Protective role of TRPV2 in synaptic plasticity through the ERK1/2-CREB-BDNF pathway in chronic unpredictable mild stress rats.

PURPOSE: Chronic stress is a significant risk factor for mood disorders such as depression, where synaptic plasticity plays a central role in pathogenesis. Transient Receptor Potential Vanilloid Type-2 (TRPV2) Ion Channels are implicated in hypothalamic-pituitary-adrenal axis disorders. Previous proteomic analysis indicated a reduction in TRPV2 levels in the chronic unpredictable mild stress (CUMS) rat model, yet its role in synaptic plasticity during depression remains to be elucidated. This study aims to investigate TRPV2's role in depression and its underlying mechanisms. METHODS: In vivo and in vitro experiments were conducted using the TRPV2-specific agonist probenecid and ERK1/2 inhibitors SCH772984. In vivo, rats underwent six weeks of CUMS before probenecid administration. Depressive-like behaviors were assessed through behavioral tests. ELISA kits measured 5-HT, DA, NE levels in rat hippocampal tissues. Hippocampal morphology was examined via Nissl staining. In vitro, rat hippocampal neuron cell lines were treated with ERK1/2 inhibitors SCH772984 and probenecid. Western blot, immunofluorescence, immunohistochemical staining, and RT-qPCR assessed TRPV2 expression, neurogenesis-related proteins, synaptic markers, and ERK1/2-CREB-BDNF signaling proteins. RESULTS: Decreased hippocampal TRPV2 levels were observed in CUMS rats. Probenecid treatment mitigated depressive-like behavior and enhanced hippocampal 5-HT, NE, and DA levels in CUMS rats. TRPV2 activation countered CUMS-induced synaptic plasticity inhibition. Probenecid activated the ERK1/2-CREB-BDNF pathway, suggesting TRPV2's involvement in this pathway via ERK1/2. CONCLUSION: These findings indicate that TRPV2 activation offers protective effects against depressive-like behaviors and enhances hippocampal synaptic plasticity in CUMS rats via the ERK1/2-CREB-BDNF pathway. TRPV2 emerges as a potential therapeutic target for depression.

Relationship between metabolic status, physical activity and cardiovascular disease in participants with obesity.

OBJECTIVE: We aimed to investigate the independent and joint associations between metabolic status, PA (physical activity) and risk of CVD (cardiovascular disease) in participants with obesity. METHODS: We included 109,301 adults with obesity free of baseline CVD enrolled from 2006 to 2010 in the UK Biobank cohort (aged 56 ± 7.9 years). Based on metabolic status, obesity was grouped into metabolically healthy obesity (MHO; free of hypertension, hypercholesterolemia and diabetes; n = 26,989; BMI 33 ± 3.3 kg/m2) and metabolically unhealthy obesity (MUO; n = 82,312; BMI 34 ± 4.0 kg/m2). PA was categorized into four groups according to moderate-to-vigorous PA (MVPA): none, low, medium, and high. Multivariable Cox regression models were used for the main analyses adjusting for sociodemographic factors, lifestyles and comorbidities. RESULTS: There were 8,059 CVD events during a median follow-up of 8.1 years. MHO was associated with a 42% reduced risk of CVD compared with MUO (HR = 0.58, 95% CI: 0.53-0.63). A significant interaction effect between PA and metabolic status on CVD risk was found. Among MUO participants, individuals with PA had significantly decreased CVD risk when compared with no MVPA (HR = 0.87, 95% CI: 0.81-0.94 for low PA; HR = 0.85, 95% CI: 0.78-0.93 for medium PA; and HR = 0.86, 95% CI: 0.80-0.92 for high PA). The lowest CVD risk was observed in MHO & medium PA group when compared with MUO & no MVPA (HR = 0.45, 95% CI: 0.37-0.56). CONCLUSIONS: Both MHO and any MVPA were associated with reduced risk of CVD in adults with obesity, while PA could modify the relationship between metabolic status and CVD risk.

Relationship between trajectories of dietary iron intake and risk of type 2 diabetes mellitus: evidence from a prospective cohort study.

BACKGROUND: The association between dietary iron intake and the risk of type 2 diabetes mellitus (T2DM) remains inconsistent. In this study, we aimed to investigate the relationship between trajectories of dietary iron intake and risk of T2DM. METHODS: This study comprised a total of 61,115 participants without a prior T2DM from the UK Biobank database. We used the group-based trajectory model (GBTM) to identify different dietary iron intake trajectories. Cox proportional hazards models were used to evaluate the relationship between trajectories of dietary iron intake and risk of T2DM. RESULTS: During a mean follow-up of 4.8 years, a total of 677 T2DM events were observed. Four trajectory groups of dietary iron intake were characterized by the GBTM: trajectory group 1 (with a mean dietary iron intake of 10.9 mg/day), 2 (12.3 mg/day), 3 (14.1 mg/day) and 4 (17.6 mg/day). Trajectory group 3 was significantly associated with a 38% decreased risk of T2DM when compared with trajectory group 1 (hazard ratio [HR] = 0.62, 95% confidence interval [CI]: 0.49-0.79), while group 4 was significantly related with a 30% risk reduction (HR = 0.70, 95% CI: 0.54-0.91). Significant effect modifications by obesity (p = 0.04) and history of cardiovascular disease (p < 0.01) were found to the relationship between trajectories of dietary iron intake and the risk of T2DM. CONCLUSIONS: We found that trajectories of dietary iron intake were significantly associated with the risk of T2DM, where the lowest T2DM risk was observed in trajectory group 3 with a mean iron intake of 14.1 mg/day. These findings may highlight the importance of adequate dietary iron intake to the T2DM prevention from a public health perspective. Further studies to assess the relationship between dietary iron intake and risk of T2DM are needed, as well as intervention studies to mitigate the risks of T2DM associated with dietary iron changes.

Relationship between obesity severity, metabolic status and cardiovascular disease in obese adults.

BACKGROUND: Evidence about the associations between obesity severity, metabolic status and risk of incident cardiovascular disease (CVD) in adults with obesity remains limited. METHODS: The study included 109,301 adults with obesity free of prior CVD based on the UK Biobank cohort. Metabolic status was categorized into metabolically healthy obesity (MHO; free of hypertension, hypercholesterolemia and diabetes) and metabolically unhealthy obesity (MUO). Obesity severity was classified into three levels: class I (body mass index of 30.0-34.9 kg/m2 ), II (35.0-39.9) and III (≥40.0). Cox proportional hazards models were used for analyses. RESULTS: There were 8059 incident CVD events during a median follow-up of 8.1 years. MUO was significantly associated with a 74% increased CVD risk compared with MHO (HR = 1.74, 95% CI: 1.62-1.83). There was a significant interaction between obesity severity and metabolic status on an additive scale regarding CVD risk. When taking class I obesity as reference, class II was nonsignificantly associated with an increased risk of CVD in the MHO group (HR = 1.07, 95% CI: 0.90-1.27), while class III was significantly related to increased risks of CVD (HR = 1.48, 95% CI: 1.12-1.96). In the MUO group, both classes II and III were significantly related to increased risks of CVD. Significant subgroup effects of age (p = .009) and sex (p = .047) were observed among participants with MUO but not in the MHO group. CONCLUSIONS: Both elevated obesity severity and MUO were significantly associated with increased risks of CVD in adults with obesity, while metabolic status could modify the relationship between obesity severity and CVD risk. More research is needed to further clarify the relationship.

Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder.

Major depressive disorder (MDD) refers to a widespread psychiatric disorder. Astrocytes play a pivotal role in regulating inflammation which is a well-acknowledged key component in depression pathogenesis. However, the effects of the neuroinflammation-inducing A1-like astrocytes on MDD are still unknown. TWIK-related K+ channel 1 (TREK-1) has been demonstrated to regulate the action of antidepressants. Nevertheless, its mechanisms and effects on A1-like astrocyte stimulation in MDD are not clear. Therefore, we conducted in vivo and in vitro experiments using TREK-1 specific inhibitor spadin. In vivo, rats were subjected to a 6-week chronic unpredictable mild stress (CUMS) followed by spadin treatment. Behavioral tests were employed to surveil depressive-like behaviors. Hippocampal proteomic analysis was carried out with the purpose of identifying differentially expressed proteins after CUMS and spadin treatments. In vitro, astrocyte-conditioned medium and spadin were used to treat rat astrocyte cell line. The activated microglia, inflammatory factors, A1 astrocyte markers, and activated nuclear factor kappa B (NF-κB) pathway were later analyzed using immunofluorescence, western blot, and RT-qPCR. Our findings indicated that blockage of TREK-1 reduced CUMS-induced depressive-like behavior in rats, inhibited the microglial stimulation, reduced inflammatory factor levels, and suppressed the activation of A1-like reactive astrocytes in the hippocampus. We also verified that the suppression of A1-like astrocytes by spadin necessitated the NF-κB pathway. According to the findings, blocking TREK-1 inhibited the activation of A1-like reactive astrocytes via the NF-κB signaling pathway in MDD. Our study preliminarily identifies a novel antidepressant mechanism of TREK-1 action and provides a therapeutic path for MDD.

Reversible Single-Crystal-to-Single-Crystal Transformations between Nanoscale 2D Nanosheets and 3D Metal-Organic Frameworks.

Single-crystal-to-single-crystal (SCSC) transformations provide more possibilities for phase transitions, which have attracted great attention in crystal engineering. In this paper, we report a series of reversible SCSC transformations between nanoscale two-dimensional layered double hydroxide (LDH) crystals and three-dimensional metal-organic framework crystals. They can proceed not only in solution systems but also on the surface of solid-state polyacrylonitrile films and fibers. Specifically, reversible SCSC transformations can be carried out between nanoscale ZIF-67 and Co-LDH. The Co-LDH nanomaterials displayed excellent oxygen evolution reaction performance. This work has good universality and scalability, which provides a novel avenue for the synthesis of crystal materials and is of great significance for the recycling of resources.

A Zn-based catalyst with high oxygen reduction activity and anti-poisoning property for stable seawater batteries.

Seawater batteries (SWBs) are a key part of the future underwater energy network for maritime safety and resource development due to their high safety, long lifespan, and eco-friendly nature. However, the complicated seawater composition and pollution, such as the S2-, usually poison the catalyst and lead to the degradation of the battery performance. Here, Zn single-atom catalysts (SACs) were demonstrated as effective oxygen reduction reaction catalysts with high anti-poisoning properties by density functional theory calculation and the Zn SACs anchoring on an N, P-doped carbon substrate (Zn-SAC@PNC) was synthesized by a one-pot strategy. Zinc active sites ensure the anti-poisoning property toward S2-, and N, P-doped carbon helps improve the activity. Therefore, Zn-SAC@PNC exhibits superior activity (E1/2: 0.87 V, Tafel slope: 69.5 mV dec-1) compared with Pt/C and shows a lower decay rate of the voltage after discharge in lean-oxygen natural seawater. In the presence of S2-, Zn-SAC@PNC can still maintain its original catalytic activity, which ensures the stable operation of SWBs in the marine environment with sulfur-based pollutants. This study provides a new strategy to design and develop efficient cathode materials for SWBs.

Utility of the pediatric liver contrast-enhanced ultrasound criteria in differentiating malignant and benign multifocal lesions.

BACKGROUND: The pediatric liver contrast-enhanced ultrasound (CEUS) criteria were developed to improve the diagnostic performance of CEUS in differentiating pediatric benign and malignant liver lesions. However, the diagnostic performance of CEUS in the evaluation of multiple focal liver lesions in the pediatric population has not yet been fully evaluated. OBJECTIVE: To evaluate the diagnostic performance of the pediatric liver CEUS criteria in differentiating benign and malignant multifocal liver lesions in children. MATERIALS AND METHODS: From April 2017 to September 2022, the CEUS characteristics of multifocal liver lesions in patients < 18 years were analyzed. Lesions classified as CEUS-1, CEUS-2 or CEUS-3 were considered benign and lesions classified as CEUS-4 or CEUS-5 were considered malignant. The diagnostic performance of the pediatric liver CEUS criteria (i.e. sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV] and accuracy) was assessed. RESULTS: After exclusion, 21 patients (median age, 36.0 months; range, 1.0-204 months; 7 boys) were included. There were significant differences in the serum alpha fetoprotein level (P= 0.039) and the presence of washout (P < 0.001) between children with malignant and benign lesions. The sensitivity, specificity, PPV, NPV and accuracy of the pediatric liver CEUS criteria were 100.0% (10/10), 90.9% (10/11), 90.9% (10/11), 100.0% (10/10) and 95.2% (20/21), respectively. CONCLUSION: The pediatric liver CEUS criteria had excellent diagnostic performance in differentiating benign and malignant multifocal liver lesions in children.

Highly Efficient Selective Hydrogenation of Cinnamaldehyde to Cinnamyl Alcohol over CoRe/TiO2 Catalyst.

Allylic alcohols typically produced through selective hydrogenation of α,ß-unsaturated aldehydes are important intermediates in fine chemical industry, but it is still a challenge to achieve its high selectivity transformation. Herein, we report a series of TiO2-supported CoRe bimetallic catalysts for the selective hydrogenation of cinnamaldehyde (CAL) to cinnamyl alcohol (COL) using formic acid (FA) as a hydrogen donor. The resultant catalyst with the optimized Co/Re ratio of 1:1 can achieve an exceptional COL selectivity of 89% with a CAL conversion of 99% under mild conditions of 140 °C for 4 h, and the catalyst can be reused four times without loss of activity. Meanwhile, the Co1Re1/TiO2/FA system was efficient for the selective hydrogenation of various α,ß-unsaturated aldehydes to the corresponding α,ß-unsaturated alcohols. The presence of ReOx on the Co1Re1/TiO2 catalyst surface was advantageous to the adsorption of C=O, and the ultrafine Co nanoparticles provided abundant hydrogenation active sites for the selective hydrogenation. Moreover, FA as a hydrogen donor improved the selectivity to α,ß-unsaturated alcohols.

A Self-Deoxidizing Electrolyte Additive Enables Highly Stable Aqueous Zinc Batteries.

In aqueous zinc (Zn) batteries, the Zn anode suffers from severe corrosion reactions and consequent dendrite growth troubles that cause fast performance decay. Herein, we uncover the corrosion mechanism and confirm that the dissolved oxygen (DO) other than the reputed proton is a principal origin of Zn corrosion and by-product precipitates, especially during the initial battery resting period. In a break from common physical deoxygenation methods, we propose a chemical self-deoxygenation strategy to tackle the DO-induced hazards. As a proof of concept, sodium anthraquinone-2-sulfonate (AQS) is introduced to aqueous electrolytes as a self-deoxidizing additive. As a result, the Zn anode sustains a long-term cycling of 2500 h at 0.5 mA cm-2 and over 1100 h at 5 mA cm-2 together with a high Coulombic efficiency up to 99.6 %. The full cells also show a high capacity retention of 92 % after 500 cycles. Our findings provide a renewed understanding of Zn corrosion in aqueous electrolytes and also a practical solution towards industrializing aqueous Zn batteries.

Relationship between glucosamine use and the risk of lung cancer: data from a nationwide prospective cohort study.

BACKGROUND: Research on glucosamine shows anti-inflammatory and anti-cancer benefits with minimal adverse effects. We aimed to explore the relationship between use of glucosamine and risk of lung cancer and lung cancer mortality based on data from the large-scale nationwide prospective UK Biobank cohort study. METHODS: Participants were enrolled between 2006 and 2010 and followed-up to 2020. The Cox proportional hazards model was used to assess the relationship between glucosamine use and risk of lung cancer and lung cancer mortality. Subgroup analyses and sensitivity analyses were performed to explore the potential effect modifications and the robustness of the main findings. RESULTS: 439 393 participants (mean age 56 years; 53% females) with a mean follow-up of 11 years were included for analyses. 82 603 (18.80%) participants reported regular use of glucosamine at baseline. During follow-up, 1971 (0.45%) lung cancer events were documented. Glucosamine use was significantly associated with a decreased risk of lung cancer (hazard ratio (HR) 0.84, 95% CI 0.75-0.92; p<0.001) and lung cancer mortality (HR 0.88, 95% CI 0.81-0.96; p=0.002) in fully adjusted models. A stronger association between glucosamine use and decreased lung cancer risk was observed in participants with a family history of lung cancer when compared with those without a family history. CONCLUSION: Regular use of glucosamine was significantly related with decreased risk of lung cancer and lung cancer mortality, based on data from this nationwide prospective cohort study.

Association between metabolically healthy obesity and risk of atrial fibrillation: taking physical activity into consideration.

The modification of physical activity (PA) on the metabolic status in relation to atrial fibrillation (AF) in obesity remains unknown. We aimed to investigate the independent and joint associations of metabolic status and PA with the risk of AF in obese population. Based on the data from UK Biobank study, we used Cox proportional hazards models for analyses. Metabolic status was categorized into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). PA was categorized into four groups according to the level of moderate-to-vigorous PA (MVPA): none, low, medium, and high. A total of 119,424 obese participants were included for analyses. MHO was significantly associated with a 35% reduced AF risk compared with MUO (HR = 0.65, 95% CI: 0.57-0.73). No significant modification of PA on AF risk among individuals with MHO was found. Among the MUO participants, individuals with medium and high PA had significantly lower AF risk compared with no MVPA (HR = 0.84, 95% CI: 0.74-0.95, and HR = 0.87, 95% CI: 0.78-0.96 for medium and high PA, respectively). As the severity of MUO increased, the modification of PA on AF risk was elevated accordingly. To conclude, MHO was significantly associated with a reduced risk of AF when compared with MUO in obese participants. PA could significantly modify the relationship between metabolic status and risk of AF among MUO participants, with particular benefits of PA associated with the reduced AF risk as the MUO severity elevated.

A comparative study of forest methods for time-to-event data: variable selection and predictive performance.

BACKGROUND: As a hot method in machine learning field, the forests approach is an attractive alternative approach to Cox model. Random survival forests (RSF) methodology is the most popular survival forests method, whereas its drawbacks exist such as a selection bias towards covariates with many possible split points. Conditional inference forests (CIF) methodology is known to reduce the selection bias via a two-step split procedure implementing hypothesis tests as it separates the variable selection and splitting, but its computation costs too much time. Random forests with maximally selected rank statistics (MSR-RF) methodology proposed recently seems to be a great improvement on RSF and CIF. METHODS: In this paper we used simulation study and real data application to compare prediction performances and variable selection performances among three survival forests methods, including RSF, CIF and MSR-RF. To evaluate the performance of variable selection, we combined all simulations to calculate the frequency of ranking top of the variable importance measures of the correct variables, where higher frequency means better selection ability. We used Integrated Brier Score (IBS) and c-index to measure the prediction accuracy of all three methods. The smaller IBS value, the greater the prediction. RESULTS: Simulations show that three forests methods differ slightly in prediction performance. MSR-RF and RSF might perform better than CIF when there are only continuous or binary variables in the datasets. For variable selection performance, When there are multiple categorical variables in the datasets, the selection frequency of RSF seems to be lowest in most cases. MSR-RF and CIF have higher selection rates, and CIF perform well especially with the interaction term. The fact that correlation degree of the variables has little effect on the selection frequency indicates that three forest methods can handle data with correlation. When there are only continuous variables in the datasets, MSR-RF perform better. When there are only binary variables in the datasets, RSF and MSR-RF have more advantages than CIF. When the variable dimension increases, MSR-RF and RSF seem to be more robustthan CIF CONCLUSIONS: All three methods show advantages in prediction performances and variable selection performances under different situations. The recent proposed methodology MSR-RF possess practical value and is well worth popularizing. It is important to identify the appropriate method in real use according to the research aim and the nature of covariates.

Therapeutic effect of pulsed electromagnetic field on bone wound healing in rats.

This study aimed to investigate the therapeutic effect of pulsed electromagnetic field (PEMF) on bone wound in rats as a potential therapy for bone fracture-related conditions. Male rats, aged 3 months, were used to construct model of bone wounding. Wound models were randomly selected to receive PEMF therapy at 1 to 10 mT intensity. Models that did not receive PEMF therapy were used as control. The serum concentrations of calcium (Ca), phosphorus (P) and alkaline phosphatase (ALP) were determined. Bone density and biomechanical properties of callus were measured using a tensile tester. Compared with control, rats subjected to PEMF therapy had similar weight gain, but significantly higher levels of serum Ca and ALP (P < .05) at 5 and 10 mT, while the serum level of P remained unchanged after PEMF therapy. The bone mineral density of callus increased after the therapy, particularly, after 5 and 10 mT therapy (P < .05). Biomechanical measurements showed that 21 days after the therapy, the maximum load, fracture load, elastic load and bending energy were significantly greater in rats receiving 5 and 10 mT PEMF therapy as compared with control (P < .05). Our experiments demonstrate that PEMF at 5 and 10 mT can significantly accelerate wound healing and enhance the repairing ability of bone tissue.

Two highly oxygenated nor-clerodane diterpenoids from Croton caudatus.

Two highly oxygenated nor-clerodane diterpenoids, crocleropenes A and B (1 and 2), together with four known compounds (3-6) were isolated from the leaves and twigs of Croton caudatus. Their structures were elucidated by combination of extensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. 1 and 2 represent the first examples of nor-clerodane-3,5(10)-diene diterpenoids. Compounds 1 and 2 exhibited weak cytotoxicity in vitro against MCF-7 cancer cells with IC50 values of 35.8 and 40.2 µM, respectively. [Formula: see text].

Assembly, Gelation, and Helicoidal Consolidation of Nanocellulose Dispersions.

The ability to probe the assembly, gelation, and helicoidal consolidation of cellulose nanocrystal (CNC) dispersions at high concentrations can provide unique insight into the assembly and can assist optimized manufacturing of CNC-based photonic and structural materials. In this Feature Article, we review and discuss the concentration dependence of the structural features, characterized by the particle separation distance and the helical pitch, at CNC concentrations ( c) that range from the isotropic state, over the biphasic range, to the fully liquid crystalline state. The structure evolution of CNC dispersions probed by time-resolved small-angle X-ray scattering during evaporation-induced assembly highlighted the importance of gelation and consolidation at high concentrations. We briefly discuss how the homogeneity of helicoidal nanostructures in dry CNC films can be improved and present an outlook for future work.

Gsdma3 is required for mammary gland development in mice.

AE (alopecia and excoriation) is a mouse mutant phenotype that harbours a mutation in Gsdma3. Gsdma3 has been reported to regulate the development of skin and hair follicles. However, its role in the mammary glands has not been reported. In this study, we found that descendants bred from an AE mother died within 12 days after birth. Then, we found that the expression of Gsdma3 varied among the developmental stages of mammary glands. Subsequently, we systematically studied the phenotype of the mammary glands of AE and wild-type mice, revealing that the mammary glands were smaller in AE mice. The mammary glands of AE mice exhibited shorter ductal extension and less bifurcation. Immunohistochemistry staining indicated that the mammary glands of AE mice displayed more proliferating cells during puberty while secreting less ß-casein during pregnancy and lactation. The lymph nodes in the mammary glands of the AE mice were larger and showed some pigmentation, suggesting that the immune reaction in the mammary glands was up-regulated. Under a transmission electron microscope, residual bodies were observed in the lymph nodes in the mammary glands of AE mice. Thus, we report a new function of Gsdma3 in regulating the development of mammary glands, and we demonstrate that the Gsdma3 gene may act as a suppressor of the immune reaction.

[Epidemiological analysis for prehypertension and its risk factors in community of Changsha].

OBJECTIVE: To explore the epidemiological features of prehypertension in community of Changsha and its relevant risk factors.
 METHODS: A total of 15 000 participants from 5 communities in Changsha were surveyed by randomly stratified cluster sampling. The questionnaire interviews and physical examination were conducted for these people, and their serum biochemical indexes were also collected and analyzed.
 RESULTS: The prevalence of prehypertension was 34.6%. The prevalence for males was higher than that in females (44.7% vs 21.7%, P<0.01). The prevalence for males was declined in older age, but for females was increased. Central obesity, age, overweight, male, drinking, smoking, high-level total cholesterol, high-level triglyceride, high-level density-lipoprotein cholesterol, low-level density-lipoprotein cholesterol, high-level fasting blood glucose, high-level creatinine, high-level uric acid were the risk factors for prehypertension, while high level of education was a protective factor.
 CONCLUSION: The prevalence for prehypertension is 34.6% in community of Changsha, and the prevalence for males is higher than that for females. It is important to strengthen the health publicity and education in community for earlier prevention.

Relationship Between Lipoprotein(a), Renal Function Indicators, and Chronic Kidney Disease: Evidence From a Large Prospective Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) poses a significant global public health challenge. While lipoprotein(a) (Lp[a]) has been established as a significant factor in cardiovascular disease, its connection to CKD risk remains a topic of debate. Existing evidence indicates diverse risks of kidney disease among individuals with various renal function indicators, even when within the normal range. OBJECTIVE: This study aims to investigate the joint associations between different renal function indicators and Lp(a) regarding the risks of incident CKD in the general population. METHODS: The analysis involved a cohort of 329,415 participants without prior CKD who were enrolled in the UK Biobank between 2006 and 2010. The participants, with an average age of 56 (SD 8.1) years, included 154,298/329,415 (46.84%) males. At baseline, Lp(a) levels were measured using an immunoturbidimetric assay and classified into 2 groups: low (<75 nmol/L) and high (≥75 nmol/L). To assess participants' baseline renal function, we used the baseline urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The relationship between Lp(a), renal function indicators, and the risk of CKD was evaluated using multivariable Cox regression models. These models were adjusted for various factors, including sociodemographic variables, lifestyle factors, comorbidities, and laboratory measures. RESULTS: A total of 6003 incident CKD events were documented over a median follow-up period of 12.5 years. The association between elevated Lp(a) levels and CKD risk did not achieve statistical significance among all participants, with a hazard ratio (HR) of 1.05 and a 95% CI ranging from 0.98 to 1.13 (P=.16). However, a notable interaction was identified between Lp(a) and UACR in relation to CKD risk (P for interaction=.04), whereas no significant interaction was observed between Lp(a) and eGFR (P for interaction=.96). When compared with the reference group with low Lp(a) and low-normal UACR (<10 mg/g), the group with high Lp(a) and low-normal UACR exhibited a nonsignificant association with CKD risk (HR 0.98, 95% CI 0.90-1.08; P=.74). By contrast, both the low Lp(a) and high-normal UACR (≥10 mg/g) group (HR 1.16, 95% CI 1.08-1.24; P<.001) and the high Lp(a) and high-normal UACR group (HR 1.32, 95% CI 1.19-1.46; P<.001) demonstrated significant associations with increased CKD risks. In individuals with high-normal UACR, elevated Lp(a) was linked to a significant increase in CKD risk, with an HR of 1.14 and a 95% CI ranging from 1.03 to 1.26 (P=.01). Subgroup analyses and sensitivity analyses consistently produced results that were largely in line with the main findings. CONCLUSIONS: The analysis revealed a significant interaction between Lp(a) and UACR in relation to CKD risk. This implies that Lp(a) may act as a risk factor for CKD even when considering UACR. Our findings have the potential to provide valuable insights into the assessment and prevention of CKD, emphasizing the combined impact of Lp(a) and UACR from a public health perspective within the general population. This could contribute to enhancing public awareness regarding the management of Lp(a) for the prevention of CKD.

Combined exposure with microplastics increases the toxic effects of PFOS and its alternative F-53B in adult zebrafish.

Microplastics (MPs) can adsorb and desorb organic pollutants, which may alter their biotoxicities. Although the toxicity of perfluorooctane sulfonate (PFOS) and its alternative 6:2 chlorinated polyfluorinated ether sulfonate (F-53B) to organisms has been reported, the comparative study of their combined toxic effects with MPs on aquatic organisms is limited. In this study, adult female zebrafish were exposed to 10 µg/L PFOS/F-53B and 50 µg/L MPs alone or in combination for 14 days to investigate their single and combined toxicities. The results showed that the presence of MPs reduced the concentration of freely dissolved PFOS and F-53B in the exposure solution but did not affect their bioaccumulation in the zebrafish liver and gut. The combined exposure to PFOS and MPs had the greatest impact on liver oxidative stress, immunoinflammatory, and energy metabolism disorders. 16S rRNA gene sequencing analysis revealed that the combined exposure to F-53B and MPs had the greatest impact on gut microbiota. Functional enrichment analysis predicted that the alternations in the gut microbiome could interfere with signaling pathways related to immune and energy metabolic processes. Moreover, significant correlations were observed between changes in gut microbiota and immune and energy metabolism indicators, highlighting the role of gut microbiota in host health. Together, our findings demonstrate that combined exposure to PFOS/F-53B and MPs exacerbates liver immunotoxicity and disturbances in energy metabolism in adult zebrafish compared to single exposure, potentially through dysregulation of gut microbiota.