organs of the immune system, such as the spleen, lymph node and thymus, but lowly expressed in heart, liver, brain and kidneys. TRIM65 was also highly expressed in macrophages and endothelial cells. TRIM65 mRNA and protein expression levels were found to be decreased in LPS-treated macrophages in vitro and in tissues isolated from C57BL/6J mice intraperitoneally injected with LPS in vivo. In addition, to identify the signaling pathways by which LPS regulates TRIM65 expression, inhibitors of MAPK and Akt signaling pathways were used to treat macrophages followed by examination the expression of TRIM65 by western blotting. The results demonstrated that LPS-inhibited TRIM65 expression was blocked by treatment with the ERK1/2 inhibitor U0126. Moreover, the RT-qPCR results showed that TRIM65 knockout potentiated LPS-induced expression of inflammatory cytokines in macrophages. Taken together, data from the present study suggest that LPS decreased TRIM65 expression in macrophages and C57BL/6J mouse by activating the ERK1/2 signaling pathway, whilst TRIM65 knockout promoted macrophage activation. This information may facilitate the development of potential therapeutic strategies for the prevention and treatment of inflammatory diseases, such as atherosclerosis.

Osteopontin Promotes Macrophage M1 Polarization by Activation of the JAK1/STAT1/HMGB1 Signaling Pathway in Nonalcoholic Fatty Liver Disease.

Background and Aims: Osteopontin (OPN) is reported to be associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, the function of OPN in NAFLD is still inconclusive. Therefore, our aim in this study was to evaluate the role of OPN in NAFLD and clarify the involved mechanisms. Methods: We analyzed the expression change of OPN in NAFLD by bioinformatic analysis, qRT-PCR, western blotting and immunofluorescence staining. To clarify the role of OPN in NAFLD, the effect of OPN from HepG2 cells on macrophage polarization and the involved mechanisms were examined by FACS and western blotting. Results: OPN was significantly upregulated in NAFLD patients compared with normal volunteers by microarray data, and the high expression of OPN was related with disease stage and progression. OPN level was also significantly increased in liver tissue samples of NAFLD from human and mouse, and in HepG2 cells treated with oleic acid (OA). Furthermore, the supernatants of OPN-treated HepG2 cells promoted the macrophage M1 polarization. Mechanistically, OPN activated the janus kinase 1(JAK1)/signal transducers and activators of transcription 1 (STAT1) signaling pathway in HepG2 cells, and consequently HepG2 cells secreted more high-mobility group box 1 (HMGB1), thereby promoting macrophage M1 polarization. Conclusions: OPN promoted macrophage M1 polarization by increasing JAK1/STAT1-induced HMGB1 secretion in hepatocytes.

Cascade Radical Annulation of 2-Alkynylthio(seleno)anisoles with Acetone or Acetonitrile: Synthesis of 3-Acetomethyl- or Cyanomethyl-Substituted Benzothio(seleno)phenes.

An efficient method for the direct preparation of 3-aceto(cyano)methyl-substituted benzothio(seleno)phenes has been achieved through C(sp3)-H bond activation of easily available acetone or acetonitrile and cascade radical cyclization reaction. In this cascade radical cyclization reaction, C(sp2)-C(sp3) and C(sp2)-S bonds, as well as benzenethio(seleno)phene skeletons, can be built along with the cleavage of the C(sp3)-S bond, demonstrating the high step-economics and efficiency of this approach.

TRIM59 expression is regulated by Sp1 and Nrf1 in LPS-activated macrophages through JNK signaling pathway.

Activated macrophages play an important role in many inflammatory diseases including septic shock and atherosclerosis. TRIM59 has been showed to participate in many pathological processes, such as inflammation, cytotoxicity and tumorigenesis. However, the molecular mechanisms controlling its expression in activated macrophages are not fully understood. Here we report that TRIM59 expression is regulated by Sp1 and Nrf1 in LPS-activated macrophages. TRIM59 is highly expressed in macrophages, and markedly decreased by LPS stimuli in vivo and in vitro. TRIM59 promoter activity is also significantly suppressed by LPS and further analysis demonstrated that Sp1 and Nrf1 directly bound to the proximal promoter of TRIM59 gene. LPS treatment significantly decreased Sp1 expression, nuclear translocation and reduced its binding to the promoter, whereas increased Nrf1 expression, nuclear translocation and enhanced its binding to the promoter. Moreover, LPS-decreased TRIM59 expression was reversed by JNK inhibitor. Finally, TRIM59 level is significantly decreased during atherosclerosis progression. Taken together, our results demonstrated that TRIM59 expression was precisely regulated by Sp1 and Nrf1 in LPS-activated macrophages, which may be dependent on the activation of JNK signaling pathway and TRIM59 may be a potential therapeutic target for inflammatory diseases such as atherosclerosis.

[Efficacy observation in treating patients with postmenopausal coronary heart disease by bushen peiyuan principle].

OBJECTIVE: To observe the effect of Bushen Peiyuan Principle (BSPY, a TCM principle for tonifying Kidney and nourishing primordial energy) in treating patients with postmenopausal coronary heart disease (PCHD) instead of hormone treatment. METHODS: Twenty-five healthy women, who were monepaused for over 5 years but without CHD complication were allocated in Group A, 25 patients with PCHD complication suffered from estrogen contraindications such as embolism, hysteromyoma and mammary adenoma, were arranged in Group B, and 25 patients of PCHD without above-mentioned complications were divided into Group C. Group B and C was treated with BSPY and hormone replacement therapy respectively, and the drugs for hypolipidemics were withdrawn 1 month before the study. All the patients were observed for 3.5 months, with their blood levels of estradiol (E2) and lipids determined before and after treatment. RESULTS: Before treatment, the level of E2 in the two treated groups was lower than that in the normal group significantly (P < 0.01), and the parameters of blood lipids were abnormal in them. These abnormalities were improved after treatment significantly (P < 0.05 or P < 0.01). The level of E2 raised significantly (P < 0.01) after treatment in patients of Group C, with withdrawal vaginal bleeding presented in 90% of less than 56 years in age. In the Group B after treatment, level of E2 showed a slight rising and withdrawal vaginal bleeding was not found but with improvement of symptoms and signs better than that in Group C. CONCLUSION: Using BSPY in treating PCHD displayed significant adjustment on disturbance of blood lipid spectrum and improvement on clinical manifestations. As compared with the therapeutic effect of hormone replacement therapy, the risk of carcinogenesis caused by endometrial hyperplasia could be avoided because the blood level of E2 is only slightly increased by BSPY.