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Receptor activator of nuclear factor-κB ligand (RANKL) has been found to induce osteoclastogenesis and bone resorption. However, the underlying molecular mechanisms remain unclear. Via conducting a series of biochemical experiments with in vitro cell lines, this study investigated the role and mechanism of NADPH oxidase 4 (Nox4) in RANKL-induced autophagy and osteoclastogenesis. In the current study, we found that RANKL dramatically induced autophagy and osteoclastogenesis, inhibition of autophagy with chloroquine (CQ) markedly attenuates RANKL-induced osteoclastogenesis. Interestingly, we found that the protein level of Nox4 was remarkably upregulated by RANKL treatment. Inhibition of Nox4 by 5-O-methyl quercetin or knockdown of Nox4 with specific shRNA markedly attenuated RANKL-induced autophagy and osteoclastogenesis. Furthermore, we found that Nox4 stimulated the production of nonmitochondrial reactive oxygen species (ROS), activating the critical unfolded protein response (UPR)-related signaling pathway PERK/eIF-2α/ATF4, leading to RANKL-induced autophagy and osteoclastogenesis. Blocking the activation of PERK/eIF-2α/ATF4 signaling pathway either by Nox4 shRNA, ROS scavenger (NAC) or PERK inhibitor (GSK2606414) significantly inhibited autophagy during RANKL-induced osteoclastogenesis. Collectively, this study reveals that Nox4 promotes RANKL-induced autophagy and osteoclastogenesis via activating ROS/PERK/eIF-2α/ATF4 pathway, suggesting that the pathway may be a novel potential therapeutic target for osteoclastogenesis-related disease.

Malignant pleural mesothelioma (MPM) is a type of cancer originating from the pleura with high aggressiveness and poor prognosis. A timely diagnosis is crucial to improve its prognosis. Laboratory biomarkers have significant advantages of reduced invasiveness, low cost, and are observer‐independent, and therefore represent a promising diagnostic tool for MPM. MicroRNA is a family of non‐coding RNA that regulates gene expression at the post‐transcriptional level. Accumulated studies showed that microRNA, either in tissue, circulating, and body fluid, has potential diagnostic value for various disorders. Here, we reviewed the diagnostic value of microRNA for MPM., Malignant pleural mesothelioma (MPM) is a type of cancer originating from the pleura with high aggressiveness and poor prognosis, Laboratory biomarkers have significant advantages of reduced invasiveness, low cost, and are observer‐independent, and therefore represent a promising diagnostic tool for MPM. Here, we reviewed the diagnostic value of microRNA for MPM.

Background: Whether routine urinary analysis has a net benefit for urinary tract infection (UTI) screening is unclear. Methods: Using the laboratory information system (LIS), we retrospectively extracted the data of urine culture and routine analysis between January 2017 and April 2017. Receiver operating characteristic (ROC) curve, logistic regression model, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used to estimate the screening performance of routine urinary analysis. Decision curve analysis (DCA) was used to estimate the net benefit of routine urinary analysis. Results: A total of 927 specimens with 156 UTIs were included in the present study. The area under ROC curves (AUCs) of white blood cells (WBCs) and bacteria were 0.729 and 0.836, respectively. The logistic regression model incorporating WBCs, bacteria and nitrite together had an AUC of 0.851, which is significantly higher than that of WBCs. NRI and IDI analyses also indicated that WBCs, bacteria and nitrite, when used together, had better a screening performance than each single test alone. DCA revealed that 0.08 net benefit can be obtained for bacteria and the model, while the net benefit of WBCs is limited. Conclusions: WBCs, bacteria and nitrite, when used together, can significantly improve the efficiency for UTI screening. Bacteria and the model incorporating WBCs, bacteria and nitrite have a net benefit in UTI screening, while the net benefit of WBCs, when used alone, is limited.

Most lung cancer bone metastasis are characterized by osteolytic destruction and osteoblastic activity is significantly decreased, suggesting that hypoxia may play a critical role in the process, but the underlying mechanisms remain unknown. Semaphorin 4D (Sema4D) is a recently discovered osteogenic inhibitory factor that is expressed at high levels in lung cancers. Here, CoCl2-induced hypoxia significantly enhanced the inhibitory effect of lung cancer cell conditioned media on osteoblast differentiation by inducing the expression and secretion of Sema4D in a HIF-1α- but not HIF-2α-dependent manner. Moreover, HIF-1α directly regulated Sema4D expression by binding to bases 1171 to 798 in the Sema4D promoter. Furthermore, hypoxia increased Sema4D secretion by upregulating a disintegrin and metalloproteinase 17 (ADAM17) expression in lung cancer in a HIF-1α-dependent manner. In bone metastasis samples from 49 patients with lung cancer, Sema4D and ADAM17 expression significantly correlated with HIF-1α expression and strongly correlated with a poor differentiation status and osteolytic bone destruction. These results provide the first evidence that HIF-1α-induced Sema4D expression and secretion play important roles in lung cancer osteolytic bone metastasis by inhibiting osteoblast differentiation, thereby providing potential strategies for the treatment of bone metastasis via targeting osteoblasts.

Objective To observe the expression changes in substance P (SP) and c-fos in rat spinal cord after acute millimeter-wave (MMW) exposure, and explore the mechanism of thermal hyperalgesia at the spinal level. Methods The back skin of SD rats was exposed to 35 GHz MMW (40W/cm2) for 0s (control group), 30s, 1min, or 3min. The corresponding segment of the spinal cord was taken at 0min, 5min, 10min, 1h and 3h after MMW irradiation for total RNA and protein extraction. The expressions of SP and c-fos mRNA were measured by real-time RT-PCR, and the expression of c-fos protein was detected by Western blotting. Results No significant difference was found between the control group and irradiation groups in SP and c-fos mRNA expression in the corresponding segment of spinal cord after MMW irradiation for 30s. After MMW irradiation for 1min, the SP and c-fos mRNA expressions in the corresponding segment of spinal cord increased significantly at 10min time point, and then decreased to the level of control group. After MMW irradiation for 3min, the SP and c-fos mRNA expression in the corresponding segment of spinal cord increased significantly at 5min, 10min and 1h time points, and decreased to the level of control group at 3h. No significant change was found in c-fos protein expression in the corresponding segment of spinal cord after MMW irradiation for 30s and 1min. After MMW irradiation for 3min, the c-fos protein expression in the corresponding segment of spinal cord increased significantly at 5min and 10min time point, and then decreased to the level of control group. Conclusion The increase of SP expression in rat skin after MMW irradiation may be related to the increase of SP and c-fos expressions in the corresponding segment of the spinal cord induced by thermal pain stimulation.

To determine the differential protein expressions of epithelial mesenchymal transition (EMT) markers E-cadherin and vimentin in hepatocellular carcinorma (HCC) and to investigate their correlation to the molecular mechanisms of metastasis to explore their potential utility as prognostic indicators of HCC.Tumor tissues and patient-matched adjacent non-tumor tissues were collected from individuals diagnosed with HCC. E-cadherin and vimentin protein expressions in the tissue specimens were quantified by western blot with densitometry of fluorescence emission and comparatively analyzed to determine the associations with molecular and clinical features. The expressions of E-cadherin and vimentin, as well as the other EMT-related protein Twist, were also detected in the tissue specimens by immunohistochemistry. Statistical analyses were carried out by paired-samples t-test, Mann-Whitney test, and Spearman rank correlation analysis.E-cadherin expression was significantly lower in tumor tissues (0.082 +/- 0.063 vs. adjacent non-tumor tissues: 0.226 +/- 0.215, t = -4.050, P less than 0.01), lower in patients with portal vein tumor thrombus (vs. non-thrombic HCC patients, P = 0.001), and correlated with TNM stage (III/IVI/II, P = 0.003). Vimentin expression was significantly higher in tumor tissues (vs. adjacent non-tumor tissues, P = 0.002), negatively correlated with E-cadherin expression (t = -0.509, P = 0.004), and closely associated with some clinical parameters, such as portal vein tumor thrombus (P less than 0.01), TNM stage (P less than 0.01), and Milan criteria (P = 0.005). Immunohistochemistry showed that E-cadherin expression was very weak in tumors but very strong in the cell membranes of non-tumor tissues, and that vimentin and Twist expressions were strong in tumors but undetectable in non-tumor tissue.Expression levels of the EMT markers E-cadherin and vimentin in HCC are related to clinical parameters, including portal vein tumor thrombus and TNM stage, and may represent useful prognostic markers of metastasis.

A novel heptacyclic alkaloid, for which we coin the name chilocorine , was isolated from a ladybird beetle, Chilocorus cacti . It has a unique structure made up of two tricyclic substructures, 2-methylperhydro- 9b -azaphenalene and 3,4-dimethyloctahydro- 8b -azaacenaphthylene. The proposed structure is based on mass spectrometric, ultraviolet spectroscopic, and NMR evidence.

Recent studies suggest that oxidative stress and mitochondrial dysfunction play important roles in the neurotoxicity of nickel. Because mitochondrial DNA (mtDNA) is highly vulnerable to oxidative stress and melatonin can efficiently protect mtDNA against oxidative damage in various pathological conditions, the aims of this study were to determine whether mtDNA oxidative damage was involved in the neurotoxicity of nickel and to assay the neuroprotective effects of melatonin in mtDNA. In this study, we exposed mouse neuroblastoma cell lines (Neuro2a) to different concentrations of nickel chloride (NiCl(2), 0.125, 0.25, and 0.5 mm) for 24 hr. We found that nickel significantly increased reactive oxygen species (ROS) production and mitochondrial superoxide levels. In addition, nickel exposure increased mitochondrial 8-hydroxyguanine (8-OHdG) content and reduced mtDNA content and mtDNA transcript levels. Consistent with this finding, nickel was found to destroy mtDNA nucleoid structure and decrease protein levels of Tfam, a key protein component for nucleoid organization. However, all the oxidative damage to mtDNA induced by nickel was efficiently attenuated by melatonin pretreatment. Our results suggest that oxidative damage to mtDNA may account for the neurotoxicity of nickel. Melatonin has great pharmacological potential in protecting mtDNA against the adverse effects of nickel in the nervous system.

Six quinones were identified from the defensive secretion of the millipede Floridobolus penneri. The two major components, 2-methyl-1,4-benzoquinone [1] and 2-methoxy-3-methyl-1,4-benzoquinone [3], previously characterized, comprise 95% of the secretion. One of the minor compounds, 2,5-dimethyl-3-methoxy-1,4-benzoquinone [4], is a new natural product. Another, 2-hydroxy-3-methyl-1,4-benzoquinone [2], had been tentatively characterized from a microbial source. The other two components are 2,3-dimethoxy-1,4-benzoquinone [5] and 2,3-dimethoxy-5-methyl-1,4-benzoquinone [6]. No sex difference in the composition of the secretion was noted.

Two novel alkaloids, 2-(12-aminotridecyl)-pyrrolidine and its 1-(2-hydroxyethyl) derivative, are characterized from extracts of adult Mexican bean beetles. These pyrrolidines, together with a previously identified homotropane alkaloid, euphococcinine, account for 90% of the alkaloids present in this beetle. A number of piperidine derivatives are also identified as minor components. The total mixture represents the most complex bouquet of alkaloids reported hitherto from any coccinellid beetle.

Microorganisms that bring about the aerobic transformation of imidacloprid (IMI) were isolated and screened, and the microbial regio- and stereoselective hydroxylation of IMI was studied. Some bacteria and fungi transformed IMI to 5-hydroxyl IMI. Bacterium Stenotrophomonas maltophilia CGMCC 1.1788 resting cells transformed IMI into R-5-hydroxyl IMI at the highest conversion rate. The enzyme catalyzed the stereoselective hydroxylation at position C12 of IMI in the imidazolidine ring. Under acidic conditions, 5-hydroxyl IMI was converted into olefin IMI in high molar conversion yield. The olefin IMI exhibited about 19 and 2.2 times more insecticidal efficacy than IMI against horsebean aphid imago and nymph, respectively, and about 1.4 times more active than IMI against brown planthopper imago. The transformation rate of IMI by resting cells of S. maltophilia CGMCC 1.1788 was promoted significantly by some carbohydrates and organic acids. The reaction medium with 5% sucrose resulted in 8.3 times greater biotransformation yield as compared with that without sucrose.