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The utilization of assisted reproductive technologies (ART) is on the rise, resulting in a growing population of ART-conceived offspring. The health concerns of this unique population have attracted significant attention. During ART procedures, gametes and early-stage embryos are exposed to various non-physiological conditions, such as manipulation, culture media, and cryopreservation, which may disrupt embryonic development and potentially impact the health of offspring. Notably, the potential impact of ART on neurodevelopment and its association with an increased risk of neurodevelopmental disorders (NDD) later in life remains a subject of debate. This review aims to summarize the current research advancements concerning the effects of ART on neurodevelopment, specifically focusing on the evidence of the relationship between ART, epigenetic modifications, and NDD, including autism spectrum disorder, intellectual disability, attention deficit hyperactivity disorder, and cerebral palsy. Future studies should prioritize large sample sizes, rigorous adjustment for confounding factors, and the use of interdisciplinary approaches to effectively monitor the neurodevelopmental outcomes of ART-conceived children.

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BACKGROUND: Observational studies have established a strong association between frailty and obstructive lung diseases. However, the causal nature of this association remains unclear. To address this gap, we conducted a bidirectional Mendelian randomization (MR) study to investigate the causal relationship between frailty, as measured by the frailty index (FI), and chronic obstructive pulmonary disease (COPD) or asthma. METHODS: The latest meta-analysis of genome-wide association studies for FI, which included individuals of European ancestry from UK Biobank and TwinGene (N = 175,226), yielded the genetic instruments for frailty and outcome summary statistics. The genetic instrument for COPD and asthma, as well as the outcome summary data, were derived from the GWAS conducted on individuals of European ancestry from the FinnGen, with a sample size of 16,410 cases and 283,589 controls for COPD, and 37,253 cases and 187,112 controls for asthma. The analysis of MR was conducted employing the inverse-variance weighted (IVW) method, complemented by the weighted median method, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO) test. RESULTS: Our results showed that genetically predicted higher FI was significantly associated with increased risk of COPD (odds ratio [OR] 1.75, 95 % confidence interval [CI] 1.29-2.36) and asthma (OR 2.10, 95 % CI 1.44-3.16). In the reverse direction analysis, genetic liability to both COPD (beta 0.06, 95 % CI 0.01-0.10) and asthma (beta 0.08, 95 % CI 0.06-0.11) showed significant associations with a higher FI. CONCLUSIONS: Our research has reinforced the existing evidence supporting a reciprocal causal relationship between frailty and obstructive lung diseases. A deeper comprehension of this interconnection is imperative for the prevention and treatment of obstructive lung diseases.

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BACKGROUND: Both pulmonary tuberculosis (PTB) and cigarette smoke (CS) exposure may lead to lung damage. The potential impact of CS exposure on tuberculosis-associated lung damage and the disturbance of immune cells and mediators involved, need to be further elucidated. METHODS: We firstly evaluated the chest X-ray (CXR) scores of a retrospective cohort of male patients with active PTB, followed for 6 months, and compared the scores between smoker (≥10 pack-years) and non-smoker patients. In a cross-sectional study, we measured the peripheral blood NK cell subsets and plasma inflammatory cytokines in male smoker and non-smoker patients with active PTB before anti-tuberculosis therapy, and the proportions of NK cell subsets and the levels of cytokines were analyzed for correlation with the CXR scores. RESULTS: In the retrospective cohort, male smoker patients with active PTB showed a higher CXR score, characterized by more cavitary lesions, enlarged lymph nodes and emphysema, as compared to non-smokers. The cross-sectional study revealed that the CXR score in smoker patients was correlated inversely with the percentages of blood CD107a+, NKP46+, and TIGIT+ NK cells. CONCLUSION: In patients with active PTB, CS exposure was associated with more severe lung lesions, which were correlated with peripheral NK cell subsets.

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Background: It has been reported that a disintegrin and metalloproteinase 9 (ADAM9) is involved in the pathogenesis of cigarette smoke (CS)-associated chronic obstructive pulmonary disease (COPD). But how CS exposure leads to upregulation of ADAM9 remains unknown. Methods: Patients who underwent lobectomy for a solitary pulmonary nodule were enrolled and divided into three groups: non-smokers with normal lung function, smokers without COPD and smoker patients with COPD. Immunoreactivity of interleukin (IL)-17A and ADAM9 in small airways and alveolar walls was measured by immunohistochemistry. Wild-type and Il17a -/- C57BL/6 mice were exposed to CS for six months, and ADAM9 expression in the airway epithelia was measured by immunoreactivity. In addition, the protein and mRNA expression levels of IL-17A and ADAM9 were assessed in CS extract (CSE) and/or IL-17A-treated human bronchial epithelial (HBE) cells. Results: The immunoreactivity of ADAM9 was increased in the airway epithelia and alveolar walls of patients with COPD compared to that of the controls. The expression of IL-17A was also upregulated in airway epithelial cells of patients with COPD and correlated positively with the level of ADAM9. The results from the animal model showed that Il17a -/- mice were protected from emphysema induced by CS exposure, together with a reduced level of ADAM9 expression in the airway epithelia, suggesting a possible link between ADAM9 and IL-17A. Consistently, our in vitro cell model showed that CSE stimulated the expression of ADAM9 and IL-17A in HBE cells in a dose- and time-dependent manner. Recombinant IL-17A induced ADAM9 upregulation in HBE cells and had a synergistic effect with CSE, whereas blocking IL-17A inhibited CSE-induced ADAM9 expression. Further analysis revealed that IL-17A induced c-Jun N-terminal kinase (JNK) phosphorylation, thereby increasing ADAM9 expression. Conclusion: Our results revealed a novel role of IL-17A in CS-related COPD, where IL-17A contributes to ADAM9 expression by activating JNK signaling.

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Small extracellular vesicles (sEVs) miRNAs are promising diagnosis and prognosis biomarkers for ischemic stroke (IS). This study aimed to determine the impact of IS on the serum sEVs miRNA profile of IS patients and a transient middle cerebral artery occlusion (tMCAO) mouse model. Small RNAseq was used to define the serum sEVs miRNA profile in IS patients and healthy controls (HC), and tMCAO mice and sham controls. Among the 1,444 and 1,373 miRNAs identified in human and mouse serum sEVs, the expression of 424 and 37 miRNAs was significantly altered in the IS patients and tMCAO mice, respectively (| Log2FC| ≥ 1, p < 0.01). Notably, five of the top 25 upregulated miRNAs in IS patients were brain-specific or enriched, including hsa-miR-9-3p, hsa-miR-124-3p, hsa-miR-143-3p, hsa-miR-98-5p, and hsa-miR-93-5p. Upregulation of these four miRNAs was further validated by qPCR. Nine of the 20 upregulated miRNAs in tMCAO mice were also brain-specific or enriched miRNAs. Temporal analysis indicated that the dynamics of mmu-miR-9-5p, mmu-miR-124-3p, mmu-miR-129-5p, and mmu-miR-433-3p were closely correlated with the evolution of ischemic brain injury, as their expression increased at 0.5 days after the onset of ischemia, peaked at day 1 or 3, and returned to normal levels at day 7 and 14. Notably, with the exceptions of mmu-miR-128-3p, the expression of the other eight miRNAs in the mouse serum sEVs was unaffected in the lipopolysaccharide (LPS)-induced neuroinflammation model. Together, in this study, we provided a comprehensive view of the influences of IS on the serum sEVs miRNA profile of IS patients and tMCAO mice and demonstrated the increment of a set of brain-specific miRNAs in serum sEVs after acute cerebral ischemia, which could be promising candidates directly reflecting the ischemic brain injury.

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The complement component 3 (C3) is a pivotal element of the complement system and plays an important role in innate immunity. A previous study showed that intracellular C3 was upregulated in airway epithelial cells (AECs) from individuals with end-stage chronic obstructive pulmonary disease (COPD). Accumulating evidence has shown that cigarette smoke extract (CSE) induces oxidative stress and apoptosis in AECs. Therefore, we investigated whether C3 modulated cigarette smoke-induced oxidative stress and apoptosis in AECs and participated in the pathogenesis of COPD. We found increased C3 expression, together with increased oxidative stress and apoptosis, in a cigarette smoke-induced mouse model of COPD and in AECs from patients with COPD. Different concentrations of CSEinduced C3 expression in 16HBE cells in vitro. Interestingly, C3 knockdown (KD) exacerbated oxidative stress and apoptosis in 16HBE cells exposed to CSE. Furthermore, C3 exerted its pro-survival effects through JNK inhibition, while exogenous C3 partially rescued CSE-induced cell death and oxidative stress in C3 KD cells. These data indicate that locally produced C3 is an important pro-survival molecule in AECs under cigarette smoke exposure, revealing a potentially novel mechanism in the pathogenesis of COPD.

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Chronic obstructive pulmonary disease (COPD) is a prevalent chronic airway disease with varied frequencies of acute exacerbations, which are the main cause of morbidity and mortality of the disease. It is, therefore, urgent to develop novel therapies for COPD and its exacerbations, which rely heavily on understanding of the pathogenesis and investigation for potential targets. Current evidence indicates that natural killer (NK) cells play important roles in the pathological processes of COPD. Although novel data are revealing the significance of NK cells in maintaining immune system homeostasis and their involvement in pathogenesis of COPD, the specific mechanisms are largely unknown. Specific and in-depth studies elucidating the underlying mechanisms are therefore needed. In this review, we provided a brief overview of the biology of NK cells, from its development to receptors and functions, and outlined their subsets in peripheral blood and lungs. Then we reviewed published findings highlighting the important roles played by NK cells in COPD and its exacerbations, with a view of providing the current state of knowledge in this area to facilitate related in-depth research.

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We investigated the association between plasma microRNA (miR)-204 and coronary artery calcification (CAC) in patients with type 2 diabetes mellitus (T2DM). We consecutively enrolled 179 individuals with T2DM who underwent coronary computed tomography at Anzhen Hospital from January 2015 to September 2016. The CAC score (CACS) was expressed in Agatston units and >10 Hounsfield units were defined as CAC-positive status. Significant CAC was observed in 98 (54.7%) patients. Plasma miR-204 levels (relative expression) were significantly lower in patients with significant CAC than controls (1.001 ± 0.100 vs 0.634 ± 0.211, P < .001). Plasma miR-204 levels were also negatively correlated with the glycosylated hemoglobin A1c (HbA1c) level (r = -0.702, P < .001), CACS (r = -0.710, P < .001), and the United Kingdom Prospective Diabetes Study (UKPDS) score (r = -0.355, P < .001). After multivariate logistic analyses, plasma miR-204 levels were still significantly and independently associated with the presence of CAC (odds ratio = 0.103, CI = 0.018-0.583, P < .001) after adjustment for conventional risk factors. Receiver operating characteristic curve analysis showed that plasma miR-204 levels can predict the severity and extent of CAC, and the specificity was higher than that of the traditional risk factors UKPDS score and HbA1c. In conclusion, the downregulation of miR-204 was independently associated with CAC in patients with T2DM.

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BACKGROUND: Previous studies have demonstrated that microRNA-204 (miR-204) is involved in atherosclerosis and vascular calcification. However, the value of miR-204 as the predictive biomarker for cardiovascular disease (CVD) remains unclear. We aimed to evaluate the association between the circulating miR-204 level and ten-year CVD risk based on the Framingham risk score (FRS). METHODS: In this retrospective study, we enrolled 194 consecutive patients with type 2 diabetes mellitus (T2DM) without CVD in Beijing Anzhen Hospital between January 2015 and September 2016. We used the FRS to evaluate the risk of CVD for each patient. Circulating miR-204 levels were measured by quantitative real-time polymerase chain reaction. RESULTS: Circulating miR-204 levels were significantly lower in the group of patients (0.49 ± 0.13) at high risk of CVD (FRS > 20%) than in the low (FRS < 10%) and intermediate (FRS: 10%-20%) risk groups (0.87 ± 0.19 and 0.75 ± 0.25, respectively; P < 0.001). FRS was negatively correlated with miR-204 levels (r = -0.421, P < 0.001). According to multivariate logistic analyses, reduced miR-204 level was independently associated with an increased risk of CVD after adjusting for conventional risk factors (OR = 0.876, 95% CI: 0.807-0.950, P = 0.001). Receiver-operating characteristic curve analysis showed that the circulating miR-204 level can predict the high risk of CVD with higher specificity than the traditional risk factor of high systolic blood pressure or the protective factor of high-density lipoprotein cholesterol. CONCLUSIONS: Our study demonstrated that patients with lower circulating miR-204 levels were at high risk for CVD. After adjustment for potential confounders, miR-204 was independently associated with CVD in patients with T2DM.

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OBJECTIVE: Coronary slow flow (CSF) is characterized by delayed opacification of distal epicardial coronary arteries without significant coronary stenosis. In addition, The changes of lipoprotein-associated phospholipase A2 (Lp-PLA2) as a significant predictive factor for CSF remain controversial. The study aims to investigate the association between plasma Lp-PLA2 and CSF. METHODS: In this retrospective study, 170 consecutive patients who underwent coronary angiography were enrolled in Beijing Anzhen Hospital from January 2017 to September 2019, and were divided into CSF group and normal control groups. According to coronary blood flow rate measured by the thrombolysis in myocardial infarction frame count (TFC) method, CSF was defined as TFC > 27. Serum Lp-PLA2 levels were measured in an enzyme-linked immunosorbent assay. RESULTS: Lp-PLA2 levels were higher in the CSF group than in the control group (288.6 ± 50.3 versus 141.9 ± 49.7, P < 0.001) and were significantly correlated with the mean coronary artery thrombolysis in myocardial infarction (TIMI) frame count (r = 0.790, P<0.001). Logistic regression analysis showed that high Lp-PLA2 was independently associated with CSF after adjustment for conventional risk factors (OR = 1.040, CI = 1.022-1.059, P<0.001). Male sex (OR = 2.192, CI = 1.161-4.140, P = 0.016) and hypertension (OR = 1.965, CI = 1.034-3.736, P = 0.039) were also CSF risk factors. Receiver-operating characteristic curve (ROC) analysis showed that Lp-PLA2 levels can predict CSF severity; the predictive power was higher than the other risk factors. CONCLUSION: Our study demonstrated that patients with CSF had higher circulating levels of Lp-PLA2 than normal controls. After adjustment for potential confounders, increased Lp-PLA2 was independently associated with presence of CSF.

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Background: Triptolide (TP), a naturally derived compound from Tripterygium wilfordii, has been proven effective in protecting against cardiovascular system, but the molecular mechanisms underlying its protective effects are poorly understood. In the current study, we sought to test the potential protective role of TP in the regulation of vascular calcification in a rat model and explore whether TP attenuates medial vascular calcification by upregulating miRNA-204. Methods: Vitamin D3 plus nicotine (VDN) was used to induce a vascular calcification (VC) model of rat aorta. Von Kossa and Hematoxylin-Eosin staining were applied to assess the degree of calcification of rat aortas. Calcium content and alkaline phosphatase activity were measured. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was applied to quantify miRNA-204 expression. The localization of runt-related transcription factor-2 (RUNX2) and bone morphogenetic protein-2 (BMP2) expressions were detected by immunohistochemistry and western blotting. Results: Administration of TP greatly reduced vascular calcification in a dose-dependent manner compared with VC controls. The increase in ALP activity and calcium content was ameliorated by TP. Moreover, protein expression levels of BMP2 and RUNX2 were significantly reduced in calcified aortas. MiRNA-204 expression was increased in the TP-treated groups compared with VC controls and the effects of TP were reversed by the intravenous injection of miRNA-204-interfering lentivirus. However, the miRNA-204-overexpressing lentivirus had no additional effects on ALP activity, calcium content, BMP2 and RUNX2 expressions compared with those from TP group. Conclusion: TP inhibited BMP2 and RUNX2 expression and attenuated vascular calcification via upregulating the level of miRNA-204. TP appears to be a potential new therapeutic option for treating vascular calcification.