[Bombyx Batryticatus extract promotes microglia polarization to improve neuron injury and behaviors of cerebral ischemia/reperfusion rats].

This study aims to investigate the effect of Bombyx Batryticatus extract(BBE) on behaviors of rats with global cerebral ischemia reperfusion(I/R) and the underlying mechanism. The automatic coagulometer was used to detect the four indices of human plasma coagulation after BBE intervention for quality control of the extract. Sixty 4-week-old male SD rats were randomized into sham operation group(equivalent volume of normal saline, ip), model group(equivalent volume of normal saline, ip), positive drug group(900 IU·kg~(-1) heparin, ip), and low-, medium-, and high-dose BBE groups(0.45, 0.9, and 1.8 mg·g~(-1)·d~(-1) BBE, ip). Except the sham operation group, rats were subjected to bilateral common carotid artery occlusion followed by reperfusion(BCCAO/R) to induce I/R. The administration lasted 7 days for all the groups. The behaviors of rats were examined by beam balance test(BBT). Morphological changes of brain tissue were observed based on hematoxylin-eosin(HE) staining. Immunofluorescence method was used to detect common leukocyte antigen(CD45), leukocyte differentiation antigen(CD11b), and arginase-1(Arg-1) in cerebral cortex(CC). The protein expression of interleukin-1ß(IL-1ß), interleukin-4(IL-4), interleukin-6(IL-6), and interleukin-10(IL-10) was detected by enzyme-linked immunosorbent assay(ELISA). The non-targeted metabonomics was employed to detect the levels of metabolites in plasma and CC of rats after BBE intervention. The results of quality control showed that the BBE prolonged the activated partial thromboplastin time(APTT), prothrombin time(PT), and thrombin time(TT) of human plasma, which was similar to the anticoagulation effect of BBE obtained previously. The results of behavioral test showed that the BBT score of the model group increased compared with that of the sham operation group. Compared with the model group, BBE reduced the BBT score. As for the histomorphological examination, compared with the sham operation group, the model group showed morphological changes of a lot of nerve cells in CC. The nerve cells with abnormal morphology in CC decreased after the intervention of BBE compared with those in the model group. Compared with the sham operation group, the model group had high average fluorescence intensity of CD45 and CD11b in the CC. The average fluorescence intensity of CD11b decreased and the average fluorescence intensity of Arg-1 increased in CC in the low-dose BBE group compared with those in the model group. The average fluorescence intensity of CD45 and CD11b decreased and the average fluorescence intensity of Arg-1 increased in medium-and high-dose BBE groups compared with those in the model group. The expression of IL-1ß and IL-6 was higher and the expression of IL-4 and IL-10 was lower in the model group than in the sham operation group. The expression of IL-1ß and IL-6 was lower and the expression of IL-4 and IL-10 was higher in the low-dose, medium-dose, and high-dose BBE groups than in the model group. The results of non-targeted metabonomics showed that 809 metabolites of BBE were identified, and 57 new metabolites in rat plasma and 45 new metabolites in rat CC were found. BBE with anticoagulant effect can improve the behaviors of I/R rats, and the mechanism is that it promotes the polarization of microglia to M2 type, enhances its anti-inflammatory and phagocytic functions, and thus alleviates the damage of nerve cells in CC.

Developmental immunotoxicity of maternal exposure to yttrium nitrate on BALB/c offspring mice.

Yttrium is a typical heavy rare earth element with widespread use in numerous sectors. Only one previous study has indicated that yttrium has the potential to cause developmental immunotoxicity (DIT). Therefore, there remains a paucity of evidence on the DIT of yttrium. This study aimed to explore the DIT of yttrium nitrate (YN) and the self-recovery of YN-induced DIT. Dams were treated with 0, 0.2, 2, and 20 mg/kg bw/day YN by gavage during gestation and lactation. No significant changes were found in innate immunity between the control and YN-treated groups in offspring. In female offspring at postnatal day 21 (PND21), YN markedly inhibited humoral and cellular immune responses, the proliferative capacity of splenic T lymphocytes, and the expression of costimulatory molecules in splenic lymphocytes. Moreover, the inhibitory effect on cellular immunity in female offspring persisted to PND42. Unlike females, YN exposure did not change the adaptive immune responses in male offspring. Overall, maternal exposure to YN showed a strong DIT to offspring, with the lowest effective dose of 0.2 mg/kg in the current study. The toxicity of cellular immunity could persist throughout development into adulthood. There were sex-specific differences in YN-induced DIT, with females being more vulnerable.

1,4-Naphthoquinone-coated black carbon nanoparticles up-regulation POR/FTL/IL-33 axis in THP1 cells.

Black carbon (BC) is an important component of atmospheric PM 2.5 and the second largest contributor to global warming. 1,4-naphthoquinone-coated BC (1,4 NQ-BC) is a secondary particle with great research value, so we chose 1,4 NQ-BC as the research object. In our study, mitochondria and lysosomes were selected as targets to confirm whether they were impaired by 1,4 NQ-BC, label free proteomics technology, fluorescent probes, qRT-PCR and western blots were used to investigate the mechanism of 1,4 NQ-BC toxicity. We found 494 differentially expressed proteins (DEPs) in mitochondria and 86 DEPs in lysosomes using a proteomics analysis of THP1 cells after 1,4 NQ-BC exposure for 24 h. Through proteomics analysis and related experiments, we found that 1,4 NQ-BC can damage THP-1-M cells by obstructing autophagy, increasing lysosomal membrane permeability, disturbing the balance of ROS, and reducing the mitochondrial membrane potential. It is worth noting that 1,4 NQ-BC prevented the removal of FTL by inhibiting autophagy, and increased IL-33 level by POR/FTL/IL-33 axis. We first applied proteomics to study the damage mechanism of 1,4 NQ-BC on THP1 cells. Our research will enrich knowledge of the mechanism by which 1,4 NQ-BC damages human macrophages and identify important therapeutic targets and adverse outcome pathways for 1,4 NQ-BC-induced damage.

Integrated proteomic analysis to explore the molecular regulation mechanism of IL-33 mRNA increased by black carbon in the human endothelial cell line EA.hy926.

Black carbon (BC) correlates with the occurrence and progression of atherosclerosis and other cardiovascular diseases. Increasing evidence has demonstrated that BC could impair vascular endothelial cells, but the underlying mechanisms remain obscure. It is known that IL-33 exerts a significant biological role in cardiovascular disease, but little is known about the molecular regulation of IL-33 expression at present. We first found that BC significantly increased IL-33 mRNA in EA.hy926 cells in a concentration and time-dependent manner, and we conducted this study to explore its underlying mechanism. We identified that BC induced mitochondrial damage and suppressed autophagy function in EA.hy926 cells, as evidenced by elevation of the aspartate aminotransferase (GOT2), reactive oxygen species (ROS) and p62, and the reduction of mitochondrial membrane potential (ΔΨm). However, ROS cannot induce IL-33 mRNA-production in BC-exposed EA.hy926 cells. Further, experiments revealed that BC could promote IL-33 mRNA production through the PI3K/Akt/AP-1 and p38/AP-1 signaling pathways. It is concluded that BC could induce oxidative stress and suppress autophagy function in endothelial cells. This study also provided evidence that the pro-cardiovascular-diseases properties of BC may be due to its ability to stimulate the PI3K/AKT/AP-1 and p38/AP-1 pathway, further activate IL-33 and ultimately result in a local vascular inflammation.

Exploration of potential mechanism of interleukin-33 up-regulation caused by 1,4-naphthoquinone black carbon in RAW264.7 cells.

BACKGROUND: As air pollution has been paid more attention to by public in recent years, effects and mechanism in particulate matter-triggered health problems become a focus of research. Lysosomes and mitochondria play an important role in regulation of inflammation. Interleukin-33 (IL-33) has been proved to promote inflammation in our previous studies. In this research, macrophage cell line RAW264.7 was used to explore the potential mechanism of upregulation of IL-33 induced by 1,4-naphthoquinone black carbon (1,4-NQ-BC), and to explore changes of lysosomes and mitochondria during the process. RESULTS: 50 µg/mL 1,4-NQ-BC exposure for 24 h dramatically increased expression of IL-33 in RAW264.7 cells. Lysosomal membrane permeability was damaged by 1,4-NQ-BC treatment, and higher mitochondrial membrane potential and ROS level were induced by 1,4-NQ-BC. The results of proteomics suggested that expression of ferritin light chain was increased after cells were challenged with 1,4-NQ-BC, and it was verified by Western blot. Meanwhile, expressions of p62 and LC3B-II were increased by 50 µg/mL 1,4-NQ-BC in RAW264.7 cells. Ultimately, expression of IL-33 could return to same level as control in cells treated with 50 µg/mL 1,4-NQ-BC and 50 µM deferoxamine combined. CONCLUSIONS: 1,4-NQ-BC induces IL-33 upregulation in RAW264.7 cells, and it is responsible for higher lysosomal membrane permeability and ROS level, lower mitochondrial membrane potential, and inhibition of autophagy. Ferritin light chain possibly plays an important role in the upregulation of IL-33 evoked by 1,4-NQ-BC.

Associations of maternal exposure to fine particulate matter with preterm and early-term birth in high-risk pregnant women.

BACKGROUND: Environmental pollution is a risk factor for adverse birth outcomes, especially preterm birth (PTB) and early-term birth (ETB). It has been revealed that exposure to fine particulate matter (PM2.5) during pregnancy increase the prevalence of PTB. However, the relationship between PM2.5 exposure and ETB has not been elucidated. In high-risk pregnancies, whether PM2.5 exposure will bring higher risk of PTB and ETB than in normal pregnancies is still unclear, and the susceptible exposure window is obscure. Therefore, it is worthy of assessing the risk on PTB and ETB and identifying the susceptible exposure windows of PM2.5 exposure in high-risk pregnant women. RESULTS: This paper collected the clinical data of 7974 singletons, high-risk pregnant women in Peking University First Hospital from 2014 to 2018, and analyzed them using logistic regression and stratified analysis. We observed that exposure to high-level (≥ 75 µg/m3) of PM2.5 during the third trimester of pregnancy increases the risk of PTB and ETB (PTB: odds ratio[OR] = 1.43, 95% confidence interval [CI]:1.05-1.93. ETB: OR = 1.29, 95%CI: 1.09-1.54). Furthermore, the effects of each 10ug/m3 increase in PM2.5 on PTB and ETB were significant during the third trimester (PTB: OR = 1.35, 95%CI:1.16-1.58. ETB: OR = 1.12, 95%CI:1.02-1.22) and the entire pregnancy (PTB: OR = 6.12, 95%CI:4.27-8.89. ETB: OR = 1.96, 95%CI:1.59-2.43) in the high-level exposure group. CONCLUSIONS: These results suggest that high-level PM2.5 exposure during pregnancy is associated with high risk of PTB and ETB in high-risk pregnancies. The third trimester of pregnancy is speculated to be the susceptible exposure window.

Effects of intrauterine and lactational exposure to lanthanum nitrate on BALB/c offspring mice: Developmental immunotoxicity and self-recovery.

Lanthanum, a major rare earth element, can exert detrimental effects on the adult immune system, but its developmental immunotoxicity (DIT) remains obscure. This study was designed to evaluate the DIT of lanthanum nitrate (LN) and the self-recovery of LN-induced DIT 21 days following cessation of exposure. BALB/c pregnant dams were exposed to 0, 0.1, 1, and 10 mg/kg body weight/day LN by gavage during gestation and lactation. Results showed that in male offspring, LN markedly inhibited the adaptive immunity at postanal day 21 (PND21) and the inhibitory effect on cellular immunity continued to PND42 (after three weeks of self-recovery). In female offspring, LN suppressed cellular immunity at both PND21 and PND42. Moreover, decreased relative organ weight of thymus, humoral immunity and proportion of double-positive T cells in thymus were also observed at PND42. Bcl-xl protein level decreased in thymus of female at PND42, while the level of ß-catenin increased. These changes might contribute to accelerating the degeneration and weight loss of thymus. Overall, in-utero and postanal exposure to LN could induce impairments of immunity in offspring, especially the female, and adaptive immunosuppression would persist throughout development into adulthood. The LOAEL of LN for DIT should be 1 mg/kg.

The impact of polystyrene microplastics on cardiomyocytes pyroptosis through NLRP3/Caspase-1 signaling pathway and oxidative stress in Wistar rats.

The extensive existing of microplastics (MPs) in the ecosystem have increased considerable attention concerning their potential adverse effects, the toxicities and the underlying mechanism of MPs are still scarce. To explore the effect of MPs on cardiac tissue in Wistar rats and unravel the mechanism of pyroptosis and oxidative stress in the process of cardiomyocytes injury, 32 male Wister rats were divided into control group and three model groups, which were exposed to 0.5 mm PS MPs at 0.5, 5 and 50 mg/L for 90 days. Results revealed that MPs could damage cardiac structure and function with impaired mitochondria integrity, as well as increased levels of creatine kinase-MB and cardiac troponinI (cTnI). Moreover, MPs administration triggered oxidative stress as indicated by increased levels of malondialdehyde and decreased activity of superoxide dismutase, glutathione peroxidase and catalase. Treatment with MPs resulted in apoptosis and pyroptosis as evidenced by increasing expressions of interleukin (IL)-1ß, IL-18. Additionally, MPs were shown to induce the NOD-like receptor protein 3 inflammasomes activation in cardiac tissue, enabling activation of Caspase-1-dependent signaling pathway induced by inflammatory stimuli resulting from oxidative stress. In summary, these results illustrated that pyroptosis played a vital role in polystyrene MPs-induced cardiotoxicity, which might be helpful to understand the mechanism of cardiac dysfunction and induced by MPs.

Polystyrene microplastics cause cardiac fibrosis by activating Wnt/ß-catenin signaling pathway and promoting cardiomyocyte apoptosis in rats.

Microplastics (MPs) are new persistent organic pollutants derived from the degradation of plastics. They can accumulate along the food chain and enter the human body through oral administration, inhalation and dermal exposure. To identify the impact of Polystyrene (PS) MPs on the cardiovascular system and the underlying toxicological mechanism, 32 male Wister rats were divided into control group and three model groups, which were exposed to 0.5 µm PS MPs at 0.5, 5 and 50 mg/L for 90 days. Our results suggested that PS MPs exposure increased Troponin I and creatine kinase-MB (CK-MB) levels in serum, resulted in structure damage and apoptosis of myocardium, and led to collagen proliferation of heart. Moreover, PS MPs could induce oxidative stress and thus activate fibrosis-related Wnt/ß-catenin signaling pathway. These results suggested that PS MPs could lead to cardiovascular toxicity by inducing cardiac fibrosis via activating Wnt/ß-catenin pathway and myocardium apoptosis triggered by oxidative stress. The present study provided some novelty evidence to elucidate the potential mechanism of cardiovascular toxicity induced by PS MPs.

Stepwise arms race between AvrPik and Pik alleles in the rice blast pathosystem.

A stepwise mutation that occurred in both pathogens and their respective hosts has played a seminal role in the co-evolutionary arms race evolution in diverse pathosystems. The process driven by rice blast AvrPik and Pik alleles was investigated through population genetic and evolutionary approaches. The genetic diversity of the non-signal domain of AvrPik was higher than that in its signal peptide domain. Positive selection for particular AvrPik alleles in the northeastern region of China was stronger than in the south. The perfect relationship between the functional lineages and AvrPik allele-specific pathotypes was established by ruling out the nonfunctional lineages derived from additional copies. Only four alleles conditioning stepwise pathotypes were detected in natural populations, which were likely created by only one evolutionary pathway with three recognizable mutation steps. Two non-stepwise pathotypes were determined by two blocks in a network constructed by all 16 possible alleles, indicating that a natural evolution process can be artificially changed by a combination of specific single-nucleotide polymorphisms. Assuming that AvrPik evolution has been largely driven by host selection, the co-evolutionary stepwise relationships between AvrPik and Pik was established. The experimental validation of stepwise mutation is required for the development of sustainable management strategies against plant disease.