N-MYC-interacting protein enhances type II interferon signaling by inhibiting STAT1 sumoylation.

Signaling desensitization is key to limiting signal transduction duration and intensity. Signal transducer and activator of transcription 1 (STAT1) can mediate type II interferon (IFNγ)-induced immune responses, which are enhanced and inhibited by STAT1 phosphorylation and sumoylation, respectively. Here, we identified an N-MYC interacting protein, NMI, which can enhance STAT1 phosphorylation and STAT1-mediated IFNγ immune responses by binding and sequestering the E2 SUMO conjugation enzyme, UBC9, and blocking STAT1 sumoylation. NMI facilitates UBC9 nucleus-to-cytoplasm translocation in response to IFNγ, thereby inhibiting STAT1 sumoylation. STAT1 phosphorylation at Y701 and sumoylation at K703 are mutually exclusive modifications that regulate IFNγ-dependent transcriptional responses. NMI could not alter the phosphorylation level of sumoylation-deficient STAT1 after IFNγ treatment. Thus, IFNγ signaling is modulated by NMI through sequestration of UBC9 in the cytoplasm, leading to inhibition of STAT1 sumoylation. Hence, NMI functions as a switch for STAT1 activation/inactivation cycles by modulating an IFNγ-induced desensitization mechanism.

Interleukin-2 enhancer binding factor 2 negatively regulates the replication of duck hepatitis A virus type 1 by disrupting the RNA-dependent RNA polymerase activity of 3D polymerase.

The interaction between viral components and cellular proteins plays a crucial role in viral replication. In a previous study, we showed that the 3'-untranslated region (3'-UTR) is an essential element for the replication of duck hepatitis A virus type 1 (DHAV-1). However, the underlying mechanism is still unclear. To gain a deeper understanding of this mechanism, we used an RNA pull-down and a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assay to identify new host factors that interact with the 3'-UTR. We selected interleukin-2 enhancer binding factor 2 (ILF2) for further analysis. We showed that ILF2 interacts specifically with both the 3'-UTR and the 3D polymerase (3Dpol) of DHAV-1 through in vitro RNA pull-down and co-immunoprecipitation assays, respectively. We showed that ILF2 negatively regulates viral replication in duck embryo fibroblasts (DEFs), and that its overexpression in DEFs markedly suppresses DHAV-1 replication. Conversely, ILF2 silencing resulted in a significant increase in viral replication. In addition, the RNA-dependent RNA polymerase (RdRP) activity of 3Dpol facilitated viral replication by enhancing viral RNA translation efficiency, whereas ILF2 disrupted the role of RdRP in viral RNA translation efficiency to suppress DHAV-1 replication. At last, DHAV-1 replication markedly suppressed the expression of ILF2 in DEFs, duck embryo hepatocytes, and different tissues of 1 day-old ducklings. A negative correlation was observed between ILF2 expression and the viral load in primary cells and different organs of young ducklings, suggesting that ILF2 may affect the viral load both in vitro and in vivo.

Oleanolic acid inhibits mercury chloride induced-liver ferroptosis by regulating ROS/iron overload.

Mercury chloride can cause severe liver injury, which involves multiple mechanisms. Ferroptosis plays an important role in regulating the development and progression of liver pathology. Oleanolic acid (OA), a triterpenoid compound widely exists in fruits, has liver protective properties. In this study, we investigated the role of ferroptosis in mercury chloride-induced liver injury and the intervention effect of OA, and clarified the potential mechanism. We found that mercury chloride-induced oxidative stress in liver tissues and cells, leading to lipid peroxidation and iron overload, thereby reducing the expression levels of GPX4 and SLC7A11, and increasing the expression level of TRF1, OA pretreatment improved the changes of GPX4, SLC7A11 and TRF1 induced by mercury chloride, which were related to its inhibition of oxidative stress. Furthermore, We pretreated cells with OA, VC, and Fer-1, respectively and found that VC pretreatment reduced oxidative stress and significantly reversed the gene and protein expressions of GPX4, SLC7A11, and TRF1 in mercury chloride-exposed cells (P < 0.05, vs. HgCl2 group), however, the protein expression level of GPX4 in OA pre-treatment group was lower than that in VC pre-treatment group (P < 0.05). Fer-1 pretreatment decreased the level of iron ions in cells, increased the gene and protein expression levels of GPX4 and SLC7A11, and decreased the gene and protein expression levels of TRF1 (P < 0.05, vs. HgCl2 group), however, the protein expression levels of GPX4 and SLC7A11 in OA pre-treatment group were lower than those in Fer-1 pre-treatment group (P < 0.05). Moreover, vivo experiments also demonstrated that pre-treatment with OA, VC, and Fer-1 reversed the changes in gene expression levels of Nrf2 and SOD1, and protein expression of GPX4 induced by mercury chloride (P < 0.05, vs. HgCl2 group), meanwhile, the difference was not statistically significant among OA, VC, and Fer-1 pretreatment. The improvement effect of OA pretreatment on the change in TFR1 protein expression caused by mercury chloride was similar to that of Fer-1 and VC, however, the intervention effect of OA on SLC7A11 protein expression was not as good as Fer-1 and VC pre-treatment. To sum up, all these results suggest that ferroptosis is involved in mercury chloride-induced liver injury, OA pretreatment alleviated mercury chloride-induced ferroptosis by inhibiting ROS production and iron ion overload, and then alleviate the liver injury.

HMGB1-NLRP3-P2X7R pathway participates in PM2.5-induced hippocampal neuron impairment by regulating microglia activation.

Neuroinflammation is a key mechanism underlying the cognitive impairment induced by PM2.5, and activated microglia plays an important role in this process. However, the mechanisms by which activated microglia induced by PM2.5 impair hippocampal neurons have not been fully elucidated. In this study, we focused on the role of HMGB1-NLRP3-P2X7R pathway which mediated the microglia activation in hippocampal neurons impairment induced by PM2.5 using a co-culture model of microglia and hippocampal neurons. We found that PM2.5 resulted in activated microglia and HMGB1-NLRP3 inflammatory pathway, and elevated proinflammatory cytokines of IL-18 and IL-1ß in a dose-dependent manner. Notably, we next utilized previously reported pharmacological inhibitors or siRNA for HMGB1 and found that they significantly inhibited the activation of downstream NLRP3 and MAPK pathways derived from PM2.5 exposure, and down-regulated IL-18 and IL-1ß in microglia. Furthermore, we employed co-cultured hippocampal neurons and microglia and found that reducing HMGB1 significantly decreased neuron impairment, apoptosis related protein of cl-caspase3, synaptic damage, and neurotransmitter receptor of 5-HT2A, along with notably elevated presynaptic and postsynaptic proteins of SYP and PSD-95, as well as learning and memory related proteins of p-CREB and BDNF. The neuronal impairment induced by PM2.5 could not be prevented in the case of simultaneous employment of HMGB1 siRNA and NLRP3 agonist. After silencing NLRP3 alone in microglia, hippocampal neurons demonstrated decreased excessive autophagy and up-regulated synaptic protein of GAP43 as well as learning and memory related protein of NCAM1. Therefore, we further studied how hippocampal neurons affected microglia under PM2.5 exposure, Further investigation indicated that silencing HMGB1 could affect the activation of P2X7R and reduce the release of ATP from hippocampal neurons, thus protecting the interaction between microglia and hippocampal neurons. The present work suggests that regulation of HMGB1-NLRP3-P2X7R pathway can inhibit the microglia activation induced by PM2.5 to alleviate hippocampal neuron impairment and stabilize the microenvironment between microglia and neurons. This contributes to maintaining the normal function of hippocampal neurons and alleviating the cognitive impairment derived from PM2.5 exposure.

Salidroside prevents PM2.5-induced BEAS-2B cell apoptosis via SIRT1-dependent regulation of ROS and mitochondrial function.

PM2.5 is a harmful air pollutant currently threatening public health. It has been closely linked to increased morbidity of bronchial asthma and lung cancer worldwide. Salidroside (Sal), an active component extracted from Rhodiola rosea, has been reported to ameliorate the progression of asthma. However, there are few studies on the protective effect of salidroside on PM2.5-induced bronchial epithelial cell injury, and the related molecular mechanism is not clear. Here, we aimed to explore the protective effect and related mechanism of Sal on PM2.5 bronchial injury. We chose 50 µg/mL PM2.5 for 24 h as a PM2.5-induced cell damage model. After that BEAS-2B cells were pretreated with 40, 80, 160 µM Sal for 24 h and then exposed to 50 µg/mL PM2.5 for 24 h. We found that Sal pretreatment significantly inhibited the decrease of cell viability induced by PM2.5. Sal was effective in preventing PM2.5-induced apoptotic features, including Ca2+ overload, the cleavages of caspase 3, and the increases in levels of caspase 9 and Bcl-2-associated X protein (Bax), ultimately, Sal significantly inhibited PM2.5-induced apoptosis. Sal improved mitochondrial membrane potential, inhibited the release of cytochrome c from the mitochondria to cytoplasm. Sal alleviated ROS production, decreased the level of MDA, prevented the reduction of CAT, SOD and GSH-Px and increased the expression of NF-E2-related factor 2 (Nrf2), HO-1 and superoxide dismutase 1 (SOD1) in cells exposed to PM2.5. Furthermore, Sal improved the decrease of SIRT1 and PGC-1 α expression levels caused by PM2.5. In addition, inhibition of SIRT1 by EX527 (SIRT1 inhibitor) reversed the protective effects of Sal, including the decrease of ROS level, the increase of membrane potential level and the decrease of apoptosis level. Thus, Sal may be regarded as a potential drug to prevent PM2.5-induced apoptosis of bronchial epithelial cells and other diseases with similar pathological mechanisms.

[Renal injury induced by cadmium chloride and the protective effect of vitamin C in mice].

OBJECTIVE: To investigate the renal injury induced by cadmium chloride(CdCl_2) and the protective effect of vitamin C(VC) in mice. METHODS: Forty healthy clean grade male Kunming mice were randomly divided into 4 groups: control group(double distilled water gavage and intraperitoneal injection), VC group(200 mg/kg VC gavage and double distilled water intraperitoneal injection), CdCl_2 group(double distilled water gavage and 2 mg/kg CdCl_2 intraperitoneal injection), VC+CdCl_(2 )group(200 mg/kg VC gavage and 2 mg/kg CdCl_2 intraperitoneal injection). Exposure for 30 days.24 hours after the last exposure, the eyeballs were taken out for blood, and the renal tissue was immediately taken out to calculate kidney coefficient and then separate renal cells. The levels of reactive oxygen species(ROS) were detected by DCFH-DA kit and flow cytometry. Blood urea nitrogen(BUN), serum creatinine(Scr)and ß2 microglobulin(ß2-MG), cystatin C(Cys C), superoxide dismutase(SOD), glutathione peroxidase(GSH-Px), malondialdehyde(MDA), Caspase3 and Caspase9 kits were used to detect the corresponding indicators respectively. The contents of Cd~(2+) and Zn~(2+) in serum and kidney were detected by graphite furnace atomic absorption spectrometry. RESULTS: The levels of kidney coefficient and BUN, Scr, ß2-MG were 1.36±0.10, (19.34±0.63)mmol/L, (61.30±2.04)mmol/L and(1.02±0.10)g/mL respectively in CdCl_(2 )group, which were higher than those in the control group and VC group(P<0.05). The levels of the above four indexes in VC+CdCl_(2 )group were 1.09±0.10, (9.65±0.50)mmol/L, (41.85±1.27)mmol/L and(0.61±0.01)g/mL respectively, which were lower than those in CdCl_2 group(P<0.05). CdCl_2 exposure resulted in unclear glomerular contour, swelling of renal tubules, interstitial hyperemia, and exfoliated epithelial cells in the lumen. VC pretreatment could improve the above changes. The levels of Cd~(2+) in serum and renal tissue of mice in CdCl_2 group were(4.36±0.07)µg/L, (18.6±1.95)µg/g respectively, which were higher than that of control group and VC group(P<0.05), in VC+CdCl_2 group, the level were(2.12±0.06)µg/L and(2.18±0.09)µg/g, they were lower than that of CdCl_2 group(P<0.05). The level of serum Zn~(2+ )in CdCl_2 group was(11.35±1.03)µg/L, that was lower than control group(P<0.05). The level of serum Zn~(2+) in VC+CdCl_2 group was(26.98±3.13)µg/L, which was higher than that of CdCl_2 group(P<0.05). The levels of ROS, MDA, Caspase3 and Caspase9 in kidney tissue of mice in CdCl_2 group were(1.86±0.13), (4.78±0.15)nmol/mg, 1.50±0.24 and 1.69±0.17 respectively, which were higher than those in control group(P<0.05). And the level of GSH-Px was(261.3±23.36)U/mg, it was lower than that in control group(P<0.05). Compared with the CdCl_2 group, the levels of ROS, MDA, Caspase3 and Caspase9 in VC+CdCl_2 group decreased, and the level of GSH-Px increased, the difference was statistically significant(P<0.05). CONCLUSION: CdCl_2 exposure can lead to oxidative stress, damage of glomerulus and renal tubules, imbalance of zinc ion homeostasis, and damage of renal function. VC pretreatment can reduce the damage caused by CdCl_2 to a certain extent.

[Air fine particulate matter induced alveolar type â ¡ epithelial cell injury in rats].

OBJECTIVE: To investigate the damage of rat alveolar type II epithelial cells(RLE-6 TN) caused by air fine particulate matter(PM_(2.5)) and its related mechanism. METHODS: PM_(2.5) in the atmosphere of Weifang City in 2020 was collected and cell culture medium was used to prepare particulate suspension. RLE-6 TN cells were exposed to different concentrations(25, 50, 100, 200, 400 µg/mL) of particulate matter suspensions for 24 h. The morphological changes of RLE-6 TN cells were observed under inverted microscope, and the cell viability was determined by MTT method. The concentration of lactate dehydrogenase(LDH) in cell supernatant was determined by microplate method. DCFH-DA, Annexin V-FITC/PI, JC-1 probe and laser confocal fluorescence intensity were used to determine the levels of reactive oxygen species(ROS), apoptosis and mitochondrial membrane potential. Total superoxide dismutase(T-SOD), glutathione(GSH) and malondialdehyde(MDA) contents and activity levels in cells were determined by colorimetric method. Caspase-3 and Caspase-9 kit were used to detect the relative expression activity of apoptosis proteins. RESULTS: PM_(2.5) could lead to morphological changes of RLE-6 TN cells, enlarged cell space and decreased cell viability. Compared with the control group, there were statistically significant differences in each dose group(P<0.05). LDH concentration in the supernatant of ≥50 µg/mL infected group increased, and LDH concentration was ≥(377.82±29.84), which was significantly different from that of the control group(278.51±23.76)(P<0.05). The result of laser confocal detection of ROS showed that the intracellular green fluorescence increased gradually in the ≥50 µg/mL group, and the relative fluorescence intensity was ≥(2.77±0.18), which was statistically significant compared with the control group(P<0.05). The level of apoptosis was significantly increased compared with the control group(P<0.05). The level of mitochondrial membrane potential decreased gradually, and the level of mitochondrial membrane potential in the ≥25 µg/mL group was ≤(4.22±0.45), which was statistically different from that in the control group(6.16±0.49)(P<0.05). PM_(2.5) could reduce the levels of T-SOD and GSH, and the levels of T-SOD and GSH in ≥50 µg/mL exposed group were ≤(14.67±0.49) and ≤(433.29±39.24), respectively, significantly lower than those in control group((16.58±0.60) and(542.90±45.06))(P<0.05). MDA level increased with the increase of PM_(2.5) concentration. Compared with the control group(1.15±0.19), MDA level in ≥50 µg/mL exposed group was ≥(1.72±0.13), with statistical significance(P<0.05). The activity levels of Caspase-3 and Caspase-9 increased in ≥100 µg/mL group, and the activity levels were ≥(1.62±0.27) and ≥(1.23±0.06), respectively, compared with the control group, the differences were statistically significant(P<0.05). CONCLUSION: Exposure to a certain concentration of PM_(2.5) can induce oxidative stress of rat alveolar type II epithelial cells, reduce the membrane potential, and eventually lead to cell apoptosis.

Genetic diversity and epidemiology of human rhinovirus among children with severe acute respiratory tract infection in Guangzhou, China.

BACKGROUND: Human rhinovirus (HRV) is one of the major viruses of acute respiratory tract disease among infants and young children. This work aimed to understand the epidemiological and phylogenetic features of HRV in Guangzhou, China. In addition, the clinical characteristics of hospitalized children infected with different subtype of HRV was investigated. METHODS: Hospitalized children aged < 14 years old with acute respiratory tract infections were enrolled from August 2018 to December 2019. HRV was screened for by a real-time reverse-transcription PCR targeting the viral 5'UTR. RESULTS: HRV was detected in 6.41% of the 655 specimens. HRV infection was frequently observed in children under 2 years old (57.13%). HRV-A and HRV-C were detected in 18 (45%) and 22 (55%) specimens. All 40 HRV strains detected were classified into 29 genotypes. The molecular evolutionary rate of HRV-C was estimated to be 3.34 × 10-3 substitutions/site/year and was faster than HRV-A (7.79 × 10-4 substitutions/site/year). Children who experienced rhinorrhoea were more common in the HRV-C infection patients than HRV-A. The viral load was higher in HRV-C detection group than HRV-A detection group (p = 0.0148). The median peak symptom score was higher in patients with HRV-C infection as compared to HRV-A (p = 0.0543), even though the difference did not significance. CONCLUSION: This study revealed the molecular epidemiological characteristics of HRV in patients with respiratory infections in southern China. Children infected with HRV-C caused more severe disease characteristics than HRV-A, which might be connected with higher viral load in patients infected with HRV-C. These findings will provide valuable information for the pathogenic mechanism and treatment of HRV infection.

Cr (VI) induces abnormalities in glucose and lipid metabolism through ROS/Nrf2 signaling.

The hexavalent form of chromium, Cr (VI), has been associated with various diseases in humans. In this study, we examined the mechanisms underlying the effect of Cr (VI) on glucose and lipid metabolism in vivo and in vitro. We found that Cr (VI) induced abnormal liver function, increased fasting blood glucose (FBG), as well as glucose and insulin intolerance in mice. Furthermore, Cr (VI) decreased glucose-6-phosphate (G6P) level and glucose transporter-2 (GLUT2) expression, increased the levels of triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C), reduced high-density lipoprotein-cholesterol (HDL-C), and increased sterol regulatory element-binding proteins 1 (SREBP1) and fat synthase (FAS) in vitro and in vivo. Moreover, Cr (VI) promoted intracellular ROS production in vitro, and induced reduction of antioxidant enzyme level and Nrf2/HO-1 expression in vitro and in vivo. Also, N-acetyl cysteine (NAC, effective antioxidant and free radical scavenger) pretreatment inhibited the production of intracellular ROS, significantly suppressed Cr (VI)-induced oxidative stress, lipid accumulation, decreased G6P and GLUT2, and improved impaired glucose tolerance and glucose and insulin intolerance caused by Cr (VI) in mice. Dh404 activated expression of Nrf2 decreased ROS level, increased HO-1 expression, ameliorated activity of the antioxidant enzyme, inhibited Cr (VI) increase of SREBP1, FAS level, and reduction of G6P and GLUT2. To sum up, these data suggest that dysregulation of ROS/Nrf2/HO-1 has an important role in Cr (VI)-induced glucose/lipid metabolic disorder.

[Protective effect of oleanolic acid on L02 hepatocyte injury induced by HgCl_2].

OBJECTIVE: To investigate the protective effect of oleanolic acid(OA) on HgCl_2 induced liver injury. METHODS: L02 cells were divided into four groups according to different treatment, control group(Con), oleanolic acid group(OA, 10 µmol/L), HgCl_2 group(HgCl_2, 40 µmol/L) and oleanolic acid + HgCl_2 group(OA + HgCl_2). Cells of control group were given serum-free medium, cells of OA group were pretreated with OA solution for 8 hours, cells of HgCl_2 group were exposed to HgCl_2 solution for 6 hours, cells of OA + HgCl_2 group were pretreated with OA solution for 8 hours, and then exposed to HgCl_2 solution for 6 hours. MTT assay was used to detect cell viability. Laser confocal scanning was used to detect JC-1 probe fluorescence intensity to determine mitochondrial membrane potential. DCFH-DA fluorescence probe combined with flow cytometry was used to detect reactive oxygen species(ROS) level. Annexin V/PI double staining method combined with flow cytometry was used to determine cell apoptosis rate. Catalase(CAT), total superoxide dismutase(T-SOD), glutathione(GSH), malondialdehyde(MDA), Caspase 3 and Caspase 9 kits combined with enzyme labeled instrument were used to determine their activity or content respectively. RESULTS: Compared with the control group, 40 µmol/L HgCl_2 could significantly reduce cell viability, the level was 0.52±0.03(P<0.05), OA pretreatment could significantly inhibit the decrease of cell viability induced by HgCl_2, the level was 0.86±0.05(P<0.05). The result of mitochondrial membrane potential detection showed that cell exposed to 40 µmol/L HgCl_2 significantly reduced the intensity of red fluorescence, and the ratio of red to green fluorescence was 0.23±0.02(P<0.05). OA pretreatment significantly increased red fluorescence, and the ratio of red fluorescence to green fluorescence was 1.32±0.08, which was significantly higher than that of HgCl_2(P<0.05). After exposure to 40 µmol/L HgCl_2, the relative fluorescence intensity of ROS was 1.21±0.07, the apoptosis rate was about 8%, the activity levels of Casepase 3 and Casepase 9 were 3.11±0.20 and 2.94±0.17, respectively, which were all significantly higher than those in the control group(P<0.05). OA pretreatment could significantly alleviate the changes of the above indexes, and the difference was statistically significant compared with HgCl_2 group(P<0.05). The level of T-SOD in HgCl_2 group was(7.68±0.39)U/mL, which was significantly lower than that in control group(P<0.05). Compared to the control group, the level of MDA was significantly increased to(4.99±0.26)nmol/mg(P<0.05). OA pretreatment significantly increased level of T-SOD and decreased the level of MDA, the levels were(13.97±0.71)U/mL and(3.01±0.17)nmol/mg, respectively(P<0.05). CONCLUSION: A certain concentration of HgCl_2 can induce hepatocyte damage. OA pretreatment may reduce cell damage by improving oxidative stress.

Carbon Monoxide Attenuates Lipopolysaccharides (LPS)-Induced Acute Lung Injury in Neonatal Rats via Downregulation of Cx43 to Reduce Necroptosis.

BACKGROUND Acute lung injury (ALI) is one of major causes of death in newborns, making it urgent to improve therapy. Administration of low dose carbon monoxide (CO) plays a protective role in ALI but the mechanisms are not fully understood. This study was designed to test the therapeutic effect of monoxide-releasing molecule 3 (MORM3) in lipopolysaccharide (LPS) induced neonatal ALI and the possibly associated molecular mechanisms. MATERIAL AND METHODS For this study, 3- to 8-day old Newborn Sprague-Dawley rats were subjected to intraperitoneal injection of 3 mg/kg LPS to induce ALI. Then animals received intraperitoneal injection of carbon monoxide-releasing molecules 3 (CORM3) (8 mg/kg) or inactive CORM3 (iCORM3) for 7 consecutive days. Lung tissues were collected for histological examination and total cell counts and protein content in bronchoalveolar lavage fluid (BALF) were measured. Expression of Cx43 and necroptosis-related markers were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. RESULTS LPS exposure induced significant lung injury indicated by histological damage, increased lung wet/dry weight ratio (W/D) and increased total cell counts and protein concentration in BALF. These changes were significantly ameliorated by administration of CORM3 but not iCORM3. LPS also increased necroptosis-related markers RIP1, RIP3, and MLKL and their elevation was blocked by CORM3. CORM3 administration ameliorated LPS induced elevation of Cx43 expression and adenoviral overexpression of Cx43 abolished lung protective effect of CORM3. CORM3 administration attenuated LPS induced activation of extracellular-signal-regulated kinase (ERK) and its protection against necroptosis was abolished by ERK inhibitor U0126. CONCLUSIONS CORM3 attenuates LPS-Induced ALI in neonatal rats and its lung protective effect might be through downregulation of Cx43 to attenuate ERK signaling and ameliorate necroptosis, suggesting CORM3 as a potential therapeutic drug for ALI in neonates.

Gestational B-vitamin supplementation alleviates PM2.5-induced autism-like behavior and hippocampal neurodevelopmental impairment in mice offspring.

Gestational exposure to PM2.5 is a worldwide environmental issue associated with long-lasting behavior abnormalities and neurodevelopmental impairments in the hippocampus of offspring. PM2.5 may induce hippocampus injury and lead to autism-like behavior such as social communication deficits and stereotyped repetitive behavior in children through neuroinflammation and neurodegeneration. Here, we investigated the preventive effect of B-vitamin on PM2.5-induced deleterious effects by focusing on anti-inflammation, antioxidant, synaptic remodeling and neurodevelopment. Pregnant mice were randomly divided into three groups including control group (mice subject to PBS only), model group (mice subject to both 30 µL PM2.5 of 3.456 µg/µL and 10 mL/(kg·d) PBS), and intervention group (mice subject to both 30 µL PM2.5 of 3.456 µg/µL and 10 mL/(kg·d) B-vitamin supplementation (folic acid, vitamin B6 and vitamin B12 with concentrations at 0.06, 1.14 and 0.02 mg/mL, respectively)). In the current study B-vitamin significantly alleviated neurobehavioral impairment reflected in reduced social communication disorders, stereotyped repetitive behavior, along with learning and spatial memory impairment in PM2.5-stimulated mice offspring. Next, B-vitamin corrected synaptic loss and reduced mitochondrial damage in hippocampus of mice offspring, demonstrated by normalized synapse quantity, synaptic cleft, postsynaptic density (PSD) thickness and length of synaptic active area. Furthermore, significantly down-regulated expression of pro-inflammatory cytokines including NF-κB, TNF-α and IL-1ß, and lipid peroxidation were found. We observed elevated levels of oxidant-related genes (SOD, GSH and GSH-Px). Moreover, decreased cleaved caspase-3 and TUNEL-positive cells suggested inhibited PM2.5-induced apoptosis by B-vitamin. Furthermore, B-vitamin increased neurogenesis by increasing EdU-positive cells in the subgranular zone (SGZ) of offspring. Collectively, our results suggest that B-vitamin supplementation exerts preventive effect on autism-like behavior and neurodevelopmental impairment in hippocampus of mice offspring gestationally exposed to PM2.5, to which alleviated mitochondrial damage, increased anti-inflammatory and antioxidant capacity and synaptic efficiency, reduced neuronal apoptosis and improved hippocampal neurogenesis may contribute.

Maternal Exposure to PM2.5 during Pregnancy Induces Impaired Development of Cerebral Cortex in Mice Offspring.

Air pollution is a serious environmental health problem closely related to the occurrence of central nervous system diseases. Exposure to particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5) during pregnancy may affect the growth and development of infants. The present study was to investigate the effects of maternal exposure to PM2.5 during pregnancy on brain development in mice offspring. Pregnant mice were randomly divided into experimental groups of low-, medium-, or high-dosages of PM2.5, a mock-treated group which was treated with the same amount of phosphate buffer solution (PBS), and acontrol group which was untreated. The ethology of offspring mice on postnatal days 1, 7, 14, 21, and 30, along with neuronal development and apoptosis in the cerebral cortex were investigated. Compared with the control, neuronal mitochondrial cristae fracture, changed autophagy characteristics, significantly increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cell rate, and mRNA levels of apoptosis-related caspase-8 and caspase-9 were found in cerebral cortex of mice offspring from the treatment groups, with mRNA levels of Bcl-2 and ratio of Bcl-2 to Bax decreased. Treatment groups also demonstrated enhanced protein expressions of apoptosis-related cleaved caspase-3, cleaved caspase-8 and cleaved caspase-9, along with declined proliferating cell nuclear antigen (PCNA), Bcl-2, and ratio of Bcl-2 to Bax. Open field experiments and tail suspension experiments showed that exposure to high dosage of PM2.5 resulted in decreased spontaneous activities but increased static accumulation time in mice offspring, indicating anxiety, depression, and social behavioral changes. Our results suggested that maternal exposure to PM2.5 during pregnancy might interfere with cerebral cortex development in mice offspring by affecting cell apoptosis.

The effect of moderate-intensity exercise on the expression of HO-1 mRNA and activity of HO in cardiac and vascular smooth muscle of spontaneously hypertensive rats.

The objective of this study was to observe the effects of moderate-intensity training on the activity of heme oxygenase (HO) and expression of HO-1 mRNA in the aorta and the cardiac muscle of spontaneously hypertensive rats (SHRs). After 9 weeks of swimming exercise, the activity of HO and expression of HO-1 mRNA in the SHRs were measured. The resting blood pressure in the exercise group was increased by 1.7% (P > 0.05), whereas it was significantly elevated by 10.3% (P < 0.01) in the SHR rats. Compared with animals in the control and sedentary groups, the expression level of HO-1 mRNA of aorta and cardiac muscle in the exercise group was significantly enhanced (P < 0.01). The HO activity and the content of plasma carbon monoxide (CO) in the sedentary group were dramatically decreased (P < 0.05 and P < 0.01, respectively) compared with the control group. HO activity and content of plasma CO in the exercise group were significantly higher compared with those in the sedentary group (P < 0.05 and P < 0.01, respectively). The HO/CO metabolic pathway might be involved in the regulation of blood pressure of the SHR models.

Causal relationship between iron deficiency anemia and asthma: a Mendelian randomization study.

Background: Observational studies have suggested an association between iron deficiency anemia (IDA) and asthma, which may affect the occurrence of asthma. However, whether IDA is a new management goal for asthma remains to be determined. Objective: We conducted a two-sample Mendelian randomization(MR)analysis to assess the association between IDA and asthma. Methods: We performed a two-sample MR study to assess a causal relationship between IDA (ncase = 12,434, ncontrol = 59,827) and asthma (ncase = 20,629, ncontrol = 135,449). Inverse variance weighted (IVW) was used as the primary method for the analyses. Furthermore, we used weighted medians and MR-Egger to enhance robustness. Data linking genetic variation to IDA and asthma were combined to assess the impact of IDA on asthma risk. Results: There are five single nucleotide polymorphisms (SNPs) were used as genetic tool variables for exposure factors. Genetically determined IDA was significantly associated with an increased risk of asthma (OR = 1.37, 95% CI: 1.09-1.72, p = 0.007). There was little heterogeneity in the MR studies and no evidence of level pleiotropy was found. Conclusions: In our MR study, our findings emphasize that IDA may be associated with a high risk of asthma, indicating a potential role for IDA in the development of asthma. Future research needs to elucidate its potential mechanisms to pave the way for the prevention and treatment of asthma.

Reverse complete heart block using transcutaneous pacing and repeated plasmapheresis in a neonate with lupus: a case report.

BACKGROUND: It has been reported that the complete heart block (CHB) in neonatal lupus (NL) cannot be reversed. This study reported a case of NL-CHB that was reversed by transcutaneous pacing and repeated plasmapheresis. CASE PRESENTATION: A 35+ 6-week male preterm baby was transferred to the neonatal intensive care unit of the Army Medical Center in May 2020 for slight cyanosis around the lips and nose. Two days after birth, a sudden decrease in heart rate was observed during electrocardiogram (EGG) monitoring. Physical examination revealed a bluish-purple discoloration around the lips and an irregular heartbeat. EGG showed the presence of isolated P (142 bpm) and QRS (78 bpm) waves, ventricular escape beats, and a diagnosis of NL-CHB. To reverse the condition, transcutaneous pacing and five sessions of plasmapheresis were performed. At a 1.5-year follow-up, the baby exhibited well-developed cardiac structure and normal neurodevelopment. CONCLUSIONS: Transcutaneous pacing and repeated plasmapheresis might be possible to reverse CHB in NL.

Berberine hydrochloride ameliorates PM2.5-induced pulmonary fibrosis in mice through inhibiting oxidative stress and inflammatory.

Elevated levels of respirable particulate matter (PM) have been strongly linked to disease incidence and mortality in population-based epidemiological studies. Berberine hydrochloride (BBR), an isoquinoline alkaloid found in Coptis chinensis, exhibits antipyretic, anti-inflammatory, and antioxidant properties. However, the protective effects and underlying mechanism of BBR against pulmonary fibrosis remain unclear. This study aimed to investigate the protective effect of BBR on lung tissue damage using a mouse model of PM2.5-induced pulmonary fibrosis. SPF grade C57BL/6 mice were randomly assigned to four groups, each consisting of 10 mice. The mice were pretreated with BBR (50 mg/kg) by gavage for 45 consecutive days. A tracheal drip of PM2.5 suspension (8 mg/kg) was administered once every three days for a total of 15 times to induce lung fibrosis. Moreover, the results demonstrated that PM2.5 was found to inhibit the PPARγ signaling pathway, increase ROS expression, upregulate protein levels of IL-6, IL-1ß, TNF-α, as well as regulation of gene expression of STAT3 and SOCS3. Importantly, PM2.5 induced lung fibrosis by promoting collagen deposition, upregulating gene expression of fibrosis markers (TGF-ß1, FN, α-SMA, COL-1, and COL-3), and downregulating E-cadherin expression. Remarkably, our findings suggest that these injuries could be reversed by BBR pretreatment. BBR acts as a PPARγ agonist in PM2.5-induced pulmonary fibrosis, activating the PPARγ signaling pathway to mitigate oxidative and inflammatory factor-mediated lung injury. This study provides valuable insights for the future prevention and treatment of pulmonary fibrosis.

Integration of multiomics analysis to reveal the major pathways of vitamin A deficiency aggravates acute respiratory distress syndrome in neonatal rats.

Acute respiratory distress syndrome (ARDS) is a major disease that threatens the life and health of neonates. Vitamin A (VA) can participate in early fetal lung development and affect lung immune function. Researches revealed that the serum VA level in premature infants with ARDS was lower than that in premature infants without ARDS of the same gestational age, and premature infants with VA deficiency (VAD) were more likely to develop ARDS. Moreover, the VA levels can be used as a predictor of the development and severity of neonatal ARDS. However, the critical question here is; Does ARDS develop due to VAD in these systemic diseases? Or does ARDS develop because these diseases cause VAD? We hypothesize that VAD may aggravate neonatal ARDS by affecting immunity, metabolism, barriers and other pathways. In this article, we used multiomics analysis to find that VAD may aggravate ARDS mainly through the Fc epsilon RI signaling pathway, the HIF-1 signaling pathway, glutathione metabolism, and valine, leucine and isoleucine degradation signaling pathways, which may provide the molecular pathogenic mechanism behind the pathology of VAD-aggravated ARDS and can also provide potential molecular targets for subsequent research on ARDS.

Investigation of the indoor 222Rn and 220Rn levels in the residential environment and estimation of the annual effective radiation dose for ordinary residents.

To evaluate the health risk of radon and its progeny, a large amount of accurate monitoring data is needed according to the theory and practice of health risk assessment. However, the indoor radon levels in different regions in China and worldwide reveal temporal and spatial variations. In addition, the residents living in different areas follow distinct living modes. Therefore, it is recommended and accepted by many researchers to detect the radon level in local areas and subsequently conduct health risk assessments based on local detection data. In this study, 21 bedrooms of households in Weifang city were selected, and the indoor 222Rn and 220Rn levels were detected with RAD7 radon detector in winter, while the annual effective radiation dose was calculated for ordinary residents in Weifang city. Our investigation showed that the 24- and 12-hour average levels of 222Rn were 35.7±15.2 Bq/m3 and 36.2±15.8 Bq/m3, respectively. The 24- and 12-hour average levels of 220Rn were 30.4±12.3 Bq/m3 and 22.4±11.6 Bq/m3, respectively. There were significant differences in the average levels of 222Rn and 220Rn between floors. The estimated annual effective radiation dose received by ordinary residents in Weifang city was 1.7193 mSv, of which 0.9479 mSv originated from 222Rn and its progeny and 0.7714 mSv originated from 220Rn and its progeny, accounting for 55.1% and 44.9%, respectively, of the total dose. Our findings suggest that 220Rn should not be ignored by local residents in Weifang city, and more attention should be paid to 220Rn in future research.

Probe A shown in the GeneXpert MTB/RIF assay during the detection of Mycobacterium intracellular infections.

Mycobacterium tuberculosis (MTB) is commonly diagnosed via the GeneXpert MTB/RIF assay. The cycle threshold (Ct) value of probe A from this assay produced a fluorescence signal upon Mycobacterium intracellulare detection. No other nontuberculous mycobacteria (NTM) exhibited positive probe signals. Using a confirmed mycobacterial culture as a standard, probe A of the assay exhibited 84% sensitivity (95% confidence interval [CI]: 71%-97%) and 50% specificity (95% CI: 37%-63%) for clinical samples. For M. intracellulare strains, probe A exhibited 90% sensitivity (95% CI: 80%-100%) and 50% specificity (95% CI: 37%-63%). The identity of the amino acid sequence and 81-bp core region of rpoB from MTB and NTM suggested that the highly conserved property might be associated with a mismatch between the probes and the chromosomal DNA target. Probe A yielded a positive signal upon M. intracellulare detection; thus, probe A may help diagnose M. intracellular infections.