Macrophage MSR1 promotes the formation of foamy macrophage and neuronal apoptosis after spinal cord injury.

BACKGROUND: A sustained inflammatory response following spinal cord injury (SCI) contributes to neuronal damage, inhibiting functional recovery. Macrophages, the major participants in the inflammatory response, transform into foamy macrophages after phagocytosing myelin debris, subsequently releasing inflammatory factors and amplifying the secondary injury. Here, we assessed the effect of macrophage scavenger receptor 1 (MSR1) in phagocytosis of myelin debris after SCI and explained its possible mechanism. METHODS: The SCI model was employed to determine the critical role of MSR1 in phagocytosis of myelin debris in vivo. The potential functions and mechanisms of MSR1 were explored using qPCR, western blotting, and immunofluorescence after treating macrophages and RAW264.7 with myelin debris in vitro. RESULTS: In this study, we found improved recovery from traumatic SCI in MSR1-knockout mice over that in MSR1 wild-type mice. Furthermore, MSR1 promoted the phagocytosis of myelin debris and the formation of foamy macrophage, leading to pro-inflammatory polarization in vitro and in vivo. Mechanistically, in the presence of myelin debris, MSR1-mediated NF-κB signaling pathway contributed to the release of inflammatory mediators and subsequently the apoptosis of neurons. CONCLUSIONS: Our study elucidates a previously unrecognized role of MSR1 in the pathophysiology of SCI and suggests that its inhibition may be a new treatment strategy for this traumatic condition.

Poly[µ-aqua-diaqua(µ(3)-1H-benzimid-azole-5-carboxylato-κN:O,O')(µ(2)-1H-benzimidazole-5-carboxylato-κN:O:O')-µ(5)-sulfato-µ(4)-sulfato-tri-cadmium].

The asymmetric unit of the title compound, [Cd(3)(C(8)H(5)N(2)O(2))(2)(SO(4))(2)(H(2)O)(3)](n), contains three Cd(II) ions, two sulfate anions, two 1H-benzimidazole-5-carboxyl-ate (H(2)bic) ligands and three coordinated water mol-ecules. One Cd(II) ion is six-coordinated and exhibits a distorted octa-hedral geometry, while the other two Cd(II) ions are seven-coordinated, displaying a distorted penta-gonal-bipyramidal geometry. The Cd(II) ions are bridged by two types of sulfate anions, producing inorganic chains along [100]. These chains are further connected by the H(2)bic ligands, leading to a three-dimensional framework. N-H⋯O and O-H⋯O hydrogen bonds and π-π inter-actions between the imidazole and benzene rings [centroid-centroid distances = 3.953 (2), 3.507 (2), 3.407 (2) and 3.561 (2) Å] further stabilize the crystal structure.

catena-Poly[silver(I)-µ-acridine-9-carboxyl-ato-κN:O,O'].

In the title coordination polymer, [Ag(C(14)H(8)NO(2))](n), the Ag(I) cation is coordinated by two O atoms and one N atom from two symmetry-related acridine-9-carboxyl-ate ligands in a distorted trigonal-planar geometry. The metal atoms are connected by the ligands to form chains running parallel to the b axis. π-π stacking inter-actions [centroid-to-centroid distances 3.757 (2)-3.820 (2) Å] and weak Ag⋯O inter-actions further link the chains to form a layer network parallel to the ab plane. The Ag(I) cation is disordered over two positions, with refined site-occupancy factors of 0.73 (3):0.27 (3).

Macrophage MSR1 promotes BMSC osteogenic differentiation and M2-like polarization by activating PI3K/AKT/GSK3ß/ß-catenin pathway.

Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications. Recently, the role of macrophages in regulating bone marrow stem cell (BMSC) differentiation through the osteogenic pathway during fracture healing has attracted much attention. Methods: The tibial monocortical defect model was employed to determine the critical role of macrophage scavenger receptor 1 (MSR1) during intramembranous ossification (IO) in vivo. The potential functions and mechanisms of MSR1 were explored in a co-culture system of bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and BMSCs using qPCR, Western blotting, immunofluorescence, and RNA sequencing. Results: In this study, using the tibial monocortical defect model, we observed delayed IO in MSR1 knockout (KO) mice compared to MSR1 wild-type (WT) mice. Furthermore, macrophage MSR1 mediated PI3K/AKT/GSK3ß/ß-catenin signaling increased ability to promote osteogenic differentiation of BMSCs in the co-culture system. We also identified proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) as the target gene for macrophage MSR1-activated PI3K/AKT/GSK3ß/ß-catenin pathway in the co-culture system that facilitated M2-like polarization by enhancing mitochondrial oxidative phosphorylation. Conclusion: Our findings revealed a previously unrecognized function of MSR1 in macrophages during fracture repair. Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair.

[Effects of cembrane-type diterpenes on proliferation of PC12 cells and their antagonistic effects on neurotoxicity induced by glutamate].

OBJECTIVE: To investigate the effects of cembrane-type diterpenes extracted from Sinularia flexibilis on the proliferation of PC12 cells and their protective effects on PC12 cells exposed to glutamate. METHODS: Methyl thiazolyl tetrazolium (MTT) method was adopted to observe the effects of cembrane-type diterpenes (compound 1, compound 2 and compound 3) on the proliferation of PC12 cells. And the protective effects of the three compounds on PC12 cells exposed to glutamate were also detected by MTT. Furthermore, the influence of compound 1 on intracellular concentration of calcium in PC12 cells exposed to glutamate was detected by laser confocal microscopy. RESULTS: After 72-hour PC12 cell culture, OD values in the 2, 10 and 50 micromol/L compound 1 groups were significantly higher than that in the normal group (P<0.05, P<0.01). After 24-hour glutamate damage, OD values in the 0.4, 2 and 50 micromol/L compound 1 groups, the 0.4, 2 and 100 micromol/L compound 2 groups and the 2 micromol/L compound 3 group were obviously increased as compared with the untreated group (P<0.01, P<0.05). After 48-hour glutamate damage, OD values in the compound 1 group were approximate to those in the normal control and the positive control group while were significantly higher than that in the untreated group (P<0.01, P<0.05), but no dose-dependent effect was observed. Compound 1 of 0.4, 2, 50 micromol/L could significantly reduce the intracellular concentration of calcium in PC12 cells exposed to glutamate (P<0.05, P<0.01), which was also approximate to the effect of nimodipine (positive control drug). CONCLUSION: Cembrane-type diterpenes (compound 1, compound 2 and compound 3) extracted from Sinularia flexibilis have obvious protective effects on PC12 cells damaged by glutamate, and compound 1 has the best neuroprotective effect. The mechanism of the neuroprotective effect of compound 1 may lie in reducing the intracellular concentration of calcium in PC12 cells exposed to glutamate and relieving the calcium overload.

Daily Intake Estimation for Young Children's Ingestion of Residential Dust and Soils Contaminated with Chlorpyrifos and Cypermethrin in Taiwan.

We estimated the daily intakes of chlorpyrifos and cypermethrin via ingestion of indoor dust and outdoor soils using the Stochastic Human Exposure and Dose Simulation Model on a probabilistic approach for Taiwanese young children. Variables for the estimation, such as concentration, ingestion rate, and body weight, were adopted from previous studies. Monte Carlo simulation was performed with 1,000,000 iterations to simulate a single daily intake, which was shown in terms of percentage of the Acceptable Daily Intake (ADI) of either insecticide. The daily intakes are minimal with a 99% probability, but go up steeply at the 99.9th percentile (13.1% and 20.0% of the ADIs of chlorpyrifos and cypermethrin, respectively). The sensitivity analysis indicates that concentration is the most determinant variable for daily intake estimation, suggesting that high intakes may occur when insecticide concentrations are elevated. Compared to the data of daily intakes via dietary ingestion of vegetables derived from a previous study, the estimated non-dietary intakes are negligible until reaching the highest percentile. Consequently, the non-dietary ingestion exposure to either insecticide is commonly low for young children in Taiwan’s homes, unless high contamination (e.g., indoor insecticide application) occurs in the environment. Care has to be taken to avoid high contamination indoors.

Pesticides in indoor and outdoor residential dust: a pilot study in a rural county of Taiwan.

We conducted a pilot study to examine pesticides in dust of homes in a rural county of Taiwan. A total of 56 homes of pregnant women were included in the study. Indoor and outdoor dust was collected by a vacuum sampler and a dustpan/brush set, respectively. Nine pesticides were selected for analysis on gas chromatography-mass spectrometry with the detection limits being 0.088 ng/g or lower. The most detected pesticides were cypermethrin and chlorpyrifos, which appeared in 82.7 and 78.8% of indoor samples and 48.2 and 39.3% of outdoor samples, respectively. The detection of pesticides from indoor and outdoor dust, however, was not consistent, indicating different sources of pesticides. In addition to those two most detected, permethrin, prallethrin, and tetramethrin, which were common ingredients of insecticide products for indoor use, were also frequently found in indoor dust, suggesting that indoor use of such pesticide products may have been a major source. Fewer pesticides were found in outdoor dust, but the outdoor detection of chlorpyrifos was significantly associated with farms present inside the circles with radii of 50 and 100 m surrounding the homes (P = 0.021, 0.016). It is suggested that pesticide drift from agricultural areas to residential environments may have occurred. No seasonal effect on distribution of pesticides in dust was found, indicating that pesticides could be routinely used in Taiwan regardless of season. Compared with other international studies, this study shows relatively high levels of chlorpyrifos but low levels of pyrethroids (i.e., cypermethrin), reflecting a different pattern of pesticide use in Taiwan. Further studies need to be warranted for a better understanding of exposure to pesticides and the associated health effects.

GIT1 contributes to autophagy in osteoclast through disruption of the binding of Beclin1 and Bcl2 under starvation condition.

Approximately 10-15% of all bone fractures do not heal properly, causing patient morbidity and additional medical care expenses. Therefore, better mechanism-based fracture repair approaches are needed. In this study, a reduced number of osteoclasts (OCs) and autophagosomes/autolysosomes in OC can be observed in GPCR kinase 2-interacting protein 1 (GIT1) knockout (KO) mice on days 21 and 28 post-fracture, compared with GIT1 wild-type (GIT1 WT) mice. Furthermore, in vitro experiments revealed that GIT1 contributes to OC autophagy under starvation conditions. Mechanistically, GIT1 interacted with Beclin1 and promoted Beclin1 phosphorylation at Thr119, which induced the disruption of Beclin1 and Bcl2 binding under starvation conditions, thereby, positively regulating autophagy. Taken together, the findings suggest a previously unappreciated role of GIT1 in autophagy of OCs during fracture repair. Targeting GIT1 may be a potential therapeutic approach for bone fractures.