Imperatorin ameliorates pulmonary fibrosis via GDF15 expression

Background: Pulmonary fibrosis features in damaged pulmonary structure or over-produced extracellular matrix and impaired lung function, leading to respiratory failure and eventually death. Fibrotic lungs are characterized by the secretion of pro-fibrotic factors, transformation of fibroblasts to myofibroblasts, and accumulation of matrix proteins.Hypothesis/purpose: Imperatorin shows anti-inflammatory effects on alveolar macrophages against acute lung injury. We attempt to evaluate the properties of imperatorin on the basis of fibroblasts.Methods: In in vitro, zymosan was introduced to provoke pro-fibrotic responses in NIH/3T3 or MRC-5 pulmonary fibroblasts. Imperatorin was given for examining its effects against fibrosis. The mice were stimulated by bleomycin, and imperatorin was administered to evaluate the prophylactic potential in vivo.Results: The upregulated expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen protein due to zymosan introduction was decreased by imperatorin in fibroblasts. Zymosan induced the activity of transglutaminase 2 (TGase2) and lysyl oxidase (LOX), which was also inhibited by the administration of imperatorin. Imperatorin alone enhanced sirtuin 1 (SIRT1) activity and growth differentiation factor 15 (GDF15) secretion in fibroblasts via LKB1/AMPK/CREB pathways. In addition, GDF15 exerted a beneficial effect by reducing the protein expression of CTGF, α-SMA, and collagen and the activities of TGase and LOX. Moreover, orally administered imperatorin showed prophylactic effects on bleomycin-induced pulmonary fibrosis in mice.Conclusion: Imperatorin reduces fibrotic marker expression in fibroblasts and also increases GDF15 secretion via the LKB1/AMPK/CREB pathway, attenuating pro-fibrotic responses in vitro. Imperatorin also alleviates pulmonary fibrosis induced by bleomycin in vivo

Fulvestrant-Induced Cell Death and Proteasomal Degradation of Estrogen Receptor α Protein in MCF-7 Cells Require the CSK c-Src Tyrosine Kinase

Fulvestrant is a representative pure antiestrogen and a Selective Estrogen Receptor Down-regulator (SERD). In contrast to the Selective Estrogen Receptor Modulators (SERMs) such as 4-hydroxytamoxifen that bind to estrogen receptor α (ERα) as antagonists or partial agonists, fulvestrant causes proteasomal degradation of ERα protein, shutting down the estrogen signaling to induce proliferation arrest and apoptosis of estrogen-dependent breast cancer cells. We performed genome-wide RNAi knockdown screenings for protein kinases required for fulvestrant-induced apoptosis of the MCF-7 estrogen-dependent human breast caner cells and identified the c-Src tyrosine kinase (CSK), a negative regulator of the oncoprotein c-Src and related protein tyrosine kinases, as one of the necessary molecules. Whereas RNAi knockdown of CSK in MCF-7 cells by shRNA-expressing lentiviruses strongly suppressed fulvestrant-induced cell death, CSK knockdown did not affect cytocidal actions of 4-hydroxytamoxifen or paclitaxel, a chemotherapeutic agent. In the absence of CSK, fulvestrant-induced proteasomal degradation of ERα protein was suppressed in both MCF-7 and T47D estrogen-dependent breast cancer cells whereas the TP53-mutated T47D cells were resistant to the cytocidal action of fulvestrant in the presence or absence of CSK. MCF-7 cell sensitivities to fulvestrant-induced cell death or ERα protein degradation was not affected by small-molecular-weight inhibitors of the tyrosine kinase activity of c-Src, suggesting possible involvement of other signaling molecules in CSK-dependent MCF-7 cell death induced by fulvestrant. Our observations suggest the importance of CSK in the determination of cellular sensitivity to the cytocidal action of fulvestrant

Irreducible Elbow Dislocation Associated with Hill–Sachs-like Lesion over the Capitellum

Irreducible dislocation of the elbow is an uncommon event. We present the case of a posterolateral elbow dislocation after a fall injury in a 67-year-old woman. A closed reduction performed in the emergency department was unsuccessful since the limited passive range of motion resulted in difficulty to perform longitudinal traction and flexion. Computed tomography images showed that the posterolateral aspect of the capitellum was impacted by the tip of the coronoid process, thus appearing similar to the Hill–Sachs lesion in the humeral head. Subsequent open reduction of the elbow revealed the dislocation to be irreducible since the tip of the coronoid process had wedged into a triangular Hill–Sachs-like lesion in the capitellum. The joint was reduced by providing distal traction on the forearm, and main fragments were disengaged using digital pressure. At the 3-month follow-up, the patient reported no dislocations, and had an acceptable range of motion. Thus, we propose that to avoid iatrogenic injury to the joint or other nearby structures, irreducible dislocations should not be subjected to repeated manipulation

Vulnerability of welders to manganese exposure--a neuroimaging study

Increased manganese (Mn) exposure is known to cause cognitive, psychiatric and motor deficits. Mn exposure occurs in different occupational settings, where the airborne Mn level and the size of respirable particulates may vary considerably. Recently the importance of the role of the cerebral cortex in Mn toxicity has been highlighted, especially in Mn-induced neuropsychological effects. In this study we used magnetic resonance imaging (MRI) to evaluate brain Mn accumulation using T1 signal intensity indices and to examine changes in brain iron content using T2* contrast, as well as magnetic resonance spectroscopy (MRS) to measure exposure-induced metabolite changes non-invasively in cortical and deep brain regions in Mn-exposed welders, Mn-exposed smelter workers and control factory workers with no measurable exposure to Mn. MRS data as well as T1 signal intensity indices and T2* values were acquired from the frontal cortex, posterior cingulate cortex, hippocampus, and thalamus. Smelters were exposed to higher air Mn levels and had a longer duration of exposure, which was reflected in higher Mn levels in erythrocytes and urine than in welders. Nonetheless, welders had more significant metabolic differences compared to controls than did the smelter workers, especially in the frontal cortex. T1 hyperintensities in the globus pallidus were observed in both Mn-exposed groups, but only welders showed significantly higher thalamic and hippocampal T1 hyperintensities, as well as significantly reduced T2* values in the frontal cortex. Our results indicate that (1) the cerebral cortex, in particular the frontal cortex, is clearly involved in Mn neurotoxic effects and (2) in spite of the lower air Mn levels and shorter duration of exposure, welders exhibit more extensive neuroimaging changes compared to controls than smelters, including measurable deposition of Mn in more brain areas. These results indicate that the type of exposure (particulate sizes, dust versus fume) and route of exposure play an important role in the extent of Mn-induced toxic effects on the brain

Genetic copy number variants in myocardial infarction patients with hyperlipidemia

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease is the chief cause of death in Taiwan and many countries, of which myocardial infarction (MI) is the most serious condition. Hyperlipidemia appears to be a significant cause of myocardial infarction, because it causes atherosclerosis directly. In recent years, copy number variation (CNV) has been analyzed in genomewide association studies of complex diseases. In this study, CNV was analyzed in blood samples and SNP arrays from 31 myocardial infarction patients with hyperlipidemia.</p> <p>Results</p> <p>We identified seven CNV regions that were associated significantly with hyperlipidemia and myocardial infarction in our patients through multistage analysis (P<0.001), at 1p21.3, 1q31.2 (<it>CDC73</it>), 1q42.2 (<it>DISC1</it>), 3p21.31 (<it>CDCP1</it>), 10q11.21 (<it>RET</it>) 12p12.3 (<it>PIK3C2G</it>) and 16q23.3 (<it>CDH13</it>), respectively. In particular, the CNV region at 10q11.21 was examined by quantitative real-time PCR, the results of which were consistent with microarray findings.</p> <p>Conclusions</p> <p>Our preliminary results constitute an alternative method of evaluating the relationship between CNV regions and cardiovascular disease. These susceptibility CNV regions may be used as biomarkers for early-stage diagnosis of hyperlipidemia and myocardial infarction, rendering them valuable for further research and discussion.</p

Anti-Neuroinflammatory Effects of the Calcium Channel Blocker Nicardipine on Microglial Cells: Implications for Neuroprotection

Background/Objective Nicardipine is a calcium channel blocker that has been widely used to control blood pressure in severe hypertension following events such as ischemic stroke, traumatic brain injury, and intracerebral hemorrhage. However, accumulating evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play important roles in neurodegeneration, and the effect of nicardipine on microglial activation remains unresolved. Methodology/Principal Findings In the present study, using murine BV-2 microglia, we demonstrated that nicardipine significantly inhibits microglia-related neuroinflammatory responses. Treatment with nicardipine inhibited microglial cell migration. Nicardipine also significantly inhibited LPS plus IFN-γ-induced release of nitric oxide (NO), and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, nicardipine also inhibited microglial activation by peptidoglycan, the major component of the Gram-positive bacterium cell wall. Notably, nicardipine also showed significant anti-neuroinflammatory effects on microglial activation in mice in vivo. Conclusion/Significance The present study is the first to report a novel inhibitory role of nicardipine on neuroinflammation and provides a new candidate agent for the development of therapies for inflammation-related neurodegenerative diseases

Second-Hand Smoke–Induced Cardiac Fibrosis Is Related to the Fas Death Receptor Apoptotic Pathway without Mitochondria-Dependent Pathway Involvement in Rats

Exposure to environmental tobacco smoke has been epidemiologically linked to heart disease among nonsmokers. However, the molecular mechanism behind the pathogenesis of cardiac disease is unknown. In this study, we found that Wistar rats, exposed to tobacco cigarette smoke at doses of 5, 10, or 15 cigarettes for 30 min twice a day for 1 month, had a dose-dependently reduced heart weight to body weight ratio and enhanced interstitial fibrosis as identified by histopathologic analysis. The mRNA and activity of matrix metalloprotease-2 (MMP-2), representing the progress of cardiac remodeling, were also elevated in the heart. In addition, we used reverse-transcriptase polymerase chain reaction and Western blotting to demonstrate significantly increased levels of the apoptotic effecter caspase-3 in treated animal hearts. Dose-dependently elevated mRNA and protein levels of Fas, and promoted apoptotic initiator caspase-8 (active form), a molecule of a death-receptor–dependent pathway, coupled with unaltered or decreased levels of cytosolic cytochrome c and the apoptotic initiator caspase-9 (active form), molecules of mitochondria-dependent pathways, may be indicative of cardiac apoptosis, which is Fas death-receptor apoptotic-signaling dependent, but not mitochondria pathway dependent in rats exposed to second-hand smoke (SHS). With regard to the regulation of survival pathway, using dot blotting, we found cardiac insulin-like growth factor-1 (IGF-1) and IGF-1 receptor mRNA levels to be significantly increased, indicating that compensative effects of IGF-1 survival signaling could occur. In conclusion, we found that the effects of SHS on cardiomyocyte are mediated by the Fas death-receptor–dependent apoptotic pathway and might be related to the epidemiologic incidence of cardiac disease of SHS-exposed non-smokers

Forest leaf litter beetles of Taiwan: first DNA barcodes and first insight into the fauna

We report the publication of 953 DNA barcodes of forest leaf litter beetles from central Taiwan, in total representing 334 spe- cies of 36 beetle families. This is the first bulk of data from the Taiwanese Leaf Litter beetles project focused on uncovering the under-explored diversity of leaf litter beetles across Taiwan. Based on these data, we provide the first records of the following taxa for Taiwan: family Sphindidae (genus Aspidiphorus Ziegler, 1821); tribes Trichonychini, Ctenistini, and Bythinoplectini (all Staphylinidae: Pselaphinae); genera Gyrelon Hinton, 1942, Thyroderus Sharp, 1885, Cautomus Sharp, 1885 (all Cerylonidae), Dermatohomoeus Hlisnikovský, 1963 (Leiodidae), Paraploderus Herman, 1970 (Staphylinidae: Oxytelinae), Thinocharis Kraatz, 1859 (Staphylinidae: Paederinae), Cephennodes Reitter, 1884, Napoconnus Franz, 1957 (both Staphylinidae: Scydmaeninae), Bicava Belon, 1884 (Latridiidae), Otibazo Morimoto, 1961, Seleuca Pascoe, 1871 and Acallinus Morimoto, 1962 (all Curculioni- dae); species Oodes (Lachnocrepis) japonicus (Bates, 1873) (Carabidae: Licininae), Drusilla obliqua (Bernhauer, 1916) (Staphylin- idae: Aleocharinae) and Coccotrypes advena Blandford, 1894 (Curculionidae: Scolytinae). The records of Anapleus Horn, 1873 (Histeridae) and Batraxis Reitter, 1882 (Staphylinidae: Pselaphinae) have been confirmed. The male of Sivacrypticus taiwanicus Kaszab, 1964 (Archeocrypticidae) is described for the first time. Gyrelon jenpani Hu, Fikáček &amp; Matsumoto, sp. nov. (Cerylon- idae) is described, illustrated, and compared with related species. DNA barcodes associated larvae of 42 species with adults, we are concisely illustrating some of these: Oodes japonicus, Perigona cf. nigriceps Dejean, 1831 (both Carabidae), Ptilodactyla sp. (Ptilodactylidae), Maltypus ryukyuanus Wittmer, 1970 (Cantharidae), Drusilla obliqua, Myrmecocephalus brevisulcus (Pace, 2008), Diochus sp., Mimopinophilus sp. (all Staphylinidae), Stelidota multiguttata Reitter, 1877, Lasiodites inaequalis (Grouvelle, 1914) (both Nitidulidae), Lagria scutellaris Pic, 1910, and Anaedus spinicornis Kaszab, 1973 (both Tenebrionidae). We also report the first cases of Rickettsia infections in Scydmaeninae and Pselaphinae. All data (sequences, metadata, and voucher photos) are made public in BOLD database and in a Zenodo Archive

Solanum lyratum

We investigated the molecular mechanisms of cell cycle arrest and apoptotic death induced by Solanum lyratum extracts (SLE) or diosgenin in WEHI-3 murine leukemia cells in vitro and antitumor activity in vivo. Diosgenin is one of the components of SLE. Our study showed that SLE and diosgenin decreased the viable WEHI-3 cells and induced G0/G1 phase arrest and apoptosis in concentration- or time-dependent manners. Both reagents increased the levels of ROS production and decreased the mitochondrial membrane potential (ΔΨm). SLE- and diosgenin-triggered apoptosis is mediated through modulating the extrinsic and intrinsic signaling pathways. Intriguingly, the p53 inhibitor (pifithrin-α), anti-Fas ligand (FasL) mAb, and specific inhibitors of caspase-8 (z-IETD-fmk), caspase-9 (z-LEHD-fmk), and caspase-3 (z-DEVD-fmk) blocked SLE- and diosgenin-reduced cell viability of WEHI-3 cells. The in vivo study demonstrated that SLE has marked antitumor efficacy against tumors in the WEHI-3 cell allograft model. In conclusion, SLE- and diosgenin-induced G0/G1 phase arrest and triggered extrinsic and intrinsic apoptotic pathways via p53 activation in WEHI-3 cells. SLE also exhibited antitumor activity in vivo. Our findings showed that SLE may be potentially efficacious in the treatment of leukemia in the future