17ß-estradiol activates SOX6 to balance the anabolism and catabolism via estrogen receptor 2 in chondrocyte.

We investigated the influence of 17ß-estradiol (17ß-E2) on cartilage extracellular matrix (ECM) homeostasis in postmenopausal women. We focused on the roles of estrogen receptors (ESR) and SOX6 in 17ß-E2-mediated stimulation of ECM metabolism during chondrocyte (CH) degeneration. We compared the expression of anabolic genes (collagen II and aggrecan) and catabolic genes (MMPs and TIMPs) in IL-1ß-induced CH degeneration in vitro, with and without 17ß-E2 supplementation. We separately silenced the SOX6, ESR1, and ESR2 genes in CHs to determine their impact on 17ß-E2 treatment. Additionally, we used Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) and luciferase assays to investigate protein-DNA interactions within ESR2 and SOX6-promoter complexes. After three days of IL-1ß treatment, ESR1/2, SOX6, collagen II, aggrecan, and TIMP1/3 were decreased, while MMP3/9/13 were increased. The addition of 17ß-E2 partially reversed these effects, but silencing SOX6, ESR1, or ESR2 weakened the protective effects of 17ß-E2. Silencing ESR2, but not ESR1, abolished the upregulation of SOX6 induced by 17ß-E2. ESR2 was found to bind the SOX6 promoter and regulate SOX6 expression. 17ß-E2 upregulates SOX6 through ESR2 mediation, and the synergistic effect of 17ß-E2 and ESR2 on SOX6 balances ECM metabolism in CHs.

Environmental pollutant risk factors for worse COVID-19 related clinical outcomes in predominately hispanic and latino populations.

BACKGROUND: Per- and poly-fluorinated compounds (PFAS) and heavy metals constitute two classes of environmental exposures with known immunotoxicant effects. In this pilot study, we aimed to evaluate the impact of exposure to heavy metals and PFAS on COVID-19 severity. We hypothesized that elevated plasma-PFAS concentrations and urinary heavy metal concentrations would be associated with increased odds of ICU admission in COVID-19 hospitalized individuals. METHODS: Using the University of Southern California Clinical Translational Sciences Institute (SC-CTSI) biorepository of hospitalized COVID-19 patients, urinary concentrations of 15 heavy metals and urinary creatinine were measured in n = 101 patients and plasma concentrations of 13 PFAS were measured in n = 126 patients. COVID-19 severity was determined based on whether a patient was admitted to the ICU during hospitalization. Associations of metals and PFAS with ICU admission were assessed using logistic regression models, controlling for age, sex, ethnicity, smoking status, and for metals, urinary dilution. RESULTS: The average age of patients was 55 ± 14.2 years. Among SC-CTSI participants with urinary measurement of heavy metals and blood measures of PFAS, 54.5% (n = 61) and 54.8% (n = 80) were admitted to the ICU, respectively. For heavy metals, we observed higher levels of Cd, Cr, and Cu in ICU patients. The strongest associations were with Cadmium (Cd). After accounting for covariates, each 1 SD increase in Cd resulted in a 2.00 (95% CI: 1.10-3.60; p = 0.03) times higher odds of admission to the ICU. When including only Hispanic or Latino participants, the effect estimates between cadmium and ICU admission remained similar. Results for PFAS were less consistent, with perfluorodecanesulfonic acid (PFDS) exhibiting a positive but non-significant association with ICU admission (Odds ratio, 95% CI: 1.50, 0.97-2.20) and perfluorodecanoic acid (PFDA) exhibiting a negative association with ICU admission (0.53, 0.31-0.88). CONCLUSIONS: This study supports the hypothesis that environmental exposures may impact COVID-19 severity.

Exposure to perfluoroalkyl substances and longitudinal changes in bone mineral density in adolescents and young adults: A multi-cohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) may impair bone development in adolescence, which impacts life-long bone health. No previous studies have examined prospective associations of individual PFAS and their mixture with bone mineral density (BMD) changes in Hispanic young persons, a population at high risk of osteoporosis in adulthood. OBJECTIVES: To examine associations of individual PFAS and PFAS mixtures with longitudinal changes in BMD in an adolescent Hispanic cohort and examine generalizability of findings in a mixed-ethnicity young adult cohort (58.4% Hispanic). METHODS: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; n = 304; mean follow-up = 1.4 years) and young adults from the Southern California Children's Health Study (CHS; n = 137; mean follow-up = 4.1 years) were included in this study. Plasma PFAS were measured at baseline and dual x-ray absorptiometry scans were performed at baseline and follow-up to measure BMD. We estimated longitudinal associations between BMD and five PFAS via separate covariate-adjusted linear mixed effects models, and between BMD and the PFAS mixture via quantile g-computation. RESULTS: In SOLAR adolescents, baseline plasma perfluorooctanesulfonic acid (PFOS) was associated with longitudinal changes in BMD. Each doubling of PFOS was associated with an average -0.003 g/cm2 difference in change in trunk BMD per year over follow-up (95% CI: -0.005, -0.0002). Associations with PFOS persisted in CHS young adults, where each doubling of plasma PFOS was associated with an average -0.032 g/cm2 difference in total BMD at baseline (95% CI -0.062, -0.003), though longitudinal associations were non-significant. We did not find associations of other PFAS with BMD; associations of the PFAS mixture with BMD outcomes were primarily negative though non-significant. DISCUSSION: PFOS exposure was associated with lower BMD in adolescence and young adulthood, important periods for bone development, which may have implications on future bone health and risk of osteoporosis in adulthood.

Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans. OBJECTIVE: To investigate associations between PFAS concentrations and miRNA levels in children. METHODS: Data from two distinct cohorts were utilized: 176 participants (average age 16.6 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and 64 participants (average age 6.5 years, 39.1% female) from the Rhea study, a mother-child cohort in Greece. PFAS concentrations and miRNA levels were assessed in plasma samples from both studies. Associations between individual PFAS and plasma miRNA levels were examined after adjusting for covariates. Additionally, the cumulative effects of PFAS mixtures were evaluated using an exposure burden score. Ingenuity Pathways Analysis was employed to identify potential disease functions of PFAS-associated miRNAs. RESULTS: Plasma PFAS concentrations were associated with alterations in 476 miRNAs in the Teen-LABs study and 13 miRNAs in the Rhea study (FDR p < 0.1). Specifically, plasma PFAS concentrations were consistently associated with decreased levels of miR-148b-3p and miR-29a-3p in both cohorts. Pathway analysis indicated that PFAS-related miRNAs were linked to numerous chronic disease pathways, including cardiovascular diseases, inflammatory conditions, and carcinogenesis. CONCLUSION: Through miRNA screenings in two independent cohorts, this study identified both known and novel miRNAs associated with PFAS exposure in children. Pathway analysis revealed the involvement of these miRNAs in several cancer and inflammation-related pathways. Further studies are warranted to enhance our understanding of the relationships between PFAS exposure and disease risks, with miRNA emerging as potential biomarkers and/or mediators in these complex pathways.

The impact of perioperative nonsteroidal anti-inflammatory drugs on the postoperative outcomes of spinal surgery: a meta-analysis of 23 randomized controlled trials.

In recent years, nonsteroidal anti-inflammatory drug (NSAIDs), which are considered to affect the prognosis of spinal surgery, have been widely used in perioperative analgesia in spinal surgery, but the relationship between these two factors remains unclear. The purpose of this study was to explore the effect of perioperative use of NSAIDs on the prognosis of patients treated with spinal surgery. We systematically searched PubMed, Embase, and Cochrane Library for relevant articles published on or before July 14, 2023. We used a random-effect model for the meta-analysis to calculate the standardized mean difference (SMD) with a 95% confidence interval (CI). Sensitivity analyses were conducted to analyze stability. A total of 23 randomized clinical trials including 1457 participants met the inclusion criteria. Meta-analysis showed that NSAIDs were significantly associated with postoperative morphine use (mg) (SMD = -0.90, 95% CI -1.12 to -0.68) and postoperative pain (SMD = -0.71, 95% CI -0.85 to -0.58). These results were further confirmed by the trim-and-fill procedure and leave-one-out sensitivity analyses. The current study shows that perioperative use of NSAIDs appears to be an important factor in reducing postoperative pain and morphine use in patients undergoing spinal surgery. However, well-designed, high-quality randomized controlled trials (RCTs) are still required.

Effects of microplastic contamination on the hydraulic, water retention, and desiccation crack properties of a natural clay exposed to leachate.

Microplastic (MP) can significantly affect soil behaviour and the ecosystem. This paper presents an experimental study to investigate the effects of MP contamination and leachate exposure on the desiccation cracks, hydraulic conductivity, and water retention properties of the natural black clay. The leachate was from a landfill in Australia. The black clay was incorporated with up to 2.0% MPs by weight (w/w) with diverse dimensions and mixed with water/leachate. The measured properties include saturated hydraulic conductivity (ksat), soil-water characteristic curves, moisture evaporation rates, and crack intensity factors. The results suggest that the inclusion of MPs significantly increases ksat, and this increase is more obvious for soils with larger dimensions and contents of MPs, e.g., ksat of the black clay with 2.0% of 500 µm MP increases significantly by 206% (p < 0.05). The black clay exposed to leachate exhibits a slight increase in ksat due to the low viscosity of leachate. The existence of MPs decreases the residual moisture contents and air-entry pressures, and so does the water retention capacity (v/v %) of the black clay. The exposure to leachate increases the air-entry pressures by 6.0%-15.8% of the clay. The evaporation rates increase with the dimensions and concentrations of MPs. The highest evaporation rate (0.96 g/h) can be observed in samples exposed to 2.0% 500 µm MP with water addition. For all samples, the crack intensity factors increase when MP content is between 0.2% and 1.0% and decreases slightly after that. After being exposed to leachate, the evaporation rates and crack intensity factors of the black clay are decreased by 2.4%-12.6% and 3.6%-13.7%, respectively.

Application of Reverse Docking in the Research of Small Molecule Drugs and Traditional Chinese Medicine.

With the development of structural biology and data mining, computer-aided drug design (CADD) has been playing an important role in all aspects of new drug development. Reverse docking, a method of virtual screening based on molecular docking in CADD, is widely used in drug repositioning, drug rescue, and traditional Chinese medicine (TCM) research, for it can search for macromolecular targets that can bind to a given ligand molecule. This review revealed the principle of reverse docking, summarized common target protein databases and docking procedures, and enumerated the applications of reverse docking in drug repositioning, adverse drug reactions, traditional Chinese medicine, and coronavirus disease 2019 (COVID-19) treatment. Hope our work can give some inspiration to researchers engaged in drug development.

[Anti-tumor target prediction and activity verification of Ganoderma lucidum triterpenoids].

It has reported that Ganoderma lucidum triterpenoids had anti-tumor activity. However, the anti-tumor target is still unclear. The present study was designed to investigate the anti-tumor activity of G. lucidum triterpenoids on different tumor cells, and predict their potential targets by virtual screening. In this experiment, molecular docking was used to simulate the interactions of 26 triterpenoids isolated from G. lucidum and 11 target proteins by LibDock module of Discovery Studio2016 software, then the anti-tumor targets of triterpenoids were predicted. In addition, the in vitro anti-tumor effects of triterpenoids were evaluated by MTT assay by determining the inhibition of proliferation in 5 tumor cell lines. The docking results showed that the poses were greater than five, and Libdock Scores higher than 100, which can be used to determine whether compounds were activity. Eight triterpenoids might have anti-tumor activity as a result of good docking, five of which had multiple targets. MTT experiments demonstrated that the ganoderic acid Y had a certain inhibitory activity on lung cancer cell H460, with IC50 of 22.4 µmol•L ⁻¹, followed by 7-oxo-ganoderic acid Z2, with IC50 of 43.1 µmol•L ⁻¹. However, the other triterpenoids had no anti-tumor activity in the detected tumor cell lines. Taking together, molecular docking approach established here can be used for preliminary screening of anti-tumor activity of G.lucidum ingredients. Through this screening method, combined with the MTT assay, we can conclude that ganoderic acid Y had antitumor activity, especially anti-lung cancer, and 7-oxo-ganoderic acid Z2 as well as ganoderon B, to a certain extent, had anti-tumor activity. These findings can provide basis for the development of anti-tumor drugs. However, the anti-tumor mechanisms need to be further studied.

Serum Interleukin-34 Levels Are Elevated in Patients with Systemic Lupus Erythematosus.

Interleukin-34 (IL-34) was initially identified as an alternative ligand for the colony-stimulating factor-1 receptor (CSF-1R) to mediate the biology of mononuclear phagocytic cells. Recently, IL-34 was found to be associated with chronic inflammation, such as in rheumatoid arthritis (RA). Both RA and systemic lupus erythematosus (SLE) are multifactorial autoimmune diseases and are characterized by excessive immune and inflammatory responses. Thus, we investigated whether IL-34 is involved in the pathogenesis of SLE. In all, 78 SLE patients and 53 healthy controls were enrolled in the research. Enzyme-linked immunosorbent assay (ELISA) was employed to measure the concentrations of serological IL-34. Then serum IL-34 levels between the SLE group and healthy controls were analyzed by the Mann-Whitney U test. Meanwhile, the correlations between the serum IL-34 levels and disease activity indexes and other established serum markers were assessed. Furthermore, the serum IL-34 levels of 20 active SLE patients were reevaluated when diseases were in the remission stage from corticosteroids or immunosuppressive drugs. Serum IL-34 levels were significantly higher in SLE patients compared to healthy controls. Their levels were remarkably associated with accumulation of the clinical features of SLE. Additionally, IL-34 titers were positively correlated with the SLE disease activity indexes, anti-double-stranded DNA antibody (anti-dsDNA) titers and C-reactive protein (CRP) levels, and inversely with complement3 (C3) levels. Moreover, serum IL-34 levels were significantly decreased after successful treatment of SLE. Serum IL-34 could be a candidate biomarker for SLE as there are elevated serum levels in treatment-naive SLE patients and we saw a significant decrease after effective treatment.

Circulating IL-27 Is Elevated in Rheumatoid Arthritis Patients.

Cytokines are key immunoregulatory molecules that regulate T lymphocyte-mediated immune responses and inflammatory reactions. We determined whether there is aberrant expression of interleukin-27 (IL-27) in rheumatoid arthritis (RA) patients and investigated the clinical significance of these changes. IL-27 is a key cellular factor that regulates the differentiation of CD4+ T cells, which can secrete interleukin-10 (IL-10) and interleukin-17 (IL-17) in vivo. Concentrations of serum IL-27 in 67 RA patients, and 36 sex- and age-matched control subjects were measured by enzyme-linked immunosorbent assay (ELISA). Results showed that concentrations of serum IL-27 in all RA patients were significantly higher than in healthy control subjects, and there was a significant and positive correlation between serum IL-27 levels and disease activity in all RA patients. Levels of serum IL-27 in RA patients were significantly correlated with disease activity score in 28 joints (DAS28). Moreover, immunosuppressive treatment with leflunomide downregulated the levels of IL-27 in active RA patients. Therefore, the elevated production of circulating T cell inflammatory factors contributes to the pathogenesis of RA, and serum IL-27 could potentially serve as a new biomarker of RA disease activity.

Mechanical performance and water resistance of biochar admixture lightweight magnesium oxychloride cement.

The applications of magnesium oxychloride cement (MOC) have been extensively studied recently due to its eco-friendly and high-strength nature. However, one of the significant limitations of MOC is its poor water resistance. To address this limitation, this study explored the prospect of incorporating biochar particles (up to 25 % of the dry mass of MgO) to form lightweight MOC with improved water resistance. The compressive (fc) and flexural (ff) strengths were investigated after 28-day curing and under 56-day water attack. The fc of MOC after immersion was determined under both wet (directly after immersion) and dry (air-dried to constant weights) conditions. The results indicated that the inclusion of 5 % and 10 % biochar increased the 28-day fc, while the addition of biochar decreased ff regardless of its dosage. Microscopic examination uncovered that the increase in strength resulted from the promoted production of phase 5 (5 Mg(OH)2·MgCl2·8H2O) and the reduction in unreacted MgO. The inclusion of 5 % and 10 % biochar increased the compressive and flexural strength retention ratios after 56-day immersion. The ff with 5 % biochar inclusion after immersion was higher compared to that of pure MOC. Moreover, the inclusion of biochar had minimal effects on the thermal degradation of MOC. The above results suggest that biochar can be a potential additive to enhance the mechanical behaviour and water resistance of MOC. As fc of immersed MOC increased during air-drying, a new equation was developed to describe variations in fc of MOC subject to different degrees of saturation during drying.

Advances of LiCoO2 in Cathode of Aqueous Lithium-Ion Batteries.

Aqueous lithium-ion batteries offer promising advantages such as low cost, enhanced safety, high rate capability, and the ability to deliver considerable capacity at 1.8 V, making them ideal candidates for large-scale reserve power sources for renewable energy. However, the practical application of aqueous lithium-ion batteries has been hindered by the poor cycle stability of layered cathode materials, including LiCoO2, in neutral aqueous electrolytes. This review examines the working principles, material limitations, and research progress of aqueous lithium-ion batteries. The types and characteristics of materials used in the cathode of aqueous lithium-ion batteries are summarized, with a primary focus on the attenuation mechanisms of LiCoO2 when used as the cathode material in aqueous electrolytes. Furthermore, this review explores the advancements in utilizing LiCoO2 in the cathode of aqueous lithium-ion batteries, as well as the combination with machine learning. By addressing these critical aspects, this review aims to provide a comprehensive understanding of aqueous lithium-ion batteries and shed light on future development and application prospects.

Ultrasonic cavitation: Tackling organic pollutants in wastewater.

Environmental pollution and energy shortages are global issues that significantly impact human progress. Multiple methods have been proposed for treating industrial and dyes containing wastewater. Ultrasonic degradation has emerged as a promising and innovative technology for organic pollutant degradation. This study provides a comprehensive overview of the factors affecting ultrasonic degradation and thoroughly examines the technique of acoustic cavitation. Furthermore, this study summarizes the fundamental theories and mechanisms underlying cavitation, emphasizing its efficacy in the remediation of various water pollutants. Furthermore, potential synergies between ultrasonic cavitation and other commonly used technologies are also explored. Potential challenges are identified and future directions for the development of ultrasonic degradation and ultrasonic cavitation technologies are outlined.

The impact of perioperative opioid use on postoperative outcomes following spinal surgery: a meta-analysis of 60 cohort studies with 13 million participants.

BACKGROUND CONTEXT: An important factor for the prognosis of spinal surgery is the perioperative use of opioids. However, the relationship is not clear. PURPOSE: The purpose of this study was to evaluate the effect of perioperative opioid use on the prognosis of patients following spinal surgery. STUDY DESIGN/SETTING: Systematic review and meta-analysis. OUTCOME MEASURES: A meta-analysis was conducted using the random-effects method to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). METHODS: The PubMed, Embase, and Cochrane Library databases were systematically searched to find relevant articles that were published until September 2, 2022. The primary outcome was prolonged postoperative opioid use, and secondary outcomes included the length of stay (LOS), reoperation, the time to return to work (RTW), postoperative complications, gastrointestinal complications, new permanent disability, central nervous system events and infection. In addition, subgroup analysis of the primary outcome was conducted to explore the main sources of heterogeneity, and sensitivity analysis of all outcomes was performed to evaluate the stability of the results. RESULTS: A total of 60 cohort studies involving 13,219,228 individuals met the inclusion criteria. Meta-analysis showed that perioperative opioid use was specifically related to prolonged postoperative opioid use (OR 6.91, 95% CI 6.09 to 7.84, p<.01). Furthermore, the results also showed that perioperative opioid use was significantly associated with prolonged LOS (OR 1.74, 95% CI 1.39 to 2.18, p<.01), postoperative complications (OR 1.72, 95% CI 1.26 to 2.36, p<.01), reoperation (OR 2.38, 95% CI 1.85 to 3.07, p<.01), the time to RTW (OR 0.45, 95% CI 0.39 to 0.52, p<.01), gastrointestinal complications (OR 1.39, 95% CI 1.30 to 1.48, p<.01), central nervous system events (OR 1.99, 95% CI 1.21 to 3.27, p=.07) and infection (OR 1.22, 95% CI 1.09 to 1.36, p=.01). These results were corroborated by the trim-and-fill procedure and leave-one-out sensitivity analyses. CONCLUSIONS: Based on the current evidence, patients with perioperative opioid use, in comparison to controls, appear to have prolonged postoperative opioid use, which may increase the risk of poor outcomes including prolonged LOS, complications, reoperation, RTW and so on. However, these results must be carefully interpreted as the number of studies included was small and the studies were statistically heterogeneous. These findings may help clinicians to realize the harmfulness of perioperative use of opioids, reduce the use of prescription opioids, necessarily withdraw before operation or significantly wean to the lowest tolerable preoperative amount, and provide some inspiration for standardizing the use of opioids in the future.

Transparent Cellulose/Multi-Walled Carbon Nanotube Hybrids with Improved Ultraviolet-Shielding Properties Prepared from Cotton Textile Waste.

Plastics offer many advantages and are widely used in various fields. Nevertheless, most plastics derived from petroleum are slow to degrade due to their stable polymer structure, posing serious threats to organisms and ecosystems. Thus, developing environmentally friendly and biodegradable plastics is imperative. In this study, biodegradable cellulose/multi-walled carbon nanotube (MCNT) hybrid gels and films with improved ultraviolet-shielding properties were successfully prepared using cotton textile waste as a resource. It was proven that MCNTs can be dispersed evenly in cellulose without any chemical or physical pretreatment. It was found that the contents of MCNTs had obvious effects on the structures and properties of hybrid films. Particularly, the averaged transmittance of cellulose/MCNT composite films in the range of 320-400 nm (T320-400) and 290-320 nm (T290-320) can be as low as 19.91% and 16.09%, when the content of MCNTs was 4.0%, much lower than those of pure cellulose films (T320-400: 84.12% and T290-320: 80.03%). Meanwhile, the water contact angles of the cellulose/MCNT films were increased by increasing the content of MCNTs. Most importantly, the mechanical performance of cellulose/MCNT films could be controlled by the additives of glycerol and MCNTs. The tensile strength of the cellulose/MCNT films was able to reach as high as 20.58 MPa, while the elongation at break was about 31.35%. To summarize, transparent cellulose/MCNT composites with enhanced ultraviolet-shielding properties can be manufactured successfully from low-cost cotton textile waste, which is beneficial not only in terms of environmental protection, but also the utilization of natural resources.

Associations of dietary intake and longitudinal measures of per- and polyfluoroalkyl substances (PFAS) in predominantly Hispanic young Adults: A multicohort study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are pollutants linked to adverse health effects. Diet is an important source of PFAS exposure, yet it is unknown how diet impacts longitudinal PFAS levels. OBJECTIVE: To determine if dietary intake and food sources were associated with changes in blood PFAS concentrations among Hispanic young adults at risk of metabolic diseases. METHODS: Predominantly Hispanic young adults from the Children's Health Study who underwent two visits (CHS; n = 123) and young adults from NHANES 2013-2018 who underwent one visit (n = 604) were included. Dietary data at baseline was collected using two 24-hour dietary recalls to measure individual foods and where foods were prepared/consumed (home/restaurant/fast-food). PFAS were measured in blood at both visits in CHS and cross-sectionally in NHANES. In CHS, multiple linear regression assessed associations of baseline diet with longitudinal PFAS; in NHANES, linear regression was used. RESULTS: In CHS, all PFAS except PFDA decreased across visits (all p < 0.05). In CHS, A 1-serving higher tea intake was associated with 24.8 %, 16.17 %, and 12.6 % higher PFHxS, PFHpS, and PFNA at follow-up, respectively (all p < 0.05). A 1-serving higher pork intake was associated with 13.4 % higher PFOA at follow-up (p < 0.05). Associations were similar in NHANES, including unsweetened tea, hot dogs, and processed meats. For food sources, in CHS each 200-gram increase in home-prepared food was associated with 0.90 % and 1.6 % lower PFOS at baseline and follow-up, respectively, and in NHANES was associated with 0.9 % lower PFDA (all p < 0.05). CONCLUSION: Results suggest that beverage consumption habits and food preparation are associated with differences in PFAS levels in young adults. This highlights the importance of diet in determining PFAS exposure and the necessity of public monitoring of foods and beverages for PFAS contamination.

Postprandial Metabolite Profiles and Risk of Prediabetes in Young People: A Longitudinal Multicohort Study.

OBJECTIVE: Prediabetes in young people is an emerging epidemic that disproportionately impacts Hispanic populations. We aimed to develop a metabolite-based prediction model for prediabetes in young people with overweight/obesity at risk for type 2 diabetes. RESEARCH DESIGN AND METHODS: In independent, prospective cohorts of Hispanic youth (discovery; n = 143 without baseline prediabetes) and predominately Hispanic young adults (validation; n = 56 without baseline prediabetes), we assessed prediabetes via 2-h oral glucose tolerance tests. Baseline metabolite levels were measured in plasma from a 2-h postglucose challenge. In the discovery cohort, least absolute shrinkage and selection operator regression with a stability selection procedure was used to identify robust predictive metabolites for prediabetes. Predictive performance was evaluated in the discovery and validation cohorts using logistic regression. RESULTS: Two metabolites (allylphenol sulfate and caprylic acid) were found to predict prediabetes beyond known risk factors, including sex, BMI, age, ethnicity, fasting/2-h glucose, total cholesterol, and triglycerides. In the discovery cohort, the area under the receiver operator characteristic curve (AUC) of the model with metabolites and known risk factors was 0.80 (95% CI 0.72-0.87), which was higher than the risk factor-only model (AUC 0.63 [0.53-0.73]; P = 0.001). When the predictive models developed in the discovery cohort were applied to the replication cohort, the model with metabolites and risk factors predicted prediabetes more accurately (AUC 0.70 [95% CI 40.55-0.86]) than the same model without metabolites (AUC 0.62 [0.46-0.79]). CONCLUSIONS: Metabolite profiles may help improve prediabetes prediction compared with traditional risk factors. Findings suggest that medium-chain fatty acids and phytochemicals are early indicators of prediabetes in high-risk youth.

PFHpA alters lipid metabolism and increases the risk of metabolic dysfunction-associated steatotic liver disease in youth-a translational research framework.

To address the growing epidemic of liver disease, particularly in pediatric populations, it is crucial to identify modifiable risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous chemicals and have emerged as potential risk factors for liver damage. However, their impact on the etiology and severity of MASLD remains largely unexplored in humans. This study aims to bridge the gap between human and in vitro studies to understand how exposure to perfluoroheptanoic acid (PFHpA), one of the emerging PFAS replacements which accumulates in high concentrations in the liver, contributes to MASLD risk and progression. First, we showed that PFHpA plasma concentrations were significantly associated with increased risk of MASLD in obese adolescents. Further, we examined the impact of PFHpA on hepatic metabolism using 3D human liver spheroids and single-cell transcriptomics to identify major hepatic pathways affected by PFHpA. Next, we integrated the in vivo and in vitro multi-omics datasets with a novel statistical approach which identified signatures of proteins and metabolites associated with MASLD development triggered by PFHpA exposure. In addition to characterizing the contribution of PFHpA to MASLD progression, our study provides a novel strategy to identify individuals at high risk of PFHpA-induced MASLD and develop early intervention strategies. Notably, our analysis revealed that the proteomic signature exhibited a stronger correlation between both PFHpA exposure and MASLD risk compared to the metabolomic signature. While establishing a clear connection between PFHpA exposure and MASLD progression in humans, our study delved into the molecular mechanisms through which PFHpA disrupts liver metabolism. Our in vitro findings revealed that PFHpA primarily impacts lipid metabolism, leading to a notable increase of lipid accumulation in human hepatocytes after PFHpA exposure. Among the pathways involved in lipid metabolism in hepatocytes, regulation of lipid metabolism by PPAR-a showed a remarkable activation. Moreover, the translational research framework we developed by integrating human and in vitro data provided us biomarkers to identify individuals at a high risk of MASLD due to PFHpA exposure. Our framework can inform policies on PFAS-induced liver disease and identify potential targets for prevention and treatment strategies.

Exposure to 4,4'-DDE in visceral adipose tissue and weight loss in adolescents from the Teen-LABS cohort.

OBJECTIVE: Dichlorodiphenyldichloroethylene (DDE), an obesogen accumulating in adipose tissue, is released into circulation with weight loss, although its impact is underexplored among adolescents. We tested the association using an integrative translational approach of epidemiological analysis among adolescents with obesity and in vitro measures exploring the impact of DDE on adipogenesis via preadipocytes. METHODS: We included 63 participants from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort. We assessed 4,4'-DDE in visceral adipose tissue at surgery and BMI and waist circumference at surgery and 0.5, 1, 3, and 5 years after. We conducted longitudinal analysis to estimate the interaction on weight loss between DDE and time since surgery. In vitro analysis quantified adipogenic differentiation in commercial human preadipocytes exposed to 4,4'-DDE via fluorescent staining and imaging. RESULTS: A dose-response relationship was observed, with the low-exposure group having a greater reduction in BMI during the first year compared to higher-exposure groups and showing smaller regains compared to higher-exposure groups after the first year. In vitro analysis of preadipocytes treated with 4,4'-DDE during adipogenic differentiation for 12 days showed a concentration-dependent increase in lipid accumulation. CONCLUSIONS: DDE could contribute to weight trajectory among adolescents undergoing bariatric surgery, potentially mediated via promoted adipogenesis in preadipocytes.

Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in children and adolescents. NAFLD ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), wherein hepatocellular inflammation and/or fibrosis coexist with steatosis. Circulating microRNA (miRNA) levels have been suggested to be altered in NAFLD, but the extent to which miRNA are related to NAFLD features remains unknown. This analysis tested the hypothesis that plasma miRNAs are significantly associated with histological features of NAFLD in adolescents. AIM: To investigate the relationship between plasma miRNA expression and NAFLD features among adolescents with NAFLD. METHODS: This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery study. Intra-operative core liver biopsies were collected from participants and used to characterize histological features of NAFLD. Plasma samples were collected during surgery for miRNA profiling. A total of 843 plasma miRNAs were profiled using the HTG EdgeSeq platform. We examined associations of plasma miRNAs and NAFLD features using logistic regression after adjusting for age, sex, race, and other key covariates. Ingenuity Pathways Analysis was used to identify biological functions of miRNAs that were associated with multiple histological features of NAFLD. RESULTS: We identified 16 upregulated plasma miRNAs, including miR-193a-5p and miR-193b-5p, and 22 downregulated plasma miRNAs, including miR-1282 and miR-6734-5p, in adolescents with NAFLD. Moreover, 52, 16, 15, and 9 plasma miRNAs were associated with NASH, fibrosis, ballooning degeneration, and lobular inflammation, respectively. Collectively, 16 miRNAs were associated with two or more histological features of NAFLD. Among those miRNAs, miR-411-5p was downregulated in NASH, ballooning, and fibrosis, while miR-122-5p, miR-1343-5p, miR-193a-5p, miR-193b-5p, and miR-7845-5p were consistently and positively associated with all histological features of NAFLD. Pathway analysis revealed that most common pathways of miRNAs associated with multiple NAFLD features have been associated with tumor progression, while we also identified linkages between miR-122-5p and hepatitis C virus and between miR-199b-5p and chronic hepatitis B. CONCLUSION: Plasma miRNAs were associated with NAFLD features in adolescent with severe obesity. Larger studies with more heterogeneous NAFLD phenotypes are needed to evaluate miRNAs as potential biomarkers of NAFLD.