Upregulation of SEMP1 Contributes to Improving the Biological Functions of Trophoblast via the PI3K/AKT Pathway in Preeclampsia.

Disturbance of extravillous trophoblast infiltration is associated with preeclampsia (PE), a severe condition of pregnancy characterized by hypertension and proteinuria. Senescence-associated epithelial membrane protein 1 (SEMP1), an integral membrane protein, is a vital component of tight junction strands in epithelial or endothelial cells, with no clear function reported in PE. Gene Expression Omnibus (GEO) datasets showed that SEMP1 expression was downregulated in the placental tissues of PE patients, which was confirmed by assessing SEMP1 levels in placental samples collected in our hospital. Furthermore, less SEMP1 was detected in cytokeratin 7 positive trophoblast cells in the spiral arteries of rat placentas post L-arginine methyl ester hydrochloride (L-NAME) treatment. Trophoblast cells acquired robust ability of proliferation, migration, and invasion when SEMP1 was overexpressed. Such capability was weakened in SEMP1-silenced cells. Trophoblast cells overexpressing SEMP1 secreted more vascular endothelial growth factor A (VEGFA), which facilitated the tube formation of human umbilical vein endothelial cells. Blockade of PI3K/AKT signaling transduction with LY294002 dampened the effects of SEMP1 on trophoblast cells. Collectively, we firstly indicated that SEMP1 inhibition is a potential driver for PE, which may be associated with the deactivation of the PI3K/AKT pathway.

Bi-directional and multivariate mendelian randomization analysis of the relationship between circulating 25-hydroxyvitamin D concentration and obstructive sleep apnea.

BACKGROUND: 25-hydroxyvitamin D [25(OH)D] deficiency in patients with Obstructive Sleep Apnea (OSA) has long been noted, but identifying the exact causal relationship remains hard. Investigation of the causality between 25(OH)D deficiency and OSA would help facilitate disease prevention. METHODS: We conducted a two-sample bi-directional Mendelian randomization (MR) study. For forward analysis, 237 newly identified genetic variants are used as proxies for 25(OH)D to estimate the unconfounded effect on OSA among 16,761 OSA cases and 201,194 controls of European ancestry. Reverse analysis was performed to detect the causal impact of OSA on 25(OH)D levels. The inverse variance weighted (IVW) method was used as the primary analysis. Sensitivity analysis was performed to evaluate the robustness of our results. Multivariate MR analysis was conducted to evaluate the direct link between 25(OH)D and OSA after accounting for body mass index (BMI). RESULTS: IVW indicated that OSA causally associated with a lower level of 25(OH)D ((ß = -0.03, 95% CI = -0.06 ~ -0.007, P = 0.01). No evidence of the causal link from 25(OH)D to OSA was detected (OR = 0.99, 95% CI = 0.88 ~ 1.12, P = 0.85). Sensitivity analysis suggested the MR estimates were not biased. Multivariate MR analysis indicated the effect of OSA on 25(OH)D vanished upon accounting for BMI (ß = -0.011, 95% CI = -0.028 ~ 0.007, P = 0.23). CONCLUSION: This MR study provided evidence that OSA was causally associated with a lower level of 25(OH)D, which might be driven by BMI. Obesity management should be enhanced in patients with OSA to prevent 25(OH)D deficiency.

Methylation-based epigenetic studies and gene integration analysis of preeclampsia.

Background: Preeclampsia (PE) is a multi-factor and multi-mechanism disease, which may jeopardize the life safety of affected pregnant women and fetuses. Our study aimed to detect the potential molecular indicators of PE that might be helpful for its diagnosis and treatment. Methods: Methylation assay of PE and normal pregnancies placental biopsies was analyzed using the Illumina Human Methylation-27 Assay. Differentially expressed genes (DEGs) were analyzed using R-DESeq2 software. Subsequently, the relationship between DNA methylation genes and DEGs were evaluated. Furthermore, immunohistochemical (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) validation analyses were conducted for the hub genes. Results: These hub genes (including PLXNB1, PMCH, PPARG, GOPC, CD79A, and MME) were found to be differentially methylated genes and DEGs. Further analysis revealed that PPARG, CD79A, and PLXNB1 may be diagnostic gene markers for PE; down-regulation of PPARG expression was closely correlated with the development of PE. The IHC analysis demonstrated that the expression levels of PLXNB1, PMCH, GOPC, CD79A, and MME genes were increased, whereas that of PPARG was decreased in PE tissues. The PCR results showed that PLXNB1, PMCH, GOPC, CD79a, and MME were upregulated, whereas PPARG was downregulated. The results of the 2 experiments were consistent with those of bioinformatics analysis. Conclusions: The molecular indicators identified in this study could facilitate the development of potential biomarkers and therapeutic targets for PE.

Overexpression of Collapsin Response Mediator Protein 1 Inhibits Human Trophoblast Cells Proliferation, Migration, and Invasion.

Collapsin response mediator protein 1 (CRMP-1) is widely expressed in the nervous system and has tumor suppressive effects. Our previous studies have demonstrated that CRMP-1 was expressed in the trophoblasts of the whole stage of pregnancy with significantly increasing expression in the placenta of early-onset preeclampsia. Preeclampsia, especially early onset, is strongly associated with the dysfunction of trophoblast including proliferation, apoptosis, migration, and invasion. In this study, we found an inhibitory effect of CRMP-1 on proliferation, migration, invasion, and an enhanced effect on apoptosis in human trophoblast cell lines HTR-8/SVneo and JEG-3 by MTT assay, colony formation assay, cell viability assay, caspase 3/7 activity assay, scratch wound assay, and Matrigel Transwell assay. Overexpression of CRMP-1 in trophoblast cells led to downregulate expression of matrix metalloproteinase 2 and 9. The expression of CRMP-1 was detected by real-time quantitative polymerase chain reaction and Western blot analysis. Thus, we suggested that CRMP-1 might have implications for the pathogenesis of preeclampsia by regulating the biological behavior of trophoblast cells.

Downregulation of P38 phosphorylation correlates with low-grade differentiation and proliferation of lung squamous cell carcinoma.

BACKGROUND: P38MAPK has been investigated as a tumor-related signaling molecule because of its apparent association with tumorigenesis. This study aimed to investigate P38MAPK expression and its role in lung squamous carcinoma (LSCC). METHODS: The expression of P38MAPK and phosphorylated P38 (P-P38) in LSCC tissues and cells was examined by Western blot, real-time PCR, and immunohistochemistry. The influence of P38MAPK inhibitor SB203580 on the proliferation of LSCC cells was detected by MTT and flow cytometry. RESULTS: The expression of P-P38 in LSCC tissues and cells was lower than that in cancer-adjacent normal tissues and normal bronchial epithelial cells (P<0.05). In addition, the expression of P-P38 was downregulated in LSCC tissues of poor differentiation, stages III and IV, and with lymph node metastasis compared with the LSCC tissues of well differentiation, stages I and II, and without lymph node metastasis (P<0.05). Moreover, the cell proliferation of LSCC SK-MES-1 cells treated by P38MAPK inhibitor SB203580 significantly increased in a concentration-dependent manner compared with that of SK-MES-1 cells without SB203580 (P<0.05). The inhibition of P38MAPK promoted the transition of the S phase to the G2 phase. CONCLUSIONS: P-P38 was poorly expressed in LSCC tissues and cells. Its low expression was correlated with low-grade differentiation, lymph node metastasis, and advanced stage of LSCC. Inhibition of P38MAPK expression could significantly increase the proliferation of LSCC cells by promoting the transition of the S phase to the G2 phase.

3,5,4'-Tri-O-acetylresveratrol attenuates seawater aspiration-induced lung injury by inhibiting activation of nuclear factor-kappa B and hypoxia-inducible factor-1α.

Resveratrol is a phytoalexin synthesized by a wide variety of plants, which has been proven to be effective in suppressing oxidative stress and inflammation. The aim of the present study was to investigate the effect of Resveratrol's prodrug: 3,5,4'-tri-O-acetylresveratrol, on seawater drowning-induced acute lung injury (SWD-ALI). Histological changes were assessed to study lung injuries; cytokines in lung samples were monitored by ELISA to reflect inflammation; T-SOD and MDA activity were detected to examine oxidative stress in lung tissues. Besides, we also tested the expression of NF-κB and HIF-1α to probe the possible protecting mechanism of 3,5,4'-tri-O-acetylresveratrol on AWD-ALI. The results showed that pretreatment with different doses of 3,5,4'-tri-O-acetylresveratrol improved seawater-induced lung histopathologic changes, alleviated lung edema, reduced the production of inflammatory mediators including TNF-α and IL-1ß, inhibited MDA activity, and enhanced T-SOD activity, which was possibly associated with inhibition of NF-κB and HIF-1α. In conclusion, the current study demonstrated that 3,5,4'-tri-O-acetylresveratrol exhibited a protective effect on SWD-ALI by inhibiting of the inflammatory response, which may also involve the suppression of oxidative stress in lung tissues.