Adipocyte-specific FAK deletion promotes pancreatic ß-cell apoptosis via adipose inflammatory response to exacerbate diabetes mellitus.

BACKGROUND: White adipose tissue (WAT) has a key role in maintaining energy balance throughout the body, and their dysfunction take part in the regulation of diabetes mellitus. However, the internal regulatory mechanisms underlying are still unknown. METHODS AND RESULTS: We generated adipocyte-specific FAK KO (FAK-AKO) mice and investigated their phenotype. The cascade of adipocyte, macrophage in adipocyte tissues, and pancreatic ß-cells were proposed in FAK-AKO mice and validated by cell line studies using 3T3-L1, Raw264.7 and Min6. The FAK-AKO mice exhibited glucose intolerance, reduced adipose tissue mass and increased apoptosis, lipolysis and inflammatory response in adipose tissue. We further demonstrate that adipocyte FAK deletion increases ß cell apoptosis and inflammatory infiltrates into islets, which is potentiated if mice were treated with STZ. In the STZ-induced diabetes model, FAK AKO mice exhibit less serum insulin content and pancreatic ß cell area. Moreover, serum pro-inflammatory factors increased and insulin levels decreased after glucose stimulation in FAK AKO mice. In a parallel vitro experiment, knockdown or inhibition of FAK during differentiation also increased apoptosis, lipolysis and inflammatory in 3T3-L1 adipocytes, whereas the opposite was observed upon overexpression of FAK. Moreover, coculturing LPS-treated RAW264.7 macrophages with knockdown FAK of 3T3-L1 adipocytes increased macrophage pro-inflammatory response. Furthermore, conditioned medium from above stimulated Min6 cells apoptosis (with or without STZ), whereas the opposite was observed upon overexpression of FAK. Mechanistically, FAK protein interact with TRAF6 in adipocytes and knockdown or inhibition of FAK activated TRAF6/TAK1/NF-κB signaling, which exacerbates inflammation of adipocytes themselves. CONCLUSION: Adipocyte FAK deletion promotes both adipocyte apoptosis and adipose tissue inflammation. Pro-inflammatory factors released by the FAK-null adipose tissue further trigger apoptosis in pancreatic islets induced by the administration of STZ, thereby exacerbating the diabetes mellitus. This study reveals a link between FAK-mediated adipose inflammation and diabetes mellitus, a mechanism that has not been previously recognized.

Trends and seasonal variation of antibiotic consumption by community residents in Hefei, China, 2012-2016.

OBJECTIVES: The aim of this study was to evaluate the trends and seasonal variations of antibiotic consumption by community residents in Hefei, China, over a 5-year period. STUDY DESIGN: This was an ecological study. METHODS: Data on antibiotic consumption by community residents in Hefei between 2012 and 2016 were collected from the Hefei Center for Disease Control and Prevention. Statistical analysis was carried out using Microsoft Excel 2021, SPSS 26.0 and R4.1.3. An interrupted time series (ITS) analysis was modelled to assess the impact of policies on antibiotic consumption trends. RESULTS: Amoxicillin and cephalosporins accounted for 63.64% and 30.48%, respectively, of the total defined daily dose per 1000 inhabitant-days (DID) of antibiotics in 2016. The total consumption of antibiotics decreased from 6.92 DID in 2012 to 5.61 DID in 2016 (Ptrend = 0.017). Seasonal analysis showed an average of 34.24% antibiotic consumption in the winter over the 5 years. The equation constructed by the ITS analysis was Y = 5.530 + 0.323X1 - 7.574X2 - 0.323X3 + Îµ. CONCLUSION: Between 2012 and 2016, overall antibiotic consumption by community residents in Hefei decreased significantly. The impact of antibiotic policies, implemented between 2011 and 2013, started to appear in 2014 when the consumption of antibiotics decreased. This study has important policy implications for the use of antibiotics at the community level. Further studies on the trends of antibiotic consumption are required, and strategies should be designed to promote appropriate use of antibiotics.

Adipose extracellular matrix deposition is an indicator of obesity and metabolic disorders.

Obesity and metabolic disorders are threats to human health. Extracellular matrix (ECM) is an important member of adipose microenvironment. ECM remodeling contributes to obesity and insulin resistance, but the roles of every single ECM component is still not fully understood. We observed glucose and lipids metabolic disorders in high-fat diet (HFD)-fed mice and humans with obesity. Higher levels of inflammatory factors and hormones existed in serum of HFD-fed mice. Multiple collagens, laminins, fibronectin, nidogen, and Hspg2 were upregulated in obese white adipose tissue (WAT) from mice and humans. These effects were stronger in subcutaneous WAT than visceral WAT in mice, but the fat depot difference was reversed in humans. The ECM structure and the morphology of adipocytes seeded on ECM were changed in the HFD group. In human visceral WAT, ECM genes showed positive correlations with blood lipids and glucose. In vitro, collagen I/IV and LAMA4 proteins showed similar changes with C/EBPα during the differentiation of adipocytes. Macromolecular crowders (MMC) promoted partial collagen and non-collagen gene expression. Oleic acid (OA) and MMC upregulated collagen I/IV and LAMA4 proteins, and the effects of MMC were stronger than that of OA. Moreover, MMC promoted the differentiation of adipocytes, but OA increased the size of lipid droplets. Positive correlations were observed between ECM genes and adipogenesis-related genes in adipocytes. In conclusion, some obesogens (such as HFD) induce ECM remodeling, and the upregulation of ECM components is closely related to adipogenesis, suggesting that adipose ECM deposition is an indicator of obesity and metabolic disorders.

Cuproptosis-related modification patterns depict the tumor microenvironment, precision immunotherapy, and prognosis of kidney renal clear cell carcinoma.

Background: Due to the different infiltration abundance of immune cells in tumor, the efficacy of immunotherapy varies widely among individuals. Recently, growing evidence suggested that cuproptosis has impact on cancer immunity profoundly. However, the comprehensive roles of cuproptosis-related genes in tumor microenvironment (TME) and in response to immunotherapy are still unclear. Methods: Based on 43 cuproptosis-related genes, we employed unsupervised clustering to identify cuproptosis-related patterns and single-sample gene set enrichment analysis algorithm to build a cuproptosis signature for individual patient's immune cell infiltration and efficacy of immune checkpoint blockade (ICB) evaluation. Then, the cuproptosis-related genes were narrowed down using univariate Cox regression model and least absolute shrinkage and selection operator algorithm. Finally, a cuproptosis risk score was built by random survival forest based on these narrowed-down genes. Results: Two distinct cuproptosis-related patterns were developed, with cuproptosis cluster 1 showing better prognosis and higher enrichment of immune-related pathways and infiltration of immune cells. For individual evaluation, the cuproptosis signature that we built could be used not only for predicting immune cell infiltration in TME but also for evaluating an individual's sensitivity to ICBs. Patients with higher cuproptosis signature scores exhibited more activated cancer immune processes, higher immune cell infiltration, and better curative efficacy of ICBs. Furthermore, a robust cuproptosis risk score indicated that patients with higher risk scores showed worse survival outcomes, which could be validated in internal and external validation cohorts. Ultimately, a nomogram which combined the risk score with the prognostic clinical factors was developed, and it showed excellent prediction accuracy for survival outcomes. Conclusion: Distinct cuproptosis-related patterns have significant differences on prognosis and immune cell infiltration in kidney renal clear cell carcinoma (KIRC). Cuproptosis signature and risk score are able to provide guidance for precision therapy and accurate prognosis prediction for patients with KIRC.

Saponins from Panax japonicus alleviate adipose tissue fibrosis and metabolic dysfunction in high-fat-diet-induced obese mice.

INTRODUCTION: Adipose tissue fibrosis is a typical feature of adipose tissue dysfunction in obese individuals, which is closely related to metabolic diseases. OBJECTIVE: To explore the effect and mechanism of Saponins from Panax japonicus (SPJ) on adipose tissue fibrosis in obese mice induced by high fat diet (HFD). MATERIALS AND METHODS: We established a HFD induced obese mice model. Then the obese mice were treated with 90 mg/kg SPJ by oral gavage for 10 weeks. The levels of adipose tissue fibrosis and molecules related to signalling pathways were measured. Then the effects of SPJ on TGFß1-induced fibrosis in 3T3-L1 differentiated adipocytes were evaluated. RESULTS: SPJ reduced body weight, fat accumulation, and improved glucose and lipid metabolism in obese mice. SPJ decreased collagen deposition and expressions of fibrotic genes in epididymal white adipose tissue (eWAT) of obese mice. SPJ decreased the levels of TGFß1 protein and pSmad2, and increased the expression of PPARγ and PGC1α, thus alleviating oxidative stress in eWAT. Consistently, SPJ inhibited TGFß1-induced fibrosis in 3T3-L1 differentiated adipocytes. CONCLUSIONS: SPJ may alleviate adipose tissue fibrosis and improve obesity by inhibiting TGFß1/Smad2 and activating PPARγ/PGC1α pathway. SPJ is expected to become an efficient medicine for treatment of obesity.

High-Fat-Diet-Induced Extracellular Matrix Deposition Regulates Integrin-FAK Signals in Adipose Tissue to Promote Obesity.

SCOPE: High-fat-diet (HFD) is an important factor in obesity. Extracellular matrix (ECM) regulates white adipose tissue (WAT), but its mechanism is unknown. METHODS AND RESULTS: This study uses three models-HFD-fed mice, human with obesity, and 3T3-L1 adipocytes with oleic acid (OA)/macromolecular crowders (MMC) treatment. Glucose and lipids metabolic disorders, increased collagen I/IV and laminin α2/4 (LAMA2/4), and upregulated integrins (ITGA1/ITGA7) - focal adhesion kinase (FAK) - c-Jun N-terminal kinase (JNK)/extracellular regulated protein kinase 1/2 (ERK1/2) signals in obese WAT from mice and human are observed. The upregulation of ECM - integrin - FAK signals is stronger in subcutaneous WAT than that in visceral WAT of mice, but these results are reversed in human. In vitro, oleic acid (OA) promotes lipid accumulation and upregulates collagen IV, LAMA4, and p-JNK. MMC is used to induce ECM deposition in adipocytes. MMC promotes adipocyte differentiation and integrins - FAK - JNK/ERK1/2 signals. When FAK phosphorylation is inhibited, downstream p-JNK is decreased. Inhibition of FAK phosphorylation reduces adipocyte differentiation, but MMC partially reverses this effect. CONCLUSION: HFD-induced ECM deposition, whose signals are transmitted into adipocytes through upregulating ITGA1/ITGA7, activates the phosphorylation of intracellular FAK - JNK/ERK1/2 signals, and promotes adipogenesis in WAT. This mechanism provides novel therapeutic targets to treat obesity.

Maternal nicotine exposure impairs brown adipose tissue via AMPK-SIRT1-PGC-1α signals in male offspring.

AIMS: Maternal nicotine exposure during pregnancy and lactation is associated with obesity in offspring. Brown adipose tissue (BAT) is correlated with energy metabolism and obesity. In this study, we explored the mechanism of maternal nicotine exposure on BAT changes in male offspring. MAIN METHODS: Pregnant rats were randomly assigned to nicotine (1.0 mg/kg twice per day, subcutaneous administration) or control groups. In vitro, C3H10T1/2 cells were induced to differentiate into mature brown adipocytes, and 0-50 µM nicotine was given to C3H10T1/2 cells during the differentiation process. KEY FINDINGS: Nicotine-exposed males had white-like adipocytes and abnormal mitochondria structure in iBAT at 26 weeks. The expression of mitochondrial genes, UCP1 and AMPK-SIRT1-PGC-1α pathway were downregulated in the nicotine group at 26 weeks rather than 4 weeks. In vitro, 50 µM nicotine decreased the expression of mitochondrial genes, UCP1 and AMPK-SIRT1-PGC-1α pathway in brown adipocytes. SIGNIFICANCE: Maternal nicotine exposure showed the "programming" effect on the decreased brown-like phenotype in BAT of adult male offspring via downregulating AMPK-SIRT1-PGC-1α pathway. This impairment of BAT may be a potential mechanism of nicotine-induced obesity in male offspring.

Maternal nicotine exposure during pregnancy and lactation induces brown adipose tissue whitening in female offspring.

Maternal nicotine exposure during pregnancy and lactation is associated with obesity in female offspring. Brown adipose tissue (BAT) is related to energy metabolism and obesity. In this study, we explored the mechanism of maternal nicotine exposure on BAT "whitening" in female offspring. Pregnant rats were randomly assigned to nicotine (1.0 mg/kg twice per day, subcutaneous administration) or control groups. The weight, structure, and microvascular density of interscapular BAT (iBAT) and the expression of PGC-1αUCP1 signals, mitochondrial biogenesis-related genes and angiogenesis-related genes were tested in 4- and 26-week-aged female offspring. In vitro, C3H10T1/2 cells were induced to differentiate into mature brown adipocytes, and 0-50 µM nicotine was treated on cells during the differentiation process. Nicotine-exposed females had higher iBAT weight, white-like adipocytes and abnormal mitochondrial structure in iBAT at 26 weeks rather than 4 weeks. The PGC-1αUCP1 signals and brown-like genes were down-regulated at 26 weeks, but the microvascular density and the expression of pro-angiogenic factors reduced more at 4 weeks in the nicotine group. In vitro, 50 µM nicotine significantly decreased the expression of PGC-1αUCP1 signals and angiogenesis-related genes. In conclusion, maternal nicotine exposure during pregnancy and lactation led to the "whitening" of BAT in adult female offspring: nicotine decreased BAT angiogenesis in the early development stage, and then, the impairment of blood vessels programed for the reduction of BAT phenotype through down-regulating the PGC-1αUCP1 signals in adulthood. This impairment of BAT may be a potential mechanism of nicotine-induced obesity in female offspring.

Maternal nicotine exposure enhances adipose tissue angiogenic activity in offspring: Sex and age differences.

Maternal nicotine exposure during pregnancy and lactation (NIC) is associated with dysfunction of white adipose tissue (WAT). We focused on the NIC-induced WAT angiogenesis and explored its sex and age differences. Pregnant rats were randomly assigned to NIC (1.0 mg/kg nicotine twice per day) or control groups. Distribution and density of blood vessels were observed. Angiogenesis-related genes were tested at 4, 12 and 26 weeks to estimate angiogenic activity. In vitro, nicotine concentration- and time-response experiments (0-50 µM) were conducted in 3T3-L1. Lipid accumulation and angiogenesis-related genes were tested. NIC increased the blood vessels in inguinal subcutaneous WAT (igSWAT) and gonadal WAT (gWAT) of 26-week-aged male and 4-week-aged female offspring. In males, nicotine showed higher angiogenic activity at 26 weeks than at 4 weeks in igSWAT and gWAT. In females, nicotine's angiogenic activity was higher at 4 weeks than 26 weeks in igSWAT and gWAT. In vitro, nicotine promoted adipocyte differentiation, and increased the expression of angiogenesis-related genes in concentration- and time dependent manners. In conclusion, NIC-induced enhancement of angiogenic activity in WAT presented sex and age differences: nicotine showed higher angiogenic activity in adulthood than in childhood of male offspring, but the converse results were observed in female offspring.

The association between maternal nicotine exposure and adipose angiogenesis in female rat offspring: A mechanism of adipose tissue function changes.

Maternal smoking during pregnancy and lactation is associated with increased fat mass in the offspring, but the mechanism by which this occurs is not fully understood. Our study focused on the relationships among maternal nicotine exposure, adipose angiogenesis and adipose tissue function in female offspring. Pregnant rats were randomly assigned to nicotine or control groups. Microvascular density, lipid metabolism and α7nAChR-Egr1-FGF2 signaling pathway genes/proteins were tested in 4-, 12- and 26-week female offspring. In vitro, nicotine concentration- and time-response experiments were conducted in 3T3-L1. Lipid metabolism and α7nAChR-Egr1-FGF2 signaling pathway genes/proteins were tested. The conditioned media of differentiated 3T3-L1 treated with nicotine were used to observe tube formation in human umbilical vein endothelial cells (HUVECs). Nicotine-exposed females presented higher adipose microvascular density. The gene expression of α7nAChR, Egr1 and FGF2 was significantly increased in gonadal white adipose tissue (gWAT) and inguinal subcutaneous WAT (igSWAT) of nicotine-exposed females at 4 weeks of age. The protein expression of α7nAChR, Egr1 and FGF2 was increased in gWAT and igSWAT of nicotine-exposed females at 4 weeks of age, and increased in gWAT at 26 weeks. In vitro, nicotine increased the expression of lipid metabolism and α7nAChR-Egr1-FGF2 signaling pathway genes/proteins in a concentration- and time-dependent manner. In the tube formation experiment, adipocytes affected by nicotine promoted HUVEC angiogenesis. Therefore, maternal nicotine exposure promoted the early angiogenesis of adipose tissue via the α7nAChR-Egr1-FGF2 signaling pathway, and this angiogenesis mechanism was associated with increased adipogenesis in adipose tissue of female offspring.

Human papillomavirus-associated oropharyngeal cancer: review of current evidence and management.

Oropharyngeal cancer (opc) has become the leading site for human papillomavirus (hpv)-associated cancers in humans. It is an epidemic that remains relatively unfamiliar to most physicians, potentially delaying diagnosis and treatment. Traditionally, cancers involving the head and neck have occurred in smokers and in those with a significant alcohol history. Typically, hpv-positive opc presents in a younger, healthier population with a different set of risk factors and good prognosis for survival. However, many head-and-neck cancer patients, including those with hpv-positive disease, develop lifelong disabilities because of the morbid nature of their treatments, and those patients have the highest level of unmet needs in studies spanning cancer sites. Knowledge of this epidemic, a high index of suspicion, and an understanding of how the tumours present in clinical practice can help physicians to make an early diagnosis, thus sparing the patient significant morbidity from treatments associated with more advanced disease stages. Furthermore, recognizing that these patients have distinct psychosocial needs and implementing a collaborative team approach is critical to providing optimal care and improving quality of life in the survivorship period.

Age Differences in the Relationship between Secondhand Smoke Exposure and Risk of Metabolic Syndrome: A Meta-Analysis.

Secondhand smoke (SHS), a common environmental exposure factor, has become a serious public health problem. Metabolic syndrome is another worldwide clinical challenge. Our study tried to determine the age differences in the relationship between SHS and the risk of metabolic syndrome. Studies were searched in PubMed and Web of Science from 11 November to 30 November 2018. Eighteen studies were finally included based on inclusion and exclusion criteria. The relationship between SHS and the risk indicators of metabolic syndrome was analyzed. The weighted mean difference (WMD) of fasting plasma glucose (FPG), insulin, body mass index (BMI), and waist circumference (WC), and the standard mean difference (SMD) of total cholesterol, triglycerides, and low- and high-density lipoprotein-cholesterol (LDL-C, HDL-C) were calculated in a meta-analysis. SHS was positively associated with the level of insulin and WC. According to the subgroup analysis based on age difference, SHS was positively associated with FPG in the upper age group, and positively associated with LDL-C and negatively associated with HDL-C in the lower age group. BMI showed a more obvious positive correlation in the adults group than in the children and the teenagers group. In conclusion, the association of metabolic syndrome with SHS varies with age. When exposed to SHS, older people may be more susceptible to glucose metabolic disorder, but younger people may be more susceptible to lipid metabolic disorder.

Validation of reflex testing rules and establishment of a new workflow for body fluid cell analysis using a Sysmex XN-550 automatic hematology analyzer.

INTRODUCTION: We developed and validated reflex testing rules for the microscopic examination (ME) of body fluids (BFs) on the Sysmex XN-550 (Sysmex Corporation) instrument. METHODS: We assessed the detection limits, precision, linearity, and carryover. To develop the reflex testing rules (derivation arm), we tested 515 samples and then validated the rules using another 507 samples (validation arm). RESULTS: All analytical performances were acceptable, and the carryover was negligible. There was agreement between the automated count and ME of red blood cells (r = .98) and total nucleated cells (TNCs) (r = .98), as well as the differential counts of neutrophils (r = .90) and lymphocytes (r = .84). We developed reflex testing rules: TNCs <10/µL, cell 2/cell 1 ratio ≤0.7, HF-BF cells >7.9/100 white blood cells, LY-X ≥85 or LY-Y ≥90, and eosinophils >2.5%. In the validation arm, implementation of the rules resulted in 126 rule-negative samples (24.9%) that were well correlated between the 2 methods. We propose a new workflow for BF cell analysis based on automated counting. CONCLUSION: The Sysmex XN-550 can be a suitable alternative to ME for BF cell analysis, especially for screening samples and subsequent automatic reporting under the rational use of laboratory-specific rules.

Effects of maternal omega-3 fatty acids supplementation during pregnancy/lactation on body composition of the offspring: A systematic review and meta-analysis.

BACKGROUND & AIMS: The effect of maternal omega-3 fatty acids intake on the body composition of the offspring is unclear. The aim of this study was to conduct a systematic review and meta-analysis to confirm the effects of omega-3 fatty acids supplementation during pregnancy and/or lactation on body weight, body length, body mass index (BMI), waist circumference, fat mass and sum of skinfold thicknesses of offspring. METHODS: Human intervention studies were selected by a systematic search of PubMed, Web of Science, the Cochrane Library and references of related reviews and studies. Randomized controlled trials of maternal omega-3 fatty acids intake during pregnancy or lactation for offspring's growth were included. The data were analyzed with RevMan 5.3 and Stata 12.0. Effect sizes were presented as weighted mean differences (WMD) or standardized mean difference (SMD) with 95% confidence intervals (95% CI). RESULTS: Twenty-six studies comprising 10,970 participants were included. Significant increases were found in birth weight (WMD = 42.55 g, 95% CI: 21.25, 63.85) and waist circumference (WMD = 0.35 cm, 95% CI: 0.04, 0.67) in the omega-3 fatty acids group. There were no effects on birth length (WMD = 0.09 cm, 95% CI: -0.03, 0.21), postnatal length (WMD = 0.13 cm, 95% CI: -0.11, 0.36), postnatal weight (WMD = 0.04 kg, 95% CI: -0.07, 0.14), BMI (WMD = 0.09, 95% CI: -0.05, 0.23), the sum of skinfold thicknesses (WMD = 0.45 mm, 95% CI: -0.30, 1.20), fat mass (WMD = 0.05 kg, 95% CI: -0.01, 0.11) and the percentage of body fat (WMD = 0.04%, 95% CI: -0.38, 0.46). CONCLUSIONS: This meta-analysis showed that maternal omega-3 fatty acids supplementation can increase offspring's birth weight and postnatal waist circumference. However, it did not appear to influence children's birth length, postnatal weight/length, BMI, sum of skinfold thicknesses, fat mass and the percentage of body fat during postnatal period. Larger, well-designed studies are recommended to confirm this conclusion.

Perinatal nicotine exposure increases obesity susceptibility by peripheral leptin resistance in adult female rat offspring.

Maternal nicotine (NIC) exposure causes overweight, hyperleptinemia and metabolic disorders in adult offspring. Our study aims to explore the underlying mechanism of perinatal NIC exposure increases obesity susceptibility in adult female rat offspring. In our model, we found that adult NIC-exposed females presented higher body weight and subcutaneous and visceral fat mass, as well as larger adipocytes, while no change was found in food intake. Serum profile showed a higher serum glucose, insulin and leptin levels in NIC-exposed females. In adipose tissue and liver, the leptin signaling pathway was blocked at 26 weeks, presented lower Janus tyrosine kinase 2 and signal transducer and activator of transcription 3 gene expression, higher suppressor of cytokine signaling 3 gene expression (in adipose tissue) and lower leptin receptors gene expression (in liver), indicating that peripheral leptin resistance occurred in NIC-exposed adult females. In female rats, the expression of lipolysis genes was affected dominantly in adipose tissue, but lipogenesis genes was affected in liver. Furthermore, the glucose and insulin tolerance tests showed a delayed glucose clearance and a higher area under the curve in NIC-exposed females. Therefore, perinatal NIC exposure programed female rats for adipocyte hypertrophy and obesity in adult life, through the leptin resistance in peripheral tissue.

Intrauterine growth retardation-associated syncytin b hypermethylation in maternal rat blood revealed by DNA methylation array analysis.

BackgroundEmerging evidence suggests that DNA methylation in maternal blood is a promising target for intrauterine growth retardation (IUGR) screening, a common developmental toxicity. Here, we aimed to screen out IUGR-related DNA methylation status in maternal blood via high-throughput profiling.MethodsPregnant Wistar rats were subcutaneously administered nicotine (1 mg/kg) twice per day from gestational day (GD) 11 to GD20 to establish the IUGR model. MeDIP array assays and the following GO analysis were used to evaluate DNA methylation status in maternal blood. One placental development-associated gene was selected for further confirmation.ResultsGenes regulating the development of multiple organs and major body systems had changed DNA methylation frequencies in the maternal blood of IUGR rats. Placental development, which can affect the development of multiple fetal organs and induce IUGR, is a hypermethylated cluster consisting of four significantly changed genes, including syncytin b (Synb), Lrrc15, Met, and Tex19.1. With the most significant change, Synb hypermethylation in maternal blood was confirmed by bisulfite-sequencing PCR (BSP). Moreover, decreased Synb expression and histological changes were observed in IUGR placentae.ConclusionThe IUGR-associated DNA methylation profile in maternal blood, such as placenta-related Synb hypermethylation, provides evidence for further studies on possible IUGR biomarkers.

Prenatal caffeine exposure induced high susceptibility to metabolic syndrome in adult female offspring rats and its underlying mechanisms.

Our previous studies have demonstrated that prenatal caffeine exposure (PCE) induced an intrauterine programming of hypothalamic-pituitary-adrenal axis (HPAA)-associated neuroendocrine metabolism in 3-month-old offspring rats. In this study, we aimed to confirm this programming disorder and high susceptibility to metabolic syndrome (MS) in 10-month-old female PCE offspring with postnatal catch-up growth. We found that PCE female offspring rats showed decreased bodyweight but a higher rate of weight gain after birth. Moreover, in the offspring, basal hyperinsulinemia and insulin resistance were observed before unpredictable chronic stress (UCS), but serum total cholesterol (TCH) levels and triglyceride/high-density lipoprotein-cholesterol (TG/HDL-C), TCH/HDL-C and low-density lipoprotein-cholesterol/HDL-C (LDL-C/HDL-C) ratio changes were increased after UCS, accompanied by morphological damage of the related tissues. These results suggested that PCE adult female offspring rats were highly susceptible to MS, which is related to HPAA-associated neuroendocrine-metabolic programming disorder.

Increased Fetal Thymocytes Apoptosis Contributes to Prenatal Nicotine Exposure-induced Th1/Th2 Imbalance in Male Offspring Mice.

Nicotine, a definite risk factor during pregnancy, is an immunomodulator. This study was designed to investigate the effects of prenatal nicotine exposure (PNE) on the balance of Th1/Th2 in offspring, and further explore the developmental origin mechanisms from the perspective of fetal thymocytes apoptosis. Pregnant Balb/c mice were administered 1.5 mg/kg nicotine subcutaneously twice per day from gestational day (GD) 9 to GD18. Results showed that PNE could cause a Th2 shift in male offspring, manifested as increased ratio of IgG1/IgG2a, IL-4 production in serum, and IL-4/IFN-γ expression ratio in spleen. Increased apoptosis of total thymocytes and CD4SP and reduced cell proportion of CD4SP were found in PNE male offspring on postnatal day (PND) 14 and PND 49. In the fetuses, decreased body weight and organ index of fetal thymus, histological changes in fetal thymus, reduced CD4SP proportion and increased fetal thymocyte apoptosis were observed in nicotine group. The increased mRNA expression of genes involved in Fas-mediated apoptotic pathway and protein expression of Fas were also detected. In conclusion, PNE could cause a Th2 shift in male offspring mediated by reduced CD4+ T cells output, which may result from the increasing apoptosis of total thymocytes and CD4SP.

Nicotine Suppressed Fetal Adrenal StAR Expression via YY1 Mediated-Histone Deacetylation Modification Mechanism.

Steroidogenic acute regulatory (StAR) protein plays a pivotal role in steroidogenesis. Previously, we have demonstrated that prenatal nicotine exposure suppressed fetal adrenal steroidogenesis via steroidogenic factor 1 deacetylation. This study further explored the potential role of the transcriptional repressor Yin Yang 1 (YY1) in nicotine-mediated StAR inhibition. Nicotine was subcutaneously administered (1.0 mg/kg) to pregnant rats twice per day and NCI-H295A cells were treated with nicotine. StAR and YY1 expression were analyzed by real-time PCR, immunohistochemistry, and Western blotting. Histone modifications and the interactions between the YY1 and StAR promoter were assessed using chromatin immunoprecipitation (ChIP). Prenatal nicotine exposure increased YY1 expression and suppressed StAR expression. ChIP assay showed that there was a decreasing trend for histone acetylation at the StAR promoter in fetal adrenal glands, whereas H3 acetyl-K14 at the YY1 promoter presented an increasing trend following nicotine exposure. Furthermore, in nicotine-treated NCI-H295A cells, nicotine enhanced YY1 expression and inhibited StAR expression. ChIP assay showed that histone acetylation decreased at the StAR promoter in NCI-H295A cells and that the interaction between the YY1 and StAR promoter increased. These data indicated that YY1-medicated histone deacetylation modification in StAR promoters might play an important role in the inhibitory effect of nicotine on StAR expression.

Prenatal and lactation nicotine exposure affects morphology and function of brown adipose tissue in male rat offspring.

The aim of this study was to investigate the effects of prenatal and lactation nicotine exposure on the morphology and function of brown adipose tissue (BAT) in male rat offspring. We conducted a morphological assay and gene expression study of interscapular BAT (iBAT) in male rat offspring. The male offspring from nicotine-exposed dams exhibited higher body weight and iBAT weight. Hematoxylin and eosin staining and transmission electron microscopy showed that iBAT from nicotine-exposed male offspring presented a "whitening" phenotype characterized by lipid droplet accumulation and impaired mitochondria with a randomly oriented and fractured cristae. The expression of the iBAT structure and function-related genes all decreased in nicotine-exposed male offspring. These data indicate that prenatal and lactation nicotine exposure affects morphology and function of iBAT in male rat offspring.