N6-methyladenosine modification of circMARK2 enhances cytoplasmic export and stabilizes LIN28B, contributing to the progression of Wilms tumor.

BACKGROUND: The potential involvement of circular RNAs (circRNAs) and N6-methyladenosine (m6A) modification in the progression of Wilms tumor (WT) has not been fully elucidated. This study investigates the regulatory mechanisms and clinical significance of m6A-modified circMARK2 and its role in WT progression. METHODS: We identified dysregulated circRNAs through deep sequencing and validated their expression by qRT-PCR in WT tissues. The biological functions of circMARK2 were assessed using clone formation, transwell migration, and orthotopic animal models. To dissect the underlying mechanisms, we employed RNA immunoprecipitation, RNA pull-down, dual-luciferase reporter assays, Western blotting, and immunofluorescence and immunohistochemical staining. RESULTS: CircMARK2, upregulated in WT tissues, was found to be m6A-modified and promoted cytoplasmic export. It facilitated WT progression by stabilizing LIN28B mRNA through the circMARK2/IGF2BP2 interaction. In vitro and in vivo studies demonstrated that circMARK2 enhances the malignant behavior of WT cells. Clinically, higher circMARK2 levels in tumor tissues of WT patients were linked to increased tumor aggressiveness and reduced survival rates. CONCLUSIONS: Our study provides the first comprehensive evidence that m6A-modified circMARK2 contributes to WT progression by enhancing LIN28B mRNA stability, promoting cellular aggressiveness. CircMARK2 emerges as a potential biomarker for prognosis and a promising target for therapeutic intervention in WT, underscoring the clinical relevance of m6A modification in pediatric renal cancer.

PABPC1L Induces IDO1 to Promote Tryptophan Metabolism and Immune Suppression in Renal Cell Carcinoma.

The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance despite having extensive T-cell infiltration. Elucidation of the mechanisms underlying immune evasion could help identify therapeutic strategies to boost the efficacy of immune checkpoint blockade (ICB) in RCC. This study uncovered a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine 2,3-dioxygenase 1 (IDO1), a prospective target for immunotherapy. PABPC1L was markedly upregulated in RCC, and high PABPC1L expression correlated with unfavorable prognosis and resistance to ICB. PABPC1L bolstered tryptophan metabolism by upregulating IDO1, inducing T-cell dysfunction and Treg infiltration. PABPC1L enhanced the stability of JAK2 mRNA, leading to increased JAK2-STAT1 signaling that induced IDO1 expression. Additionally, PABPC1L-induced activation of the JAK2-STAT1 axis created a positive feedback loop to promote PABPC1L transcription. Conversely, loss of PABPC1L diminished IDO1 expression, mitigated cytotoxic T-cell suppression, and enhanced responsiveness to anti-PD-1 therapy in patient-derived xenograft models. These findings reveal the crucial role of PABPC1L in facilitating immune evasion in RCC and indicate that inhibiting PABPC1L could be a potential immunotherapeutic approach in combination with ICB to improve patient outcomes. SIGNIFICANCE: PABPC1L functions as a key factor in renal cell carcinoma immune evasion, enhancing IDO1 and impeding T-cell function, and represents a potential target to enhance the efficacy of immune checkpoint blockade therapy.

Relationship of Early Anemia with Neurodevelopment and Brain Injury in Very Low Birth Weight Preterm Infants-A Prospective Cohort Study.

Anemia is associated with neurodevelopmental delays and brain injury in infants and toddlers, but whether early anemia has a similar effect in neonatal preterm infants is largely unknown. Thus, this study aimed to determine the relationship of early anemia with neurodevelopment and brain injury in very-low-birth-weight (VLBW) preterm infants within the neonatal period. A prospective cohort study including 110 VLBW preterm infants was conducted in Southern China from 2016 to 2018. All participants were followed from birth to 1 month corrected age. Early anemia is defined as hemoglobin of ≤145 g/L within the first week after birth. The non-anemic group (control group, N = 55) was 1:1 matched with the early anemia group (N = 55) according to birth weight and gestational age. Neurodevelopment at 1 month corrected age and brain injury within 1 month corrected age were measured by neonatal behavioral neurological assessments (NBNA) and cranial ultrasound, respectively. Compared to the control group, the early anemia group had a lower score in behavioral ability in the NBNA test [11 (10-12) vs. 10 (9.5-11), p = 0.033]. Early anemia was negatively associated with the NBNA total score (ß= -0.680, 95% CI: -1.300, -0.059), especially with the behavioral ability score (ß= -0.504, 95% CI: -0.941, -0.067) after adjusting for the confounders. However, no association between early anemia and brain injury was observed. In conclusion, in VLBW preterm infants, early anemia is negatively correlated with neurodevelopment, especially with behavioral ability.

Secular trends of birth weight and its associations with obesity and hypertension among Southern Chinese children and adolescents.

OBJECTIVES: The association of low or high birth weight (L/HBW) with obesity and hypertension in childhood remains unclear. We aimed to identify the secular trend of birth weight distribution and its relationship to obesity and hypertension in Southern Chinese children and adolescents. METHODS: 6,561 individuals (6-17-year-old) were enrolled by multistage cluster sampling to observed the trend of birth weight distribution and its associated factors. 1,218 were further selected by group matching to investigate the correlation between birth weight and obesity or hypertension. RESULTS: Between 1997 and 2008, a significant decline in the LBW rate and no significant change in the HBW rate was found. LBW was associated with maternal BMI<18 kg/m2 (OR1.79, 95% CI 1.08-2.97) during pregnancy, while maternal BMI between 25.0 and 27.9 kg/m2 (OR1.62, 95% CI 1.04-2.52) and paternal BMI>28 kg/m2 (OR1.64, 95% CI 1.02-2.63) during pregnancy were associated with HBW. The prevalence of obesity was significantly higher with HBW than normal birth weight (NBW) or LBW (16.73, 6.25 and 5.50%, respectively). The prevalence rates of suspected hypertension were 1.62, 1.25 and 1.49% among LBW, NBW and HBW, respectively (p>0.05). LBW decreased the risks of childhood overweight (OR0.31, 95% CI 0.18-0.54), but had no effect on suspected hypertension. HBW increased the risks of childhood obesity (OR2.19, 95% CI 1.50-3.20), but decreased the risks of suspected hypertension (OR0.22, 95% CI 0.09-0.58). CONCLUSIONS: HBW was positively associated with childhood obesity, and parental BMIs management might be one of the measurements to control birth weight to lessen childhood obesity.

Iron Supplementation Is Associated with Improvement of Motor Development, Hemoglobin Level, and Weight in Preterm Infants during the First Year of Life in China.

Iron supplementation is recommended for preterm infants due to impaired iron endowment. However, the health outcomes of this recommendation remain controversial. Thus, this study aimed to determine the association of iron supplementation with neurobehavioral development, hemoglobin (Hb), and anthropometric characteristics in preterm infants. A retrospective cohort design was applied to collect data from 1568 preterm infants at 0-3 months of corrected age (mo CA) from a hospital in South China. Infants were categorized into a 3-month iron supplementation group (IG, n = 697) or a control group (CG, n = 871) according to medical records, and then followed through to 12 mo CA. Data on neurobehavioral development, anthropometry, Hb level, history of diseases, and nutrition were collected at 3, 6, and 12 mo CA. The results showed that, compared with the CG, iron supplementation was positively related to improved gross motor skills and weight at 6 mo CA (ß = 1.894, ß = 5.322) and 12 mo CA (ß = 4.019, ß = 6.830) and fine motor skills at 12 mo CA (ß = 1.980), after adjustment for confounding factors including illness, nutritional supplements, and diet. Iron supplementation was also related to elevated Hb levels and its increase at 3 mo CA (ß = 2.196, ß = 3.920) and 6 mo CA (ß = 3.011, ß = 7.259). In conclusion, iron supplementation for 3 months in Chinese preterm infants is positively associated with improved motor development, elevated Hb levels, and higher body weight during the first year of life.

Adiposity measures in screening for metabolic syndrome among Chinese children and adolescents.

BACKGROUND: Existing various and complicated metabolic syndrome (MetS) definitions have contributed to the difficulty in assessing MetS in children and adolescents, and therefore it is urgently needed to develop a convenient and effective screening tool for pediatric MetS. This study aimed to identify the optimal adiposity measure to screen for pediatric MetS. METHODS: The cross-sectional data was collected from 8,150 children and adolescents aged 7-17 y living in southern China. Anthropometric indices, blood lipids, and serum glucose were determined. Results of two commonly used MetS definitions were compared: International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel Ⅲ (NCEP-ATP) modified by Cook. Receiver operating characteristic curve analyses were performed and areas under the curve (AUCs) were calculated to determine the optimal index for MetS screening. RESULTS: MetS prevalence assessed by NCEP-ATP was significantly higher than that by IDF (6.2% vs. 1.5%, p<0.001). Waist-to-height ratio (WHtR) showed the highest screening power for MetS defined by both IDF and NCEP-ATP (AUC 0.932 and 0.900, respectively), and its optimal cut-off point was 0.48 by both IDF and NCEP-ATP definition (sensitivity 0.944 and 0.847, specificity 0.800 and 0.830, respectively), regardless of age or sex. When taking sex diversity into account, the optimal WHtR cut-off point was 0.49 (IDF) or 0.50 (NCEP-ATP) in boys, and 0.46 (both definitions) in girls. CONCLUSIONS: Among children and adolescents aged 7-17 y in southern China, a WHtR greater than 0.48 can be a simple but effective screening tool for MetS.

Antenatal Iron-Rich Food Intervention Prevents Iron-Deficiency Anemia but Does Not Affect Serum Hepcidin in Pregnant Women.

BACKGROUND: Limited evidence supports the efficacy of iron-rich foods (IRFs) in improving iron status during pregnancy. OBJECTIVES: The study aims to evaluate the effect of IRFs on iron status and biomarkers of iron metabolism in the third trimester of pregnancy. METHODS: A total of 240 pregnant women at 11-13 wk of gestation without iron-deficiency anemia (IDA) in South China were recruited to this single-blind clinical trial [non-IDA referred to both hemoglobin (Hb) ≥110g/L and serum ferritin (SF) ≥15ng/mL],  randomly assigned to 1) control, 2) IRFs containing 20 mg iron/d (IRF-20), or 3) IRFs containing 40 mg iron/d (IRF-40). The IRFs were consumed 3 days a week, including pork liver, chicken/duck blood, soybean, and agaric. The IRFs started at recruitment and ended in the predelivery room. Primary outcome included anemia (Hb <110 g/L), iron deficiency (ID, definition 1: SF <15 ng/mL; definition 2: SF <12 ng/mL), and IDA (ID and Hb <110 g/L). Secondary outcome was plasma Hb and iron indices, including SF, serum hepcidin, and iron. RESULTS: All participants who completed the trial with full data (n = 170) were included in the analysis. At the endline, both intervention groups showed lower ID and IDA rates than control. Specifically, IRF-40 showed a lower ID (SF <12 ng/mL) rate than control (9.0% compared with 22.8%, P = 0.022). For IDA by definition 1, the incidence in IRF-40 was lower than that in control (1.9% compared with 8.9%, P = 0.045). For IDA by definition 2, the incidence in IRF-20 was lower than that in control (3.9% compared with 17.9%, P = 0.049). Moreover, IRF-20 showed higher SF concentrations than control (P = 0.039). No effects of IRFs on anemia (P = 0.856), plasma Hb (P = 0.697), serum hepcidin (P = 0.311), and iron (P = 0.253) concentrations were observed. The assessed iron intakes were 22.2 mg/d in IRF-20 and 25.0 mg/d in IRF-40, respectively. CONCLUSIONS: Antenatal IRFs reduce the risk of ID and IDA in late pregnancy, although the present results are inadequate to confirm an ideal dosage (No. ChiCTR1800017574).

Effects of Caloric Restriction and Rope-Skipping Exercise on Cardiometabolic Health: A Pilot Randomized Controlled Trial in Young Adults.

The aim of this study is to investigate the effects of calorie restriction (CR), rope-skipping (RS) exercise, and their joint effects on cardiometabolic health in young adults. An 8-week randomized trial was conducted on 46 undergraduates aged 19-21 y from South China. The participants were randomized into the following three groups: Calorie restriction (CR) group (n = 14), Rope-skipping (RS) group (n = 14), and CR plus RS (CR-RS) group (n = 12). At both allocation and the end of the intervention, data on anthropometry, serum metabolic, and inflammatory markers were collected. A total of 40 participants completed the intervention and were included in the analysis. After the 8-week intervention, the participants from the CR group and the CR-RS group reduced in body weight (-1.1 ± 1.7 kg, -1.3 ± 2.0 kg), body mass index (-0.4 ± 0.6 kg/m2, -0.5 ± 0.7 kg/m2), body fat percentage (-1.2 ± 1.6%, -1.7 ± 1.8%), and body fat mass (-1.1 kg (-2.2, -0.3), -1.1 kg (-2.5, -0.4)) compared to the baseline (p < 0.05 or p = 0.051). For metabolic and inflammatory factors, the participants in the CR-RS group showed significant decreases in low density lipoprotein cholesterol (-0.40 mmol/L) and interleukin-8 (-0.73 mmol/L). While all the above markers showed no significant difference among the groups after intervention, in the subgroup of overweight/obese participants (n = 23), the CR-RS group had significantly lower blood pressure, fasting insulin, homeostatic model assessment of insulin resistance, tumor necrosis factor-α, and interleukin-8 levels than the CR or RS groups (p < 0.05). In conclusion, both CR and CR-RS could reduce weight and improve body composition in young adults. More importantly, in those with overweight or obesity, CR-RS intervention might be superior to either CR or RS in improving cardiometabolic health.

Single-course antenatal corticosteroids is related to faster growth in very-low-birth-weight infant.

BACKGROUND: Antenatal corticosteroids (ACS) treatment is critical to support survival and lung maturation in preterm infants, however, its effect on feeding and growth is unclear. Prior preterm delivery, it remains uncertain whether ACS treatment should be continued if possible (repeated course ACS), until a certain gestational age is reached. We hypothesized that the association of single-course ACS with feeding competence and postnatal growth outcomes might be different from that of repeated course ACS in very-low-birth-weight preterm infants. METHODS: A multicenter retrospective cohort study was conducted in very-low-birth-weight preterm infants born at 23-37 weeks' gestation in South China from 2011 to 2014. Data on growth, nutritional and clinical outcomes were collected. Repeated course ACS was defined in this study as two or more courses ACS (more than single-course). Infants were stratified by gestational age (GA), including GA < 28 weeks, 28 weeks ≤ GA < 32 weeks and 32 weeks ≤ GA < 37 weeks. Multiple linear regression and multilevel model were applied to analyze the association of ACS with feeding and growth outcomes. RESULTS: A total of 841 infants were recruited. The results, just in very-low-birth-weight preterm infants born at 28-32 weeks' gestation, showed both single and repeated course of ACS regimens had shorter intubated ventilation time compared to non-ACS regimen. Single-course ACS promoted the earlier application of amino acid and enteral nutrition, and higher rate of weight increase (15.71; 95%CI 5.54-25.88) than non-ACS after adjusting for potential confounding factors. No associations of repeated course ACS with feeding, mean weight and weight increase rate were observed. CONCLUSIONS: Single-course ACS was positively related to feeding and growth outcomes in very-low-birth-weight preterm infants born at 28-32 weeks' gestation. However, the similar phenomenon was not observed in the repeated course of ACS regimen.

Electric Field-Assisted Orientation of Short Phosphate Glass Fibers on Stainless Steel for Biomedical Applications.

Structural and compositional modifications of metallic implant surfaces are being actively investigated to achieve improved bone-to-implant bonding. In this study, a strategy to modify bulk metallic surfaces by electrophoretic deposition (EPD) of short phosphate glass fibers (sPGF) is presented. Random and aligned orientation of sPGF embedded in a poly(acrylic acid) matrix is achieved by vertical and horizontal EPD, respectively. The influence of EPD parameters on the degree of alignment is investigated to pave the way for the fabrication of highly aligned sPGF structures in large areas. Importantly, the oriented sPGF structure in the coating, owing to the synergistic effects of bioactive composition and fiber orientation, plays an important role in directional cell migration and enhanced proliferation. Moreover, gene expression of MC3T3-E1 cells cultured with different concentrations of sPGF is thoroughly assessed to elucidate the potential stimulating effect of sPGF on osteogenic differentiation. This study represents an innovative exploitation of EPD to develop textured surfaces by orientation of fibers in the macroscale, which shows great potential for directional functionalization of metallic implants.

Bilayered BMP2 Eluting Coatings on Graphene Foam by Electrophoretic Deposition: Electroresponsive BMP2 Release and Enhancement of Osteogenic Differentiation.

Recent development of three-dimensional graphene foam (GF) with conductive and interconnected macroporous structure is attracting particular attention as platforms for tissue engineering. However, widespread application of GF as bone scaffolds is restricted due to its poor mechanical property and inert surface character. To overcome these drawbacks, in this study, a bilayered biopolymer coating was designed and successfully deposited covering the entire surface area of GF skeleton. A poly(lactic-co-glycolic acid) layer was first dip-coated to strengthen the GF substrate, followed by the electrophoretic codeposition of a hybrid layer, consisting of chitosan and BMP2, to functionalize GF with the ability to recruit and induce osteogenic differentiation of hMSC. Our data indicated that the mechanical property of GF was significantly increased without compromising the macroporous structure. Importantly, the immobilized BMP2 exhibited sustained and electroresponsive release profiles with rapid response to the electric field exerted on GF, which is beneficial to balancing BMP2 dose in a physiological environment. Moreover, the osteogenic differentiation of hMSC was significantly improved on the functionalized GF. Taking advantage of the unique macrostructure from GF as well as the superior mechanical properties and BMP2 release profile supported by the deposited coatings, it is therefore expected that the developed GF could be a promising alternative as innovative bone-forming favorable scaffolds.

Geniposide, a novel agonist for GLP-1 receptor, prevents PC12 cells from oxidative damage via MAP kinase pathway.

Alzheimer's disease (AD) is the most common form of dementia. Glucagon-like peptide-1 (GLP-1) gives a new genre in therapeutic targets for intervention in AD with its neurotrophic and neuroprotective functions. In previous work, we identified that geniposide is a novel agonist for GLP-1 receptor, which shows neurotrophic characteristics to induce the neuronal differentiation of PC12 cells. The aim of this study is to determine whether geniposide prevents neurons from oxidative damage, and to explore its signaling pathways. The results demonstrated that geniposide increased the expression of anti-apoptotic proteins, including Bcl-2 and heme oxygenase-1 (HO-1), to antagonize the oxidative damage in PC12 cells induced by hydrogen peroxide. LY294002 (a PI3K inhibitor) inhibited the effect of geniposide increasing of Bcl-2 level by activation of MAPK, MEK and c-Raf phosphorylation in hydrogen peroxide treated PC12 cells. U0126 (a selective inhibitor of MEK) also attenuated the enhancement of geniposide on Bcl-2 level by inhibiting the phosphorylation of p90RSK in the hydrogen peroxide treated PC12 cells. All these data demonstrate that geniposide, an agonist for GLP-1 receptor, regulates expression of anti-oxidative proteins including HO-1 and Bcl-2 by activating the transcriptor of p90RSK via MAPK signaling pathway in PC12 cells.