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AbstractAlveolar macrophages (AMs), the first line against the invasion of foreign invaders, play a predominant role in the pathogenesis of silicosis. Studies have shown that inhaled silica dust is recognized and engulfed by AMs, resulting in the production of large amounts of silica-induced reactive oxygen species (ROS), including particle-derived ROS and macrophage-derived ROS. These ROS change the microenvironment of the AMs where the macrophage phenotype is stimulated to swift from M0 to M1 and/or M2, and ultimately emerge as the M2 phenotype to trigger silicosis. This is a complex process accompanied by various molecular biological events. Unfortunately, the detailed processes and mechanisms have not been systematically described. In this review, we first systematically introduce the process of ROS induced by silica in AMs. Then, describe the role and molecular mechanism of M2-type macrophage polarization caused by silica-induced ROS. Finally, we review the mechanism of pulmonary fibrosis induced by M2 polarized AMs. We conclude that silica-induced ROS initiate the fibrotic process of silicosis by inducing macrophage into M2 phenotype, and that targeted intervention of silica-induced ROS in AMs can reprogram the macrophage polarization and ameliorate the pathogenesis of silicosis. [ABSTRACT FROM AUTHOR]

Objective * To test the inhibitory effect of the Na /Ca2 exchanger (NCX) blockers on the growth of human glioblastoma cells. Methods *Human glioblastoma cell lines (U87, U251 and SF188) and human astrocytes were cultured in vitro. The cells were treated with NCX blockers SN-6, YM244769, SEA0400, CB-DMB and the chemotherapeutic agent temozolomide (TMZ). SN-6, YM244769 and SEA0400 were selective inhibitors for the reverse operation of NCX; while CB-DMB was NCX bidirectional blocker, but preferentially blocked the forward mode of NCX. The TMZ was used as a reference drug. Cell counting kit-8 (CCK-8) assay was used to quantify and assess the cell viability, and half maximal inhibitory concentration (IC50) of the drug was obtained. Calcium imaging was used to detect the changes of Ca2+ signal in U87 cells treated with NCX inhibitors, and Western blotting was used to detect the expression of mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cellular apoptosis was evaluated by flow cytometry assay. Results * CCK-8 results showed that direct application of the NCX bidirectional blocker CB-DMB to glioblastoma cell lines (U87, U251 and SF188) for 48 h caused a dose-dependent growth inhibition with IC50 values of 2.06, 2.19 and 1.82 µmol/L, respectively. In contrast, NCX reverse blockers SN-6, YM244769 and SEA0400 had no significant effect on the growth activity of glioblastoma cells. CB-DMB had little effect on the growth activity of human astrocytes. Calcium imaging and Western blotting results confirmed that CB-DMB blocked the forward transport mode of NCX to elevate intracellular Ca2+, causing intracellular calcium overload and then inducing apoptosis of U87 cells and activating MAPK signaling pathway. Flow cytometry assay results showed that the rate of apoptosis induced by CB-DMB in glioblastoma cells was much faster than that induced by TMZ (P= 0.002). The combination of CB-DMB and TMZ enhanced the inhibitory effect of TMZ on the growth of tumor cells. Conclusion * The inhibitory effect of CB-DMB on the growth of human glioblastoma cells may be related to blocking the forward transport mode of NCX. The plasma membrane NCX is a potential new target for the treatment of human glioblastoma. [ABSTRACT FROM AUTHOR]

Background and Purpose: The Na+ /Ca2+ exchanger (NCX) working in either forward or reverse mode participates in maintaining intracellular Ca2+ ([Ca2+ ]i ) homeostasis, which is essential for determining cell fate. Previously, numerous blockers targeting reverse or forward NCX have been developed and studied in ischaemic tissue injury but barely examined in glioblastoma for the purpose of anti-tumour therapy. We assessed the effect of NCX blockers on glioblastoma growth and whether NCX can become a therapeutic target.Experimental Approach: Patch-clamp recording, Ca2+ imaging, flow cytometry, and Western blot were used to study the effects of specific and non-specific NCX blockers on cultured glioblastoma cells. In vivo bioluminescent imaging was used to measure effects on grafted glioblastoma.Key Results: Selectively blocking the reverse NCX with SEA0400, SN-6, and YM-244769 did not affect tumour cell viability. Blocking the forward NCX with bepridil, CB-DMB, or KB-R7943 elevated [Ca2+ ]i and killed glioblastoma cells. Bepridil and CB-DMB caused Ca2+ -dependent cell cycle arrest together with apoptosis, which were all attenuated by a Ca2+ chelator BAPTA-AM. Systemic administration of bepridil inhibited growth of brain-grafted glioblastoma. Bepridil did not appear to have a cytotoxic effect on human astrocytes, which have higher functional expression of NCX than glioblastoma cells.Conclusions and Implications: Low expression of the NCX makes glioblastoma cells sensitive to disturbance of [Ca2+ ]i . Interventions designed to block the forward NCX can cause Ca2+ -mediated injury to glioblastoma thus having therapeutic potential. Bepridil could be a lead compound for developing new anti-tumour drugs. [ABSTRACT FROM AUTHOR]

Aims: To investigate the prevalence of overactive bladder (OAB) and assess its risk factors in 5‐ to 14‐year‐old Chinese children. Methods: A cross‐sectional study of OAB prevalence was performed by distributing 11 800 anonymous self‐administered questionnaires to parents in five provinces of mainland China from July to October 2018. The questionnaires included questions on sociodemographics, history of urinary tract infection (UTI), lower urinary tract symptoms (LUTS), family history of LUTS, bowel symptoms, and details about the elimination communication (EC) start time. OAB was defined as urgency and increased the daytime frequency with or without urinary incontinence. Results: A total of 10 133 questionnaires qualified for statistical analysis. The overall prevalence of OAB was 9.01% and decreased with age, from 12.40% at 5 years to 4.55% at 14 years (χ2trend = 88.899; P <.001). The proportion of dry OAB increased with age, whereas the proportion of wet OAB decreased. A late‐onset of EC was associated with a high OAB prevalence (χ2 trend = 39.802; P <.001). Children with obesity, a history of UTI, nocturnal enuresis (NE), a family history of LUTS, constipation, and fecal incontinence had a higher prevalence of OAB than did normal children (P <.05). Conclusion: Obesity, a history of UTI, NE, a family history of LUTS, and bowel symptoms are risk factors associated with OAB. Starting EC before 12 months of age might help reduce the prevalence of OAB in children. [ABSTRACT FROM AUTHOR]