Elabela-apelin-12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1-P2X7 signaling pathway.

The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela-apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin-12, -17, and -36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)-P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela- and apelin isoforms-induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti-HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib-induced zebrafish trunk model. Overall, the elabela-apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1-P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.

Low H3K27 acetylation of SF1 in PBMC: a biomarker for prenatal dexamethasone exposure-caused adrenal insufficiency of steroid synthesis in male offspring.

Dexamethasone is widely used to treat pregnancy disorders related to premature delivery. However, lots of researches have confirmed that prenatal dexamethasone exposure (PDE) could increase the risk of offspring multiple diseases. This study was designed to elucidate the epigenetic mechanism of adrenal developmental programming and explore its early warning marker in peripheral blood mononuclear cells (PBMC). We found the adrenal morphological and functional changes of PDE male offspring rats before and after birth, which were mainly performed as the decreased serum corticosterone concentration, steroidogenic acute regulatory (StAR) protein expression, and histone 3 lysine 27 acetylation (H3K27ac) level of steroidogenic factor 1 (SF1) promoter region and its expression. Simultaneously, the expressions of glucocorticoid receptor (GR) and histone acetylation enzyme 5 (HDAC5) in the PDE male fetal rats were increased. In vitro, dexamethasone reduced the expression of SF1, StAR, and cortisol production and still increased the expression of GR and HDAC5, the binding between GR and SF1 promoter region, and protein interaction between GR and HDAC5. GR siRNA or HDAC5 siRNA was able to reverse the above roles of dexamethasone. Furthermore, in vivo, we confirmed that H3K27ac levels of SF1 promoter region and its expression in PBMC of the PDE group were decreased before and after birth, showing a positive correlation with the same indexes in adrenal. Meanwhile, in clinical trials, we confirmed that prenatal dexamethasone application decreased H3K27ac of SF1 promoter region and its expression in neonatal PBMC. In conclusion, PDE-caused adrenal insufficiency of male offspring rats was related to adrenal GR activated by dexamethasone in uterus. The activated GR, on the one hand, increased its direct binding to SF1 promoter region to inhibit its expression, on the other hand, upregulated and recruited HDAC5 to decrease H3K27ac level of SF1 promoter region, and strengthened the inhibition of SF1 and subsequent StAR expression.

The efficacy of 3D personalized insoles in moderate adolescent idiopathic scoliosis: a randomized controlled trial.

BACKGROUND: Bracing and exercise methods were used in scoliosis rehabilitation and proven effective. There was little evidence about the efficacy of insoles on scoliosis. OBJECTIVE: This study aimed to investigate the effects of 3D personalized insoles on curve magnitude, postural stability, and quality of life (QOL) in moderate adolescent idiopathic scoliosis (AIS) patients. METHODS: Thirty-six volunteers with adolescent idiopathic scoliosis, who had moderate curves (20°-45°), were randomly divided into the experimental and control groups. The control group received traditional rehabilitation with bracing and exercises, and the experimental group received the insole interventions in addition to traditional rehabilitation. The outcome measures were Cobb angle, angle of trunk rotation (ATR), postural stability, and quality of life (Scoliosis Research Society-22 questionnaire). Measurements were conducted at baseline examination, two months and six months. RESULTS: After two and six months of treatment, the Cobb angle and ATR in both groups were significantly decreased as compared with the baseline (p < 0.05), but no significant group difference in Cobb angle and ATR was found in the study (p > 0.05). There was a significant difference in the sagittal balance index at six months compared to the control group (p < 0.05), and a significant difference in the coronal balance index was observed at six months compared to baseline in the experimental group (p < 0.05). Quality of life did not change in either group (p > 0.05). CONCLUSION: Combining bracing with exercise in patients with moderate AIS is effective. 3D personalized insoles cannot reduce the Cobb angle and angle of trunk rotation of patients with moderate AIS but might have the potential to improve postural stability.

Apelin/APJ system: an emerging therapeutic target for respiratory diseases.

Apelin is an endogenous ligand of G protein-coupled receptor APJ. It is extensively expressed in many tissues such as heart, liver, and kidney, especially in lung tissue. A growing body of evidence suggests that apelin/APJ system is closely related to the development of respiratory diseases. Therefore, in this review, we focus on the role of apelin/APJ system in respiratory diseases, including pulmonary arterial hypertension (PAH), pulmonary embolism (PE), acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), obstructive sleep apnoea syndrome (OSAS), non-small cell lung cancer (NSCLC), pulmonary edema, asthma, and chronic obstructive pulmonary diseases. In detail, apelin/APJ system attenuates PAH by activating AMPK-KLF2-eNOS-NO signaling and miR424/503-FGF axis. Also, apelin protects against ALI/ARDS by reducing mitochondrial ROS-triggered oxidative damage, mitochondria apoptosis, and inflammatory responses induced by the activation of NF-κB and NLRP3 inflammasome. Apelin/APJ system also prevents the occurrence of pulmonary edema via activating AKT-NOS3-NO pathway. Moreover, apelin/APJ system accelerates NSCLC cells' proliferation and migration via triggering ERK1/2-cyclin D1 and PAK1-cofilin signaling, respectively. Additionally, apelin/APJ system may act as a predictor in the development of OSAS and PE. Considering the pleiotropic actions of apelin/APJ system, targeting apelin/APJ system may be a potent therapeutic avenue for respiratory diseases.

A preliminary study to identify data needs for improving fit of hand and wrist orthosis using verbal protocol analysis.

The delayed delivery, poor fitting and discomfort of customised orthoses are reported in rehabilitation clinics as resulting in more invasive interventions. The current practice of orthosis customisation relies heavily upon the experience and fabrication processes of therapists. In order to better understand the current practice, and thus identify data that is required for better comfort moving towards a data-driven customisation, this article describes a study generating working models of therapists. Customisations of hand and wrist orthoses for 18 patients were observed. Verbal protocol analysis was employed to extend the current understanding of fabrication processes. Working models of four therapists were established with quantitative evaluation on major phases, interactive activities and iterations of performing tasks during fabrication, revealing different working models between in- and out-patient departments (e.g. fabrication for in-patients was more complex and focussed on ergonomic fitting whereas fabrication for out-patients paid attention to durability) which were qualitatively explained. Practitioner summary: Fit and comfort are imperative for orthosis design and fabrication, however the current practice of customisation of an orthosis relies upon the experience of individual hand therapist. The article presents working models of hand therapists, and relevant data that would enable customisation of orthosis for better fit. Abbreviations: VPA: verbal protocol analysis; h&w: hand and wrist; LTT: low temperature thermoplastic; ANOVA: analysis of variance.

ROS-Autophagy pathway mediates monocytes-human umbilical vein endothelial cells adhesion induced by apelin-13.

Apelin is the endogenous ligand of APJ receptor. Both monocytes (MCs) and human umbilical vein endothelial cells (HUVECs) express apelin and APJ, which play important roles in the physiological processes of atherosclerosis. Our previous research indicated that apelin-13 promoted MCs-HUVECs adhesion. Here, we further explore the mechanism responsible for MCs-HUVECs adhesion induced by apelin-13. Apelin-13 promoted reactive oxygen species (ROS) generation and NOX4 expression in HUVECs. Apelin-13 inducedautophagy, increased proteins beclin1 and LC3-II/I expression and induced autophagy flux in HUVECs, which was blocked by NAC, catalase and DPI. Autophagy flux induced by apelin-13 was inhibited by NAC and catalase but not hydroxychloroquine (HCQ). NAC, catalase, and DPI prevented apelin-13 induced ICAM-1 expression in HUVECs. Rapamycin enhanced MCs-HUVECs adhesion that was reversed by NAC, catalase, and DPI. Down-regulation of beclin1 and LC3 by siRNA blocked MCs-HUVECs adhesion. Apelin-13 induced atherosclerotic plaque and increased NOX4, LC3-II/I expression in ApoE-/-(HFD) mouse model. Our results demonstrated that apelin-13 induced MCs-HUVECs adhesion via a ROS-autophagy pathway.

The endoplasmic reticulum stress-autophagy pathway is involved in apelin-13-induced cardiomyocyte hypertrophy in vitro.

Apelin is the endogenous ligand for the G protein-coupled receptor APJ, and plays important roles in the cardiovascular system. Our previous studies showed that apelin-13 promotes the hypertrophy of H9c2 rat cardiomyocytes through the PI3K-autophagy pathway. The aim of this study was to explore what roles ER stress and autophagy played in apelin-13-induced hypertrophy of cardiomyocytes in vitro. Treatment of H9c2 cells with apelin-13 (0.001-2 µmol/L) dose-dependently increased the production of ROS and the expression levels of NADPH oxidase 4 (NOX4). Knockdown of Nox4 with siRNAs effectively prevented the reduction of GSH/GSSG ratio in apelin-13-treated cells. Furthermore, apelin-13 treatment dose-dependently increased the expression of Bip and CHOP, two ER stress markers, in the cells. Knockdown of APJ or Nox4 with the corresponding siRNAs, or application of NADPH inhibitor DPI blocked apelin-13-induced increases in Bip and CHOP expression. Moreover, apelin-13 treatment increased the formation of autophagosome and ER fragments and the LC3 puncta in the ER of the cells. Knockdown of APJ, Nox4, Bip or CHOP with the corresponding siRNAs, or application of DPI or salubrinal attenuated apelin-13-induced overexpression of LC3-II/I and beclin 1. Finally, knockdown of Nox4, Bip or CHOP with the corresponding siRNAs, or application of salubrinal significantly suppressed apelin-13-induced increases in the cell diameter, volume and protein contents. Our results demonstrate that ER stress-autophagy is involved in apelin-13-induced H9c2 cell hypertrophy.

PAK1-cofilin phosphorylation mediates human lung adenocarcinoma cells migration induced by apelin-13.

Adipocytokines apelin peptide, the ligand of APJ (putative receptor related to the angiotensin receptor AT1), plays key roles in the pathogenesis and deterioration of cancer. In lung cancer, apelin elevating microvessel densities has been reported. Our previous research has characterized that apelin-13 promoted lung adenocarcinoma cell proliferation. However, the effect of apelin on metastasis in lung adenocarcinoma and the underlying mechanisms remain unclear. This study shows that apelin-13 induced human adenocarcinoma cell migration via the APJ receptor. Apelin-13 phosphorylated PAK1 and cofilin increase the migration of lung adenocarcinoma cells. Moreover, the results verify that over-expression of apelin and APJ contributed to reducing the effect of doxorubicin and razoxane on inhibiting lung adenocarcinoma cells metastasis. Hypoxia activated APJ expression and apelin release in lung adenocarcinoma cells. The results demonstrate a PAK1-cofilin phosphorylation mechanism to mediate lung adenocarcinoma cells migration promoted by apelin-13. This discovery further suggests that APJ and its downstream signalling is a potential target for anti-metastatic therapies in lung adenocarcinoma patients.

ERK1/2 mediates lung adenocarcinoma cell proliferation and autophagy induced by apelin-13.

The aim of this study was to investigate the role of apelin in the cell proliferation and autophagy of lung adenocarcinoma. The over-expression of APJ in lung adenocarcinoma was detected by immunohistochemistry, while plasma apelin level in lung cancer patients was measured by enzyme-linked immunosorbent assay. Our findings revealed that apelin-13 significantly increased the phosphorylation of ERK1/2, the expression of cyclin D1, microtubule-associated protein 1 light chain 3A/B (LC3A/B), and beclin1, and confirmed that apelin-13 promoted A549 cell proliferation and induced A549 cell autophagy via ERK1/2 signaling. Moreover, there are pores on the surface of human lung adenocarcinoma cell line A549 and apelin-13 causes cell surface smooth and glossy as observed under atomic force microscopy. These results suggested that ERK1/2 signaling pathway mediates apelin-13-induced lung adenocarcinoma cell proliferation and autophagy. Under our experimental condition, autophagy associated with 3-methyladenine was not involved in cell proliferation.

Associations of Blood Cadmium Levels With Osteoarthritis Among US Adults in NHANES 2013-2018.

BACKGROUND: Osteoarthritis (OA) is a global public health problem, and limited information is available on the effects of Cd on OA. The purpose of this study is to explore the relationship between Cd and OA. METHOD: Weighted multivariable logistic regression model, trend test, restricted cubic spline, and stratified analysis were used to study the association between BCd and OA. RESULTS: In the two regression models of weighted multivariable logistic regression analysis, the correlation between BCd and OA was positive. Compared with the lowest quartile of BCd exposure, the highest quartile had a 2.03-fold (95% confidence interval, 1.67 to 2.47), displaying a dose-response relationship (P for trend <0.00001). The restrictive cubic spline shows a positive linear relationship between BCd and OA. CONCLUSION: There was a positive linear relationship between BCd and OA and a dose-response relationship.

The high-expression programming of SR-B1 mediates adrenal dysfunction in female offspring induced by prenatal caffeine exposure and its cholesterol accumulation mechanism.

The cholesterol metabolism and homeostasis of adrenal are important for steroidogenesis. Our previous studies found that prenatal caffeine exposure (PCE) can inhibit adrenal steroidogenesis in offspring, but whether the mechanism is related to local imbalance of cholesterol metabolism remains unknown. Here, we found that PCE inhibited adrenal steroidogenesis and increased the expression of cell pyroptosis and inflammatory-related indicators (NLRP3, caspase-1 and IL-1ß) in female adult offspring rats, and at the same time, the cholesterol levels in serum and adrenal gland also significantly increased. In vitro, the high level of cholesterol could inhibit adrenal corticosteroid synthesis through pyroptosis and an inflammatory response. It suggested that the low adrenal steroidogenesis in PCE female adult offspring is related to local cholesterol accumulation-mediated pyroptosis and inflammation. Furthermore, dating back to the intrauterine period, PCE increased the serum CORT level in female fetal rats, and increased the expression of the adrenal cholesterol intake gene SR-B1, which persisted after birth and even into adulthood. At the cellular level, silencing SR-B1 could reverse the increase of intracellular cholesterol content caused by high levels of cortisol in NCI-H295R cells. Finally, we confirmed that high concentrations of glucocorticoids increased the expression and H3K14ac level of the promoter region in SR-B1 by upregulating the GR/SREBP1/p300 pathway in vivo and in vitro. In conclusion, we clarified that the high-expression programming of SR-B1 mediates adrenal dysfunction in PCE female offspring and its cholesterol accumulation mechanism, which provided a favorable basis for finding novel targets to prevent and treat fetal-originated diseases.

Identification of excessive contact pressures under hand orthosis based on finite element analysis.

BACKGROUND: Implicit magnitudes and distribution of excessive contact pressures under hand orthoses hinder clinicians from precisely adjusting them to relieve the pressures. To address this, contact pressure under a hand orthosis were analysed using finite element method. METHODS: This paper proposed a method to numerically predict the relatively high magnitudes and critical distribution of contact pressures under hand orthosis through finite element analysis, to identify excessive contact pressure locations. The finite element model was established consisting of the hand, orthosis and bones. The hand and bones were assumed to be homogeneous and elastic bodies, and the orthosis was considered as an isotropic and elastic shell. Two predictions were conducted by assigning either low (fat) or high (skin) material stiffness to the hand model to attain the range of pressure magnitudes. An experiment was conducted to measure contact pressures at the predicted pressure locations. RESULTS: Identical pressure distributions were obtained from both predictions with relatively high pressure values disseminated at 12 anatomical locations. The highest magnitude was found at the thumb metacarpophalangeal joint with the maximum pressure range from 13 to 78 KPa. The measured values were within the predicted range of pressure magnitudes. Moreover, 6 excessive contact pressure locations were identified. CONCLUSIONS: The proposed method was verified by the measurement results. It renders understanding of interface conditions underneath the orthosis to inform clinicians regarding orthosis design and adjustment. It could also guide the development of 3D printed or sensorised orthosis by indicating optimal locations for perforations or pressure sensors.

Multi-omics characterization of macrophage polarization-related features in osteoarthritis based on a machine learning computational framework.

Background: OA imposes a heavy burden on patients and society in that its mechanism is still unclear, and there is a lack of effective targeted therapy other than surgery. Methods: The osteoarthritis dataset GSE55235 was downloaded from the GEO database and analyzed for differential genes by limma package, followed by analysis of immune-related modules by xcell immune infiltration combined with the WGCNA method, and macrophage polarization-related genes were downloaded according to the Genecard database, and VennDiagram was used to determine their intersection. These genes were also subjected to gene ontology (GO), disease ontology (DO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Using machine learning, the key osteoarthritis genes were finally screened. Using single gene GSEA and GSVA, we examined the significance of these key gene functions in immune cell and macrophage pathways. Next, we confirmed the correctness of the hub gene expression profile using the GSE55457 dataset and the ROC curve. Finally, we projected TF, miRNA, and possible therapeutic drugs using the miRNet, TargetScanHuman, ENCOR, and NetworkAnalyst databases, as well as Enrichr. Results: VennDiagram obtained 71 crossover genes for DEGs, WGCNA-immune modules, and Genecards; functional enrichment demonstrated NF-κB, IL-17 signaling pathway play an important role in osteoarthritis-macrophage polarization genes; machine learning finally identified CSF1R, CX3CR1, CEBPB, and TLR7 as hub genes; GSVA analysis showed that CSF1R, CEBPB play essential roles in immune infiltration and macrophage pathway; validation dataset GSE55457 analyzed hub genes were statistically different between osteoarthritis and healthy controls, and the AUC values of ROC for CSF1R, CX3CR1, CEBPB and TLR7 were more outstanding than 0.65. Conclusions: CSF1R, CEBPB, CX3CR1, and TLR7 are potential diagnostic biomarkers for osteoarthritis, and CSF1R and CEBPB play an important role in regulating macrophage polarization in osteoarthritis progression and are expected to be new drug targets.

11ß-hydroxysteroid dehydrogenases and biomarkers in fetal development.

It is known that basal glucocorticoid levels in utero are essential for regulating fetal development and maturation, and determine the fate of later life. Recently, more and more studies suggest that adverse prenatal environments may cause abnormal maternal glucocorticoid levels in utero. 11ß-hydroxysteroid dehydrogenases (11ß-HSDs) are widely distributed in the target organs of glucocorticoids (GCs) and mineralocorticoids. 11ß-HSDs is involved in fetal physiological and pathological development by activating or inactivating GCs. Prenatal adverse environments (including exogenous and maternal environments) can affect the expression and activity of 11ß-HSDs in the placenta and fetus via multiple pathways. It induces abnormal local glucocorticoid levels in fetal multiple tissues, fetal developmental programming and homeostasis changes, and the susceptibility to various diseases after birth. We also discuss the interventions of 11ß-HSDs inhibitors on fetal developmental programming and susceptibility to multiple diseases. Finally, we propose that 11ß-HSD2 can be used as a molecular target for fetal developmental toxicity, while 11ß-HSD1 can be regarded as an intervention target to prevent fetal-originated diseases. This review will provide a theoretical basis for the early prevention and treatment of fetal-originated diseases.

Association of Interleukin-10 Polymorphism (rs1800896, rs1800871, and rs1800872) With Breast Cancer Risk: An Updated Meta-Analysis Based on Different Ethnic Groups.

Background: The interleukin10 (IL-10) gene polymorphisms have been indicated to be associated with breast cancer (BC) risk, but the findings are still controversial. To derive a more precise evaluation, we performed a comprehensive meta-analysis. Methods: A systematic literature search was conducted using PubMed, Embase, CNKI, China biomedical (CBM), and Google Scholar to 29 March 2020. Revman5.3 and Stata 12.0 software analyzed the data, and the strength of the association was identified using the odds ratio (OR) and the corresponding 95% confidence interval (CI). Results: A total of 23 studies (7,250 cancer cases and 7,675 case-free controls) were included in this meta-analysis. The results show that IL-10 gene polymorphisms were significantly correlated with BC risk based on subgroup analysis by ethnicity. The IL-10 rs1800896 polymorphism was significantly associated with the risk of BC in Asians (G vs. A: OR = 0.78, 95% CI = 0.65-0.95, p = 0.01; GG vs. AA: OR = 0.51, 95% CI = 0.31-0.84, p = 0.007; GA vs. AA: OR = 0.6, 95% CI = 0.44-0.81, p = 0.0009; GG + GA vs. AA: OR = 0.6, 95% CI = 0.45-0.81, p = 0.0007); Moreover, an increased BC risk in Asians were also associated with the IL-10 rs1800872 polymorphism (AA vs CC: OR = 0.74, 95% CI = 0.55-0.99, p = 0.04; A vs C: OR = 0.85, 95% CI = 0.74-0.98, p = 0.03). In addition, The IL-10 rs1800871 (CT vs. TT: OR = 1.8, 95% CI = 1.03-3.13, p = 0.04) and rs1800872 polymorphism (A vs C: OR = 0.65, 95% CI 0.43-0.98, p = 0.04) were associated with BC risk in Caucasians. Conclusion: Collectively, this meta-analysis demonstrated that IL-10 rs1800896 and rs1800872 (AA vs. CC; A vs. C) polymorphisms significantly increased the risk of BC in Asians, while the rs1800871 and rs1800872 (A vs. C) were associated with the risk of BC in Caucasians. Therefore, this may provide new ideas for predicting and diagnosing BC susceptibility through the detection of IL-10 gene polymorphism. Systematic Review Registration: [https://www.crd.york.ac.uk/ PROSPERO], identifier [CRD42021266635].

[Management of femoral neck fracture post total knee arthroplasty].

OBJECTIVE: To investigate the risk factors, management and prognosis of femoral neck fracture post total knee arthroplasty (TKA). METHODS: From January 2003 to August 2009, 45 cases of femoral neck fracture post TKA were treated. There were 8 males and 37 females with an age range of 56 - 81 years old. Among them, there were ipsilateral (n = 36) and contralateral (n = 9) femoral neck fractures. Due to the fracture site and type, the treatment plans were formulated. And a follow-up was conducted to record the Harris hip score and complications. RESULTS: The incidence of femoral neck fracture following TKA and osteoporosis had a linear correlation. And the fracture rate increased with the aggravation of osteoporosis. The stability of ipsilateral fracture group was lower than those of contralateral fracture and no fracture groups. Except for 4 mortality cases, 41 patients were followed up for 2 to 7 years with an average period of 3.6 years. There were 12 patients in the cannulated screw fixation group. The outcomes were fracture healing (n = 5) and femoral head necrosis (n = 7). Twenty-five cases underwent femoral head replacement. And 3 died and second fracture occurred in 3 cases. Eight cases underwent total hip arthroplasty. And 1 died and there was 1 case of second fracture. The Harris scores of the cannulated screw fixation group was significantly lower than the hip replacement groups (q test, P < 0.05). COMPLICATIONS: After internal fixation, 7 cases suffered femoral head necrosis and underwent femoral head replacement. And secondary fractures after hip replacement occurred in 4 cases and they were treated by plate and cable or LISS (less invasive stabilization system) system. CONCLUSION: Femoral neck fracture following TKA is usually caused by a low-energy injury. Osteoporosis is one of its high-risk factors. Knee instability is associated with ipsilateral femoral neck fracture. Clinically it can be treated by internal fixation or hip arthroplasty. And internal fixation of femoral neck fracture frequently induces femoral head necrosis. And femoral head replacement is applicable.

Maternally derived low glucocorticoid mediates adrenal developmental programming alteration in offspring induced by dexamethasone.

Adverse environments during pregnancy can increase susceptibility to chronic diseases in adult offspring. The occurrence and development of fetal-originated diseases were associated with adrenal developmental programming and homeostasis alteration in offspring. Dexamethasone is widely used for preterm delivery-related pregnancy diseases, but the intrauterine programming alteration and its occurrence mechanism of prenatal dexamethasone exposure (PDE) on adrenal development in offspring have not been clarified. In this study, prenatal dexamethasone therapy could inhibit neonatal development and cause a low exposure of maternally derived glucocorticoid in clinic. Then, we established a rat model of PDE and observed a similar phenomenon. Further, the adrenal steroidogenic function was continuously inhibited in the PDE male offspring rats, accompanied by the decreased H3K27ac level of adrenal insulin-like growth factor 1 (IGF1) and its expression. Moreover, chronic stress in PDE adult offspring rats could reverse the changes of the above indicators through the high level of glucocorticoid. In combination with in vivo, in vitro and a series of interference experiments, we confirmed that the low level of endogenous glucocorticoids inhibited the adrenal IGF1 expression and steroidogenic function through the GRα/miR-370-3p/Sirt3 pathway. In summary, PDE could continuously inhibit the adrenal steroidogenic function in the male offspring, which is associated with the maternally derived low glucocorticoid-mediated the adrenal developmental programming alteration in offspring. This study provides a theoretical and experimental basis for explaining the adrenal development origin of PDE-induced adult chronic diseases.

Weighted gene co-expression network analysis reveals that CXCL10, IRF7, MX1, RSAD2, and STAT1 are related to the chronic stage of spinal cord injury.

BACKGROUND: The process of spinal cord injury involves acute, subacute, and chronic stages; however, the specific pathological mechanism remains unclear. In this study, weighted gene co-expression network analysis (WGCNA) was used to clarify specific modules and hub genes that associated with SCI. METHODS: The gene expression profiles GEO Series (GSE)45006 and GEO Series (GSE)2599 were downloaded, and the co-expression network modules were identified by the WGCNA package. The protein-protein interaction (PPI) network and Venn diagram were constructed to identify hub genes. Quantitative real-time polymerase chain reaction (QRT-PCR) was used to quantify the degree of the top five candidate genes. Correlation analysis was also carried out between hub genes and immune infiltration. RESULTS: In total, 14,402 genes and seven modules were identified. The brown module was considered to be the most critical module for the chronic stage of SCI, which contained 775 genes that were primarily associated with various biological processes, including extracellular structure organization, lysosome, isoprenoid biosynthesis, response to nutrients, response to wounding, sulfur compound metabolic process, cofactor metabolic process, and ossification. Furthermore, C-X-C motif chemokine ligand 10 (CXCL10), myxovirus (influenza virus) resistance 1 (MX1), signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 7 (IRF7) and radical S-adenosyl methionine domain containing 2 (RSAD2) were identified as the hub genes in the PPI and Venn diagram network, and verified by qRT-PCR. Immune infiltration analysis revealed that CD8+ T cells, macrophages, neutrophils, plasmacytoid dendritic cells, helper T cells, Th2 cells, and tumor-infiltrating lymphocytes may be involved in the SCI process. CONCLUSIONS: There were significant differences among the five hub genes (CXCL10, IRF7, MX1, RSAD2, and STAT1) of the brown module, which may be potential diagnostic and prognostic markers of SCI, and immune cell infiltration may play an important role in the chronic stage of SCI.