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Abstract Caspase-4 (CASP4) is a member of the inflammatory caspase subfamily and promotes inflammation. Here, we report that CASP4 in lung adenocarcinoma cells contributes to both tumor progression via angiogenesis and tumor hyperkinesis and tumor cell killing in response to high interferon (IFN)-γ levels. We observe that elevated CASP4 expression in the primary tumor is associated with cancer progression in patients with lung adenocarcinoma. Further, CASP4 knockout attenuates tumor angiogenesis and metastasis in subcutaneous tumor mouse models. CASP4 enhances the expression of genes associated with angiogenesis and cell migration in lung adenocarcinoma cell lines through nuclear factor kappa-light chain-enhancer of activated B cell signaling without stimulation by lipopolysaccharide or tumor necrosis factor. CASP4 is induced by endoplasmic reticulum stress or IFN-γ via signal transducer and activator of transcription 1. Most notably, lung adenocarcinoma cells with high CASP4 expression are more prone to IFN-γ-induced pyroptosis than those with low CASP4 expression. Our findings indicate that the CASP4 level in primary lung adenocarcinoma can predict metastasis and responsiveness to high-dose IFN-γ therapy due to cancer cell pyroptosis.

The Weilasituo Li–polymetallic deposit, located on the western slope of the southern Great Xing’an Range in the eastern Central Asian Orogenic Belt, is hosted by quartz porphyry with crypto-explosive breccia-type Li mineralisation atop and vein-type Sn-Mo-W-Zn polymetallic mineralisation throughout the breccia pipe. This study introduces new data on multistage quartz and mica in situ trace elements; the study was conducted using laser ablation inductively coupled plasma mass spectrometry and 40Ar/39Ar dating of zinnwaldite to delineate the metallogenic age and genesis of Li mineralisation. Zinnwaldite yields a plateau age of 132.45 ± 1.3 Ma (MSWD = 0.77), representing Early Cretaceous Li mineralisation. Throughout the magmatic–hydrothermal process, quartz trace elements showed Ge enrichment. Li, Al, and Ti contents decreased, with Al/Ti and Ge/Ti ratios increasing, indicating increased magmatic differentiation, slight acidification, and cooling. Mica’s rising Li, Rb, Cs, Mg, and Ti contents and Nb/Ta ratio, alongside its falling K/Rb ratio, indicate the magma’s ongoing crystallisation differentiation. Fractional crystallisation primarily enriched Li, Rb, and Cs in the late melt. Mica’s high Sc, V, and W contents indicate a high fO2 setting, with a slightly lower fO2 during zinnwaldite formation. Greisenisation observed Zn, Mg, and Fe influx from the host rock, broadening zinnwaldite distribution and forming minor Zn vein orebodies later. Late-stage fluorite precipitation highlights a rise in F levels, with fluid Sn and W levels tied to magma evolution and F content. In summary, the Weilasituo Li–polymetallic deposit was formed in an Early Cretaceous extensional environment and is closely related to a nearby highly differentiated Li-F granite. During magma differentiation, rare metal elements such as Li and Rb were enriched in residual melts. The decrease in temperature and the acidic environment led to the precipitation of Li-, Rb-, and W-bearing minerals, and the increased F content in the late stage led to Sn enrichment and mineralisation. Fluid metasomatism causes Zn, Mg, and Fe in the surrounding rock to enter the fluid, and Zn is enriched and mineralised in the later period.

Polyacrylic acid (PAA), an organic chemical, has been used as an intermediate in the manufacture of pharmaceuticals and cosmetics. It has been suggested recently that PAA has a high pulmonary inflammatory and fibrotic potential. Although endoplasmic reticulum stress is induced by various external and intracellular stimuli, there have been no reports examining the relationship between PAA-induced lung injury and endoplasmic reticulum stress. F344 rats were intratracheally instilled with dispersed PAA (molecular weight: 269,000) at low (0.5 mg/mL) and high (2.5 mg/mL) doses, and they were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months after exposure. PAA caused extensive inflammation and fibrotic changes in the lungs’ histopathology over a month following instillation. Compared to the control group, the mRNA levels of endoplasmic reticulum stress markers Bip and Chop in BALF were significantly increased in the exposure group. In fluorescent immunostaining, both Bip and Chop exhibited co-localization with macrophages. Intratracheal instillation of PAA induced neutrophil inflammation and fibrosis in the rat lung, suggesting that PAA with molecular weight 269,000 may lead to pulmonary disorder. Furthermore, the presence of endoplasmic reticulum stress in macrophages was suggested to be involved in PAA-induced lung injury.

Abstract Background Some organic chemicals are known to cause allergic disorders such as bronchial asthma and hypersensitivity pneumonitis, and it has been considered that they do not cause irreversible pulmonary fibrosis. It has recently been reported, however, that cross-linked acrylic acid-based polymer, an organic chemical, might cause serious interstitial lung diseases, including pulmonary fibrosis. We investigated whether or not intratracheal instillation exposure to cross-linked polyacrylic acid (CL-PAA) can cause lung disorder in rats. Methods Male F344 rats were intratracheally instilled with dispersed CL-PAA at low (0.2 mg/rat) and high (1.0 mg/rat) doses, and were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months after exposure to examine inflammatory and fibrotic responses and related gene expressions in the lungs. Rat lungs exposed to crystalline silica, asbestos (chrysotile), and NiO and CeO2 nanoparticles were used as comparators. Results Persistent increases in total cell count, neutrophil count and neutrophil percentage, and in the concentration of the cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2 and C-X-C motif chemokine 5 (CXCL5), which correlated with lung tissue gene expression, were observed in bronchoalveolar lavage fluid (BALF) from 3 days until at least 1 month following CL-PAA intratracheal instillation. Persistent increases in heme oxygenase-1 (HO-1) in the lung tissue were also observed from 3 days to 6 months after exposure. Histopathological findings of the lungs demonstrated that extensive inflammation at 3 days was greater than that in exposure to silica, NiO nanoparticles and CeO2 nanoparticles, and equal to or greater than that in asbestos (chrysotile) exposure, and the inflammation continued until 1 month. Fibrotic changes also progressed after 1 month postexposure. Conclusion Our results suggested that CL-PAA potentially causes strong neutrophil inflammation in the rat and human lung.

Abstract The roles of endogenous nitric oxide (NO) derived from the entire NO synthases (NOSs) system have yet to be fully elucidated. We addressed this issue in mice in which all three NOS isoforms were deleted. Under basal conditions, the triple n/i/eNOSs−/− mice displayed significantly longer mean alveolar linear intercept length, increased alveolar destructive index, reduced lung elastic fiber content, lower lung field computed tomographic value, and greater end-expiratory lung volume as compared with wild-type (WT) mice. None of single NOS−/− or double NOSs−/− genotypes showed such features. These findings were observed in the triple n/i/eNOSs−/− mice as early as 4 weeks after birth. Cyclopaedic and quantitative comparisons of mRNA expression levels between the lungs of WT and triple n/i/eNOSs−/− mice by cap analysis of gene expression (CAGE) revealed that mRNA expression levels of three Wnt ligands and ten Wnt/β-catenin signaling components were significantly reduced in the lungs of triple n/i/eNOSs−/− mice. These results provide the first direct evidence that complete disruption of all three NOS genes results in spontaneous pulmonary emphysema in juvenile mice in vivo possibly through down-regulation of the Wnt/β-catenin signaling pathway, demonstrating a novel preventive role of the endogenous NO/NOS system in the occurrence of pulmonary emphysema.

Abstract Joint contracture leads to major patient discomfort. Metformin, one of the most extensively used oral drugs against type 2 diabetes has recently been found to suppress tissue fibrosis as well. However, its role in suppressing tissue fibrosis in joint contractures remains unknown. In this study, we examined the role of metformin treatment in suppressing joint capsular fibrosis and the most effective time of its administration. Joint capsular fibrosis was induced by immobilizing the knee joints of mice using splints and tapes. Metformin was administered intraperitoneally every alternate day after immobilization. Histological and immunohistochemical changes and expression of fibrosis-related genes were evaluated. Metformin treatment significantly suppressed fibrosis in joint capsules based on histological and immunohistochemical evaluation. Joint capsular tissue from metformin-treated mice also showed decreased expression of fibrosis-related genes. Early, but not late, metformin administration showed the same effect on fibrosis suppression in joint capsule as the whole treatment period. The expression of fibrosis-related genes was most suppressed in mice administered with metformin early. These studies demonstrated that metformin treatment can suppress joint capsular fibrosis and the most effective time to administer it is early after joint immobilization; a delay of more than 2 weeks of administration is less effective.

Duobaoshan is the largest porphyry-related Cu–Mo–Au orefield in northeastern (NE) Asia, and hosts a number of large-medium porphyry Cu (PCDs), epithermal Au and Fe–Cu skarn deposits. Formation ages of these deposits, from the oldest (Ordovician) to youngest (Jurassic), have spanned across over 300 ​Ma. No similar orefields of such size and geological complexity are found in NE Asia, which reflects its metallogenic uniqueness in forming and preserving porphyry-related deposits. In this study, we explore the actual number and timing of magmatic/mineralization phases, their respective magma genesis, fertility, and regional tectonic connection, together with the preservation of PCDs. We present new data on the magmatic/mineralization ages (LA–ICP–MS zircon U–Pb, pyrite and molybdenite Re–Os dating), whole-rock geochemistry, and zircon trace element compositions on four representative deposits in the Duobaoshan orefield, i.e., Duobaoshan PCD, Tongshan PCD, Sankuanggou Fe–Cu skarn, and Zhengguang epithermal Au deposits, and compiled published ones from these and other mineral occurrences in the orefield.In terms of geochronology, we have newly summarized seven magmatic phases in the orefield: (1) Middle–Late Cambrian (506–491 ​Ma), (2) Early and Middle Ordovician (485–471 ​Ma and ~462 ​Ma), (3) Late Ordovician (450–447 ​Ma), (4) Early Carboniferous and Late-Carboniferous to Early Permian (351–345 and 323–291 ​Ma), (5) Middle–Late Triassic (244–223 ​Ma), (6) Early–Middle and Late Jurassic (178–168 ​Ma and ~150 ​Ma), and (7) Early Cretaceous (~112 ​Ma). Three of these seven major magmatic phases were coeval with ore formation, including (1) Early Ordovician (485–473 ​Ma) porphyry-type Cu–Mo-(Au), (2) Early–Middle Triassic (246–229 ​Ma) porphyry-related epithermal Au-(Cu–Mo), and (3) Early Jurassic (177–173 ​Ma) Fe–Cu skarn mineralization. Some deposits in the orefield, notably Tongshan and Zhengguang, were likely formed by more than one mineralization events.In terms of geochemistry, ore-causative granitoids in the orefield exhibit adakite-like or adakite-normal arc transitional signatures, but those forming the porphyry-/epithermal-type Cu–Mo–Au mineralization are largely confined to the former. The varying but high Sr/Y, Sm/Yb and La/Yb ratios suggest that the ore-forming magmas were mainly crustal sourced and formed at different depths (clinopyroxene-/amphibole-/garnet-stability fields). The adakite-like suites may have formed by partial melting of the thickened lower crust at 35–40 ​km (for the Early Ordovician arc) and >40 ​km (for the Middle–Late Triassic arc) depths. The Early Jurassic Fe–Cu skarn ore-causative granitoids show an adakitic-normal arc transitional geochemical affinity. These granitoids were likely formed by partial melting of the juvenile lower crust (35–40 ​km depth), and subsequently modified by assimilation and fractional crystallization (AFC) processes.In light of the geological, geochronological and geochemical information, we proposed the following tectonometallogenic model for the Duobaoshan orefield. The Ordovician Duobaoshan may have been in a continental arc setting during the subduction of the Paleo-Asian Ocean, and formed the porphyry-related deposits at Duobaoshan, Tongshan and Zhengguang. Subduction may have ceased in the latest Ordovician, and the regional tectonics passed into long subsidence and extension till the latest Carboniferous. This extensional tectonic regime and the Silurian terrestrial-shallow marine sedimentation had likely buried and preserved the Ordovician Duobaoshan magmatic-hydrothermal system. The south-dipping Mongol-Okhotsk Ocean subduction from north of the orefield had generated the Middle–Late Triassic continental arc magmatism and the associated Tongshan PCD and Zhengguang epithermal Au mineralization (which superimposed on the Ordovician PCD system). The Middle Jurassic closure of Mongol-Okhotsk Ocean in the northwestern Amuria block (Erguna terrane), and the accompanying Siberia-Amuria collision, may have placed the Paleo-Pacific subduction system in NE China (including the orefield) under compression, and formed the granodiorite-tonalite and Fe–Cu skarn deposits at Sankuanggou and Xiaoduobaoshan. From the Middle Jurassic, the consecutive accretion of Paleo-Pacific arc terranes (e.g., Sikhote-Alin and Nadanhada) onto the NE Asian continental margin may have gradually distant the Duobaoshan orefield from the subduction front, and consequently arc-type magmatism and the related mineralization faded. The minor Late Jurassic and Cretaceous unmineralized magmatism in the orefield may have triggered mainly by the far-field extension led by the post-collisional (Siberia-Amuria) gravitational collapse and/or Paleo-Pacific backarc-basin opening.

Objectives: Chronic obstructive pulmonary disease (COPD) is a risk factor for osteoporosis. Nevertheless, much remains unclear regarding the bone metabolism dynamics associated with COPD. The present study focuses on the associations between the COPD severity and serum bone metabolism biomarkers. Methods: We enrolled 40 patients who visited the orthopedics departments at our institutions and underwent dual-energy X-ray absorptiometry between September 2015 and December 2017. Only male osteoporosis patients over 45 years of age were included, and 5 patients were excluded due to disease or use of internal medicines affecting bone metabolism. All subjects underwent lung function testing, spine radiography, and blood tests. We measured percent forced expiratory volume in 1 second (%FEV1), which reflects COPD severity, and we examined the relationships between %FEV1 and serum levels of bone metabolism biomarkers. Results: All subjects were diagnosed with osteoporosis based on T-scores. %FEV1 correlated with body weight, body mass index (BMI), and Z-score/T-scores. %FEV1 moderately correlated with serum levels of alkaline phosphatase (ALP), procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase 5b in the partial correlation analysis adjusted for BMI or T-score in the lumbar vertebrae. We performed a hierarchical multiple regression analysis to identify that serum ALP and P1NP were the independent explanatory variables to %FEV1 independent of other factors. Conclusions: The data suggest that the COPD severity in middle-aged and older men with osteoporosis associates with decreased bone formation. COPD patients may exhibit bone metabolism dynamics characterized by low bone turnover with osteogenesis dysfunction as COPD becomes severe.

We established a quantitative detection method for immunohistochemistry based on a reference standard light-emitting diode, protein microarray and antibody-fused bioluminescent protein. In this procedure, we calibrated the bioluminescence imaging system and prepared the calibration curve between antigen and antibody-fused bioluminescent protein using a protein microarray. Then we converted the detecting light signal to antigen count via absolute photon number in the bioluminescent images; there was a resulting threefold difference in the target antigen number between normal and cancerous tissues. Our technique can easily compare immunohistological images and evaluate tumor progression in quantitative pathological diagnosis.

Abstract Background Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is life-threatening. Several serum biomarkers, such as Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), are clinically used for evaluating AE-IPF, but these biomarkers are not adequate for establishing an early and accurate diagnosis of AE-IPF. Recently, the protective roles of the members of the peroxiredoxin (PRDX) family have been reported in IPF; however, the role of PRDX4 in AE-IPF is unclear. Methods Serum levels of PRDX4 protein, KL-6, SP-D and lactate dehydrogenase (LDH) in 51 patients with stable IPF (S-IPF), 38 patients with AE-IPF and 15 healthy volunteers were retrospectively assessed using enzyme-linked immunosorbent assay. Moreover, as an animal model of pulmonary fibrosis, wild-type (WT) and PRDX4-transgenic (Tg) mice were intratracheally administered with bleomycin (BLM, 2 mg/kg), and fibrotic and inflammatory changes in lungs were evaluated 3 weeks after the intratracheal administration. Results Serum levels of PRDX4 protein, KL-6, SP-D and LDH in patients with S-IPF and AE-IPF were significantly higher than those in healthy volunteers, and those in AE-IPF patients were the highest among the three groups. Using receiver operating characteristic curves, area under the curve values of serum PRDX4 protein, KL-6, SP-D, and LDH for detecting AE-IPF were 0.873, 0.698, 0.675, and 0.906, respectively. BLM-treated Tg mice demonstrated aggravated histopathological findings and poor prognosis compared with BLM-treated WT mice. Moreover, PRDX4 expression was observed in alveolar macrophages and lung epithelial cells of BLM-treated Tg mice. Conclusions PRDX4 is associated with the aggravation of inflammatory changes and fibrosis in the pathogenesis of IPF, and serum PRDX4 may be useful in clinical practice of IPF patients.

The Haerdaban Pb-Zn deposit is located on the western edge of the Chinese Western Tianshan Orogen. This deposit consists of stratiform and veined mineralization hosted in Proterozoic carbonaceous and dolomitic limestone. Three metallogenic stages were recognized: an early sedimentary exhalative stage (stage 1), an intermediate metamorphic remobilization stage (stage 2), and a late magmatic-hydrothermal stage (stage 3). Fluid inclusions (FIs) present in stage 1 are liquid-rich aqueous, with homogenization temperatures of 206–246 C and salinities of 5.9–11.6 wt% NaCl eq. FIs present in stage 2 are also liquid-rich aqueous, with homogenization temperatures of 326–349 C and salinities of 3.4–6.6 wt% NaCl eq. FIs present in stage 3 include halite-bearing, vapor-rich aqueous, and liquid-rich aqueous FIs. Homogenization temperatures for these FIs span a range of 249–316 C. Halite-bearing, vapor-rich aqueous, and liquid-rich aqueous FIs yield salinities of 33.8–38.9, 2.6–3.5, and 4.2–8.1 wt% NaCl eq., respectively. Oxygen and hydrogen isotopic data (δ18OH2O = 2.6–13.6‰, δDH2O = −94.7 to −40.7‰) indicate that the ore-forming fluids of stages 1–3 were derived from modified seawater, metamorphic water, and magmatic-meteoric mixed water, respectively. Sulfur isotopic data (δ34S = 2.1–16.3‰) reveal that ore constituents were derived from mixing of marine sulfate and magmatic materials. Lead isotopic data (206Pb/204Pb = 17.002–17.552, 207Pb/204Pb = 15.502–15.523, 208Pb/204Pb = 37.025–37.503) reveal that ore constituents were derived from a mixed crust-mantle source. We propose that the Haerdaban deposit was a Proterozoic sedimentary exhalative deposit overprinted by later metamorphic remobilization and magmatic-hydrothermal mineralization.

We assessed the effects of chewing behavior on the lung-metastasis-promoting impact of chronic psychological-stress in mice. Human breast-cancer cells (MDA-MB-231) were injected into the tail vein of female nude mice. Mice were randomly divided into stress, stress-with-chewing, and control groups. We created chronic stress by placing mice in small transparent tubes for 45 min, 3 times a day for 7 weeks. Mice in the stress-with-chewing group were allowed to chew wooden sticks during the experimental period. The histopathological examination showed that chronic psychological-stress increased lung metastasis, and chewing behavior attenuated the stress-related lung metastasis of breast-cancer cells. Chewing behavior decreased the elevated level of the serum corticosterone, normalized the increased expression of glucocorticoid, and attenuated the elevated expression of adrenergic receptors in lung tissues. We also found that chewing behavior normalized the elevated expression of inducible nitric oxide synthase, 4-hydroxynonenal, and superoxide dismutase 2 in lung tissues, induced by chronic stress. The present study demonstrated that chewing behavior could attenuate the promoting effects of chronic psychological-stress on the lung metastasis of breast-cancer cells, by regulating stress hormones and their receptors, and the downstream signaling-molecules, involving angiogenesis and oxidative stress.

We conducted intratracheal instillations of polyacrylic acid (PAA) with crosslinking and non-crosslinking into rats in order to examine what kinds of physicochemical characteristics of acrylic-acid-based polymers affect responses in the lung. F344 rats were intratracheally exposed to similar molecular weights of crosslinked PAA (CL-PAA) (degree of crosslinking: ~0.1%) and non-crosslinked PAA (Non-CL-PAA) at low and high doses. Rats were sacrificed at 3 days, 1 week, 1 month, 3 months, and 6 months post-exposure. Both PAAs caused increases in neutrophil influx, cytokine-induced neutrophil chemoattractants (CINC) in the bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in the lung tissue from 3 days to 6 months following instillation. The release of lactate dehydrogenase (LDH) activity in the BALF was higher in the CL-PAA-exposed groups. Histopathological findings of the lungs demonstrated that the extensive fibrotic changes caused by CL-PAA were also greater than those in exposure to the Non-CL- PAA during the observation period. CL-PAA has more fibrogenicity of the lung, suggesting that crosslinking may be one of the physicochemical characteristic factors of PAA-induced lung disorder.

Background: We conducted intratracheal instillations of different molecular weights of polyacrylic acid (PAA) into rats in order to examine what kinds of physicochemical characteristics of acrylic acid-based polymer affect responses in the lung. Methods: F344 rats were intratracheally exposed to a high molecular weight (HMW) of 598 thousand g/mol or a low molecular weight (LMW) of 30.9 thousand g/mol PAA at low and high doses. Rats were sacrificed at 3 days, 1 week, 1 month, 3 months and 6 months post exposure. Results: HMW PAA caused persistent increases in neutrophil influx, cytokine-induced neutrophil chemoattractants (CINC) in the bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in the lung tissue from 3 days to 3 months and 6 months following instillation. On the other hand, LMW PAA caused only transient increases in neutrophil influx, CINC in BALF, and HO-1 in the lung tissue from 3 days to up to 1 week or 1 month following instillation. Histopathological findings of the lungs demonstrated that the extensive inflammation and fibrotic changes caused by the HMW PAA was greater than that in exposure to the LMW PAA during the observation period. Conclusion: HMW PAA induced persistence of lung disorder, suggesting that molecular weight is a physicochemical characteristic of PAA-induced lung disorder.

The hippocampus plays an important role in maintaining normal cognitive function and is closely associated with the neuropathogenesis of dementia. Wnt signaling is relevant to neuronal development and maturation, synaptic formation, and plasticity. The role of Wnt10a in hippocampus-associated cognition, however, is largely unclear. Here, we examined the morphological and functional alterations in the hippocampus of Wnt10a-knockout (Wnt10a-/-) mice. Neurobehavioral tests revealed that Wnt10a-/- mice exhibited spatial memory impairment and anxiety-like behavior. Immunostaining and Western blot findings showed that the protein expressions of β-catenin, brain-derived neurotrophic factor, and doublecortin were significantly decreased and that the number of activated microglia increased, accompanied by amyloid-β accumulation, synaptic dysfunction, and microglia-associated neuroinflammation in the hippocampi of Wnt10a-/- mice. Our findings revealed that the deletion of Wnt10a decreased neurogenesis, impaired synaptic function, and induced hippocampal neuroinflammation, eventually leading to hippocampal neurodegeneration and memory deficit, possibly through the β-catenin signaling pathway, providing a novel insight into preventive approaches for hippocampus-dependent cognitive impairment.

Abstract Background In order to examine whether myeloperoxidase (MPO) can be a useful marker for evaluating the pulmonary toxicity of nanomaterials, we analyzed MPO protein in bronchoalveolar lavage fluid (BALF) samples obtained from previous examinations of a rat model. In those examinations we performed intratracheal instillation exposures (dose: 0.2–1.0 mg) and inhalation exposures (exposure concentration: 0.32–10.4 mg/m3) using 9 and 4 nanomaterials with different toxicities, respectively. Based on those previous studies, we set Nickel oxide nanoparticles (NiO), cerium dioxide nanoparticles (CeO2), multi wall carbon nanotubes with short or long length (MWCNT (S) and MWCNT (L)), and single wall carbon nanotube (SWCNT) as chemicals with high toxicity; and titanium dioxide nanoparticles (TiO2 (P90) and TiO2 (Rutile)), zinc oxide nanoparticles (ZnO), and toner with external additives including nanoparticles as chemicals with low toxicity. We measured the concentration of MPO in BALF samples from rats from 3 days to 6 months following a single intratracheal instillation, and from 3 days to 3 months after the end of inhalation exposure. Results Intratracheal instillation of high toxicity NiO, CeO2, MWCNT (S), MWCNT (L), and SWCNT persistently increased the concentration of MPO, and inhalation of NiO and CeO2 increased the MPO in BALF. By contrast, intratracheal instillation of low toxicity TiO2 (P90), TiO2 (Rutile), ZnO, and toner increased the concentration of MPO in BALF only transiently, and inhalation of TiO2 (Rutile) and ZnO induced almost no increase of the MPO. The concentration of MPO correlated with the number of total cells and neutrophils, the concentration of chemokines for neutrophils (cytokine-induced neutrophil chemoattractant (CINC)-1 and heme oxygenase (HO)-1), and the activity of released lactate dehydrogenase (LDH) in BALF. The results from the receiver operating characteristics (ROC) for the toxicity of chemicals by the concentration of MPO proteins in the intratracheal instillation and inhalation exposures showed that the largest areas under the curves (AUC) s in both examinations occurred at 1 month after exposure. Conclusion These data suggest that MPO can be a useful biomarker for the ranking of the pulmonary toxicity of nanomaterials, especially at 1 month after exposure, in both intratracheal instillation and inhalation exposure.

The Jinba gold deposit is located in the Maerkakuli Shear Zone of the south Altay Orogenic Belt, NW China. Mineralization types are classified as altered rock–and quartz vein–type. Orebodies occur as veins or lenses controlled by NW–trending faults, and are hosted in phyllite (Early–Middle Devonian Ashele Formation) and plagiogranite (Early Devonian Habahe Pluton). Three paragenetic stages were identified: early quartz–pyrite–gold (Stage 1), middle quartz–chalcopyrite (Stage 2), and late calcite–quartz–galena–sphalerite (Stage 3). Fluid inclusions within the deposit are liquid–rich aqueous (LV–type), vapor–rich aqueous (VL–type), carbonic–aqueous (LC–type), and purely carbonic (C–type) FIs. Homogenization temperatures for stages 1–3 FIs were 373–406 °C, 315–345 °C, and 237–265 °C, respectively. Fluid salinities for stages 1–3 were 2.1–13.6 wt%, 3.2–6.1 wt% and 3.9–6.0 wt% NaCl equivalent, respectively. The ore–forming fluids evolved from a CO2–NaCl–H2O ± CH4 to a NaCl–H2O system from stage 1–3. Oxygen, hydrogen, and carbon isotopic data (δ18Ofluid = 1.7‰–8.1‰, δDfluid = –104.1‰ to –91.7‰, δ13Cfluid = –0.4‰–6.3‰) indicate that ore–forming fluids were metamorphic hydrothermal origin with the addition of a late meteoric fluid. Sulfur and lead isotope data for pyrite (δ34Spy = 3.3‰–5.3‰, 206Pb/204Pb = 17.912.3–18.495, 207Pb/204Pb = 15.564–15.590, 208Pb/204Pb = 37.813–38.422) show that the ore–forming materials were mainly derived from diorite and the Ashele Formation. Mineralization, FIs, and isotope studies demonstrate that the Jinba deposit is an orogenic gold deposit.

Alzheimer’s disease (AD), the most common form of dementia, is characterized by amyloid-β (Aβ) accumulation, microglia-associated neuroinflammation, and synaptic loss. The detailed neuropathologic characteristics in early-stage AD, however, are largely unclear. We evaluated the pathologic brain alterations in young adult App knock-in model AppNL-G-F mice at 3 and 6 months of age, which corresponds to early-stage AD. At 3 months of age, microglia expression in the cortex and hippocampus was significantly decreased. By the age of 6 months, the number and function of the microglia increased, accompanied by progressive amyloid-β deposition, synaptic dysfunction, neuroinflammation, and dysregulation of β-catenin and NF-κB signaling pathways. The neuropathologic changes were more severe in female mice than in male mice. Oral administration of dioscin, a natural product, ameliorated the neuropathologic alterations in young AppNL-G-F mice. Our findings revealed microglia-based sex-differential neuropathologic changes in a mouse model of early-stage AD and therapeutic efficacy of dioscin on the brain lesions. Dioscin may represent a potential treatment for AD.

We examined whether chewing behavior affects the tumor progression-enhancing impact of psychological stress. Human breast cancer cell line (MDA-MB-231) cells were inoculated into the mammary fat pads of athymic nude mice. The mice were assigned randomly to control, stress, and stress+chewing groups. Psychological stress was created by keeping mice in a transparent restraint cylinder for 45 min, three times a day, for 35 days after cell inoculation. Animals in the stress+chewing group were provided with a wooden stick for chewing on during the psychological stress period. Chewing behavior remarkably inhibited the tumor growth accelerated by the psychological stress. Immunohistochemical and Western blot findings revealed that chewing behavior during psychological stress markedly suppressed tumor angiogenesis and cell proliferation. In addition, chewing behavior decreased serum glucocorticoid levels and expressions of glucocorticoid and β2-adrenergic receptors in tumors. Chewing behavior decreased expressions of inducible nitric oxide synthase and 4-hydroxynonenal, and increased expression of superoxide dismutase 2 in tumors. Our findings suggest that chewing behavior could ameliorate the enhancing effects of psychological stress on the progression of breast cancer, at least partially, through modulating stress hormones and their receptors, and the subsequent signaling pathways involving reactive oxygen and nitrogen species.

We analyzed the mRNA expression of chemokines in rat lungs following intratracheal instillation of nanomaterials in order to find useful predictive markers of the pulmonary toxicity of nanomaterials. Nickel oxide (NiO) and cerium dioxide (CeO2) as nanomaterials with high pulmonary toxicity, and titanium dioxide (TiO2) and zinc oxide (ZnO) as nanomaterials with low pulmonary toxicity, were administered into rat lungs (0.8 or 4 mg/kg BW). C-X-C motif chemokine 5 (CXCL5), C-C motif chemokine 2 (CCL2), C-C motif chemokine 7 (CCL7), C-X-C motif chemokine 10 (CXCL10), and C-X-C motif chemokine 11 (CXCL11) were selected using cDNA microarray analysis at one month after instillation of NiO in the high dose group. The mRNA expression of these five genes were evaluated while using real-time quantitative polymerase chain reaction (RT-qPCR) from three days to six months after intratracheal instillation. The receiver operating characteristic (ROC) results showed a considerable relationship between the pulmonary toxicity ranking of nanomaterials and the expression of CXCL5, CCL2, and CCL7 at one week and one month. The expression levels of these three genes also moderately or strongly correlated with inflammation in the lung tissues. Three chemokine genes can be useful as predictive biomarkers for the ranking of the pulmonary toxicity of nanomaterials.

We aimed to investigate the effects of maternal chewing on prenatal stress-induced cognitive impairments in the offspring and to explore the molecular pathways of maternal chewing in a mice model. Maternal chewing ameliorated spatial learning impairments in the offspring in a Morris water maze test. Immunohistochemistry and Western blot findings revealed that maternal chewing alleviated hippocampal neurogenesis impairment and increased the expression of hippocampal brain-derived neurotrophic factor in the offspring. In addition, maternal chewing increased the expression of glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase isozyme 2 (11β-HSD2) and decreased the expression of 11β-HSD1 in the placenta, thereby attenuating the increase of glucocorticoid in the offspring. Furthermore, maternal chewing increased the expression of 11β-HSD2, FK506-binding protein 51 (FKBP51) and FKBP52 and decreased the expression of 11β-HSD1, thereby increasing hippocampal nuclear GR level. In addition, maternal chewing attenuated the increase in expression of DNMT1 and DNMT3a and the decrease in expression of histone H3 methylation at lysine 4, 9, 27 and histone H3 acetylation at lysine 9 induced by prenatal stress in the offspring. Our findings suggest that maternal chewing could ameliorate prenatal stress-induced cognitive impairments in the offspring at least in part by protecting placenta barrier function, alleviating hippocampal nuclear GR transport impairment and increasing the hippocampal brain-derived neurotrophic factor (BDNF) level.

Eastern Tianshan hosts a number of porphyry Cu deposits. However, these mainly formed in the Jueluotage Belt, in the middle part of Eastern Tianshan. The Tonggou porphyry Cu mineralization is an exception to this, since it is located in the Bogda Orogenic Belt, north of Eastern Tianshan. We obtained new zircon U-Pb ages, whole-rock geochemical data, zircon Hf isotope data, and zircon trace element compositions. LA-ICP-MS zircon U-Pb dating indicates a crystallization age of 302.2–303.0 Ma for the Tonggou mineralized granodiorite (TMG), which suggests that the Tonggou porphyry Cu mineralization formed in the Late Carboniferous period. εHf (t) data (1.8–14.1) for TMG suggests it was sourced from juvenile crustal melts, mixed with some mantle materials. TMG displays low ΣREE, compatible elements (Ba, Sr, Zr, and Hf), Zr/Hf and Nb/Ta ratios, as well as clearly negative Eu anomalies in whole rocks analyses. In addition, TMG is enriched in P, Hf and Th/U ratios in zircon, and has lower crystallization temperatures (734 to 735 °C) than the Daheyan barren granodiorite (DBG) (753 to 802 °C). Whole rock and zircon geochemical analyses show that the TMG was formed by fractional crystallization to a greater extent than the DBG in the Bogda Orogenic Belt. Moreover, zircon grains of the TMG show high Ce4+/Ce3+ ratios (159–286), which are consistent with related values from large porphyry deposits of the Central Asian Orogenic Belt (CAOB). High Ce4+/Ce3+ ratios reflect oxidizing magmas as a result of fractional crystallization, which indicates that the Tonggou deposit has potential to host a large porphyry Cu deposit.

BACKGROUND:We have reported that WNT10A plays a critical role in the growth of fibroblasts/myofibroblasts and microvascular endothelial cells, i.e.; wound healing/scarring. To ascertain the in vivo regulatory, central functions of WNT10A, we examined the net effects of WNT10A depletion using WNT10A-deficient mice (WNT10A-/-). METHODS AND RESULTS:We generated WNT10A-/-mice, displaying a range of unique phenotypes of morpho/organogenetic failure, such as growth retardation, alopecia, kyphosis and infertility, and then focused on the functions of WNT10A in wound healing. We subjected C57BL/6J wild-type (WT) or WNT10A-/-mice to skin ulcer formation. The WNT10A-/-mice had significantly larger injured areas and delayed wound healing, which were associated with (a) a smaller number of fibroblasts/myofibroblasts and microvessels; and (b) more reduced expression and synthesis of collagen, compared with WT mice with intact WNT10A expression, especially in those with activated myofibroblasts. CONCLUSIONS:These observations indicate that WNT10A signaling can play a pivotal in vivo role in wound healing by regulating the expression and synthesis of collagen, as one of fibrogenic factors, at least in part, and critical in vivo roles of WNT10A-mediated effective wound healing are extremely closely associated with collagen expression.

Mitochondria are important cellular organelles that function as control centers of the energy supply for highly proliferative cancer cells and regulate apoptosis after cancer chemotherapy. Cisplatin is one of the most important chemotherapeutic agents and a key drug in therapeutic regimens for a broad range of solid tumors. Cisplatin may directly interact with mitochondria, which can induce apoptosis. The direct interactions between cisplatin and mitochondria may account for our understanding of the clinical activity of cisplatin and development of resistance. However, the basis for the roles of mitochondria under treatment with chemotherapy is poorly understood. In this review, we present novel aspects regarding the unique characteristics of the mitochondrial genome in relation to the use of platinum-based chemotherapy and describe our recent work demonstrating the importance of the mitochondrial transcription factor A (mtTFA) expression in cancer cells.

The Qibaoshan polymetallic ore field is located in the Wulian area, Shandong Province, China. Four ore deposits occur in this ore field: the Jinxiantou Au−Cu, Changgou Cu−Pb−Zn, Xingshanyu Pb−Zn, and Hongshigang Pb−Zn deposits. In the Jinxiantou deposit, three paragenetic stages were identified: quartz−pyrite−specularite−gold (Stage 1), quartz−pyrite−chalcopyrite (Stage 2), and quartz−calcite−pyrite (Stage 3). Liquid-rich aqueous (LV type), vapor-rich aqueous (V type), and halite-bearing (S type) fluid inclusions (FIs) are present in the quartz from stages 1−3. Microthermometry indicates that the initial ore-forming fluids had temperatures of 351−397 °C and salinities of 42.9−45.8 mas. % NaCl equivalent. The measured hydrogen and calculated oxygen isotopic data for fluid inclusion water (δ18OFI = 11.1 to 12.3‰; δDFI = −106.3 to −88.6‰) indicates that the ore-forming fluids were derived from magmatic water; then, they were mixed with meteoric water. In the Changgou deposit, three paragenetic stages were identified: quartz−pyrite−specularite (Stage 1), quartz−pyrite−chalcopyrite (Stage 2), and quartz−galena−sphalerite (Stage 3). LV, V, and S-type FIs are present in the quartz from stages 1−3. Microthermometry indicates that the initial ore-forming fluids had temperatures of 286−328 °C and salinities of 36.7−40.2 mas. % NaCl equivalent. The measured hydrogen and calculated oxygen isotopic data for fluid inclusion water (δDFI = −115.6 to −101.2‰; δ18OFI = 12.2 to 13.4‰) indicates that the ore-forming fluids were derived from magmatic water mixed with meteoric water. The characteristics of the Xingshanyu and Hongshigang deposits are similar. Two paragenetic stages were identified in these two deposits: quartz−galena−sphalerite (Stage 1) and quartz−calcite−poor sulfide (Stage 2). Only LV-type FIs are present in the quartz in stages 1−2. The ore-forming fluids had temperatures of 155−289 °C and salinities of 5.6−10.5 mas. % NaCl equivalent. The measured hydrogen and calculated oxygen isotopic data for fluid inclusion water (δDFI = −109.8 to −100.2‰; δ18OFI = 10.2 to 12.1‰) indicates that the ore-forming fluids were derived from circulating meteoric waters. The sulfur isotopes (δ34Ssulfide = 0.6 to 4.3‰) of the four deposits are similar, indicating a magmatic source for the sulfur with minor contributions from the wall rocks. The ore field underwent at least two phases of mineralization according to the chronology results of previous studies. Based on the mineral assemblage and fluid characteristics, we suggest that the late Pb−Zn mineralization was superimposed on the early Cu (−Au) mineralizaton in the Changgou deposit.

The Jinchang gold deposit is located in the eastern Yanji–Dongning Metallogenic Belt in Northeast China. The orebodies of the deposit are hosted within granite, diorite, and granodiorite, and are associated with gold-mineralized breccia pipes, disseminated gold in ores, and fault-controlled gold-bearing veins. Three paragenetic stages were identified: (1) early quartz–pyrite–arsenopyrite (stage 1); (2) quartz–pyrite–chalcopyrite (stage 2); and (3) late quartz–pyrite–galena–sphalerite (stage 3). Gold is hosted predominantly within pyrite. Pyrite separated from quartz–pyrite–arsenopyrite cement within the breccia-hosted ores (Py1) yield a Re–Os isochron age of 102.9 ± 2.7 Ma (MSWD = 0.17). Pyrite crystals from the quartz–pyrite–chalcopyrite veinlets (Py2) yield a Re–Os isochron age of 102.0 ± 3.4 Ma (MSWD = 0.2). Pyrite separated from quartz–pyrite–galena–sphalerite veins (Py3) yield a Re–Os isochron age of 100.9 ± 3.1 Ma (MSWD = 0.019). Re–Os isotopic analyses of the three types of auriferous pyrite suggest that gold mineralization in the Jinchang Deposit occurred at 105.6–97.8 Ma (includes uncertainty). The initial 187Os/188Os values of the pyrites range between 0.04 and 0.60, suggesting that Os in the pyrite crystals was derived from both crust and mantle sources.

BACKGROUND:Accumulating evidence has shown that methionine- and choline-deficient high fat (MCD+HF) diet induces the development of nonalcoholic fatty liver disease (NAFLD), in which elevated reactive oxygen species play a crucial role. We have reported that peroxiredoxin 4 (PRDX4), a unique secretory member of the PRDX antioxidant family, protects against NAFLD progression. However, the detailed mechanism and potential effects on the intestinal function still remain unclear. METHODS & RESULTS:Two weeks after feeding mice a MCD+HF diet, the livers of human PRDX4 transgenic (Tg) mice exhibited significant suppression in the development of NAFLD compared with wild-type (WT) mice. The serum thiobarbituric acid reactive substances levels were significantly lower in Tg mice. In contrast, the Tg small intestine with PRDX4 overexpression showed more suppressed shortening of total length and villi height, and more accumulation of lipid in the jejunum, along with lower levels of dihydroethidium binding. The enterocytes exhibited fewer apoptotic but more proliferating cells, and inflammation was reduced in the mucosa. Furthermore, the small intestine of Tg mice had significantly higher expression of cholesterol absorption-regulatory factors, including liver X receptor-α, but lower expression of microsomal triglyceride-transfer protein. CONCLUSION:Our present data provide the first evidence of the beneficial effects of PRDX4 on intestinal function in the reduction of the severity of NAFLD, by ameliorating oxidative stress-induced local and systemic injury. We can suggest that both liver and intestine are spared, to some degree, by the antioxidant properties of PRDX4.