Bisphenol S decreased lifespan and healthspan via insulin/IGF-1-like signaling-against mitochondrial stress in Caenorhabditis elegans.

Bisphenol S (BPS) is widely presented and affects aging with unclear mechanisms. Here, we applied C. elegans to evaluate the effects of BPS on lifespan and healthspan and to investigate the underlying mechanisms. Both early-life and whole-life exposure to BPS at environmentally relevant doses (0.6, 6, 60 µg/L) significantly decreased lifespan, and healthspan (body bend, pharyngeal pumping, and lipofuscin accumulation). BPS exposure impaired mitochondrial structure and function, which promoted ROS production to induce oxidative stress. Furthermore, BPS increased expressions of the insulin/IGF-like signaling (IIS). Also, BPS inhibited expression of the IIS transcription factor daf-16 and its downstream anti-oxidative genes. Quercetin effectively improved BPS-induced oxidative stress byreversing BPS-regulated IIS/daf-16 pathway and anti-oxidative gene expressions. In daf-2 and daf-16 mutants, the effects of BPS and quercetin on lifespan, healthspan, oxidative stress, and anti-oxidative genes expressions were reversed, demonstrating the requirement of IIS/daf-16 for aging regulation. Molecular docking and molecular dynamics simulations confirmed the stable interaction between DAF-2 and BPS mainly via three residues (VAL1260, GLU1329, and MET1395), which was attenuated by quercetin. Our results highlighted that adverse effects of BPS on impairing lifespan and healthspan by affecting IIS/daf-16 function against mitochondrial stress, which could be inhibited by quercetin treatment. Thus, we first revealed the underlying mechanisms of BPS-induced aging and the potential treatment.

Low serum Metrnl levels are associated with increased risk of sarcopenia in the older adults.

PURPOSE: Sarcopenia is a geriatric syndrome characterized by progressive loss of muscle mass and function. Meteorin-like (Metrnl) is a secretory protein that has protective effects on skeletal muscle injury. However, the association of Metrnl level with sarcopenia remains unclear. METHODS: A total of 772 community-dwelling older adults (median age = 76 years), comprising 409 males and 363 females, from both urban and rural areas were enrolled. Serum Metrnl was measured by enzyme-linked immunosorbent assay. Appendicular skeletal muscle mass index (ASMI), grip strength, and gait speed were measured for the assessment of sarcopenia. RESULTS: We found that serum Metrnl levels were lower in patients with sarcopenia [median (IQR) = 180.1 (151.3-220.3) pg/mL] than older adults without sarcopenia [211.9 (163.2-270.0) pg/mL, P < 0.001]. Receiver-operating characteristic curve analysis showed that the optimal cut-off value of serum Metrnl level that predicted sarcopenia was 197.2 pg/mL with a sensitivity of 59.2% and a specificity of 63.8% (AUC = 0.63, 95% CI = 0.59-0.67, P < 0.001). Multivariate logistic regression analyses showed that lower serum Metrnl level (< 197.2 pg/mL) was significantly associated with increased risk of sarcopenia (adjusted OR = 2.358, 2.36, 95% CI = 1.528-3.685, P < 0.001). Moreover, serum Metrnl concentration was positively correlated with the components of sarcopenia including ASMI (r = 0.135, P < 0.001), grip strength (r = 0.102, P = 0.005), and gait speed (r = 0.106, P = 0.003). CONCLUSIONS: Taken together, our findings demonstrate that low serum Metrnl level is correlated with increased risk of sarcopenia in the older adults.

The role of TERT C228T and KDM6A alterations and TME in NMIBC treated with BCG.

We aimed to investigate the genomic and tumor microenvironmental (TME) profiles in non-muscle invasive bladder cancer (NMIBC) and explore potential predictive markers for Bacillus Calmette-Guérin (BCG) treatment response in high-risk NMIBC patients (according to European Association of Urology (EAU) risk stratification). 40 patients with high-risk NMIBC (cTis-T1N0M0) who underwent en bloc resection followed by BCG instillation were retrospectively enrolled. Surgical samples were subjected to Next Generation Sequencing (NGS) and multiplex immunofluorescence (mIF) assay. Genomic profiling revealed high prevalences of alterations in TERT (55%), KDM6A (32.5%), FGFR3(30%), PIK3CA (30%), TP53(27.5%) and ARID1A (20%). TME analysis showed different proportions of macrophages, NK cells, T cells subsets in tumoral and stromal compartment. Multivariate analysis identified TERT C228T and alteration in KDM6A as two independent factors associated with inferior RFS. The study comprehensively depicted the genomic and TME profiles in NMIBC and identified potential predictive biomarkers for BCG treatment.

An ADSC-loaded dermal regeneration template promotes full-thickness wound healing.

Introduction: Full-thickness wounds lead to delayed wound healing and scarring. Adipose-derived stem cell (ADSC) grafting promotes wound healing and minimizes scarring, but the low efficiency of grafting has been a challenge. We hypothesized that loading ADSCs onto a clinically widely used dermal regeneration template (DRT) would improve the efficacy of ADSC grafting and promote full-thickness wound healing. Methods: ADSCs from human adipose tissue were isolated, expanded, and labeled with a cell tracker. Labeled ADSCs were loaded onto the DRT. The viability, the location of ADSCs on the DRT, and the abundance of ADSCs in the wound area were confirmed using CCK8 and fluorescence microscopy. Full-thickness wounds were created on Bama minipigs, which were applied with sham, ADSC, DRT, and ADSC-DRT. Wounds from the four groups were collected at the indicated time and histological analysis was performed. RNA-seq analysis was also conducted to identify transcriptional differences among the four groups. The identified genes by RNA-seq were verified by qPCR. Immunohistochemistry and western blotting were used to assess collagen deposition. In vitro, the supernatant of ADSCs was used to culture fibroblasts to investigate the effect of ADSCs on fibroblast transformation into myofibroblasts. Results: ADSCs were successfully isolated, marked, and loaded onto the DRT. The abundance of ADSCs in the wound area was significantly greater in the ADSC-DRT group than in the ADSC group. Moreover, the ADSC-DRT group exhibited better wound healing with improved re-epithelialization and denser collagen deposition than the other three groups. The RNA-seq results suggested that the application of the integrated ADSC-DRT system resulted in the differential expression of genes mainly associated with extracellular matrix remodeling. In vivo, wounds from the ADSC-DRT group exhibited an earlier increase in type III collagen deposition and alleviated scar formation. ADSCs inhibited the transformation of fibroblasts into myofibroblasts, along with increased levels of CTGF, FGF, and HGF in the supernatant of ADSCs. Wounds from the ADSC-DRT group had up-regulated expressions of CTGF, HGF, FGF, and MMP3. Conclusion: The integral of ADSC-DRT increased the efficacy of ADSC grafting, and promoted full-thickness wound healing with better extracellular matrix remodeling and alleviated scar formation.

Interfacial Dipole Engineering for Energy Level Alignment in NiOx-Based Quantum Dot Light-Emitting Diodes.

The solution-derived non-stoichiometric nickel oxide (NiOx) is a promising hole-injecting material for stable quantum dot light-emitting diodes (QLEDs). However, the carrier imbalance due to the misalignment of energy levels between the NiOx and polymeric hole-transporting layers (HTLs) curtails the device efficiency. In this study, the modification of the NiOx surface is investigated using either 3-cyanobenzoic acid (3-CN-BA) or 4-cyanobenzoic acid (4-CN-BA) in the QLED fabrication. Morphological and electrical analyses revealed that both 4-CN-BA and 3-CN-BA can enhance the work function of NiOx, reduce the oxygen vacancies on the NiOx surface, and facilitate a uniform morphology for subsequent HTL layers. Moreover, it is found that the binding configurations of dipole molecules as a function of the substitution position of the tail group significantly impact the work function of underlying layers. When integrated in QLEDs, the modification layers resulted in a significant improvement in the electroluminescent efficiency due to the enhancement of energy level alignment and charge balance within the devices. Specifically, QLEDs incorporating 4-CN-BA achieved a champion external quantum efficiency (EQE) of 20.34%, which is a 1.8X improvement in comparison with that of the devices utilizing unmodified NiOx (7.28%). Moreover, QLEDs with 4-CN-BA and 3-CN-BA modifications exhibited prolonged operational lifetimes, indicating potential for practical applications.

Association between oxidative balance scores and all-cause and cardiovascular disease-related mortality in patients with type 2 diabetes: data from the national health and nutrition examination survey (2007-2018).

BACKGROUND: Oxidative Balance Scores (OBS) is composite measures that assess the balance between pro-oxidant and antioxidant factors in an individual's diet and lifestyle. Evidence on OBS and cardiovascular disease (CVD) in diabetic patients is scarce. This study investigates the potential association between OBS and CVD-prevalence and all-cause and CVD-related mortality in adult diabetic patients. METHODS: Participants were selected from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. OBS-related data collection was initiated by linking the National Death Index to determine mortality due to all-cause and cardiovascular disease until December 31, 2019. Weighted logistic regression analyses explored the relationship between OBS and CVD. In addition, multivariable Cox proportional risk regression models and Kaplan-Meier curves were used to determine the correlation between OBS and mortality, with time to event as the time variable, as well as to estimate hazard ratios (HR) and 95% confidence interval (CI). RESULTS: A total of 3491 participants were included in the final analysis. Weighted logistic regression analysis of the relationship between OBS and CVD prevalence found that higher OBS was not associated with CVD prevalence compared with lower levels after fully adjustment in model 3 (OR: 0.82, 95% CI: 0.51-1.31, P = 0.39). During 3,491 person-years of follow-up, 408 deaths were recorded, of which 105 deaths were attributed to CVD. In fully adjusted model 3, participants in the highest quartile of OBS had significant reductions in all-cause mortality of 53% [HR: 0.47, 95% CI: 0.29-0.77), Ptrend= 0.002] and in cardiovascular disease mortality of 78% [HR: 0.22, 95% CI: 0.08-0.56), Ptrend= 0.004], compared with the lowest quartile groups of OBS. The Kaplan-Meier analysis results showed that participants in the highest quartile of OBS had the lowest risk of all-cause and CVD-related mortality and were statistically different (P < 0.05). Subgroup analysis confirmed that P for interaction was significant only concerning the educational level attained and in individuals with a history of CKD (P < 0.05). CONCLUSIONS: Although OBS wasn't very useful for assessing CVD prevalence outcomes, higher OBS was significantly associated with lower all-cause and CVD-related mortality, suggesting that maintaining adequate OBS may reduce mortality in patients with DM.

Design, synthesis and biological evaluation of dual inhibitors targeting AR/AR-Vs and PARP1 in castration resistant prostate cancer therapy.

The combination of androgen signaling inhibitors and PARP inhibitors has shown promising results in clinical trials for the treatment of castration-resistant prostate cancer (CRPC). Multi-target inhibitors can inhibit tumors through different pathways, addressing the limitations of traditional single target inhibitors. We designed and synthesized dual inhibitors targeting AR/AR-Vs and PARP1 using a pharmacophore hybridization strategy. The most potent compound, II-3, inhibits AR/AR-Vs signaling and induces DNA damage by inhibiting PARP1. The IC50 values of II-3 in the castration-resistant prostate cancer cell lines 22RV1 and C4-2 are 4.38 ± 0.56 µM, and 3.44 ± 0.63 µM, respectively. II-3 not only suppresses the proliferation and migration of 22RV1 and C4-2 cells, but also promotes their apoptosis. Intraperitoneal injection of II-3 effectively inhibits tumor growth in 22RV1 xenograft nude mice without evident drug-induced toxicity. Overall, a series of novel dual inhibitors targeting AR/AR-Vs and PARP1 were designed and synthesized, and meanwhile the in vivo and in vitro effects were comprehensively explored, which provided a potential new therapeutic strategy for CRPC.

The relationship between changes in functional connectivity gradients and cognitive-emotional disorders in sudden sensorineural hearing loss.

Sudden sensorineural hearing loss, a prevalent emergency in otolaryngology, is known to potentially precipitate cognitive and emotional disorders in affected individuals. Extensive research has documented the phenomenon of cortical functional reorganization in patients with sudden sensorineural hearing loss. However, the potential link between this neural functional remodelling and cognitive-emotional disorders remains unclear. To investigate this issue, 30 bilateral sudden sensorineural hearing loss patients and 30 healthy adults were recruited for this study. We collected clinical data and resting-state functional magnetic resonance imaging data from the participants. Gradient mapping analysis was employed to calculate the first three gradients for each subject. Subsequently, gradient changes in sudden sensorineural hearing loss patients were compared with healthy controls at global, regional and network levels. Finally, we explored the relationship between gradient values and clinical variables. The results revealed that at the global level, sudden sensorineural hearing loss did not exhibit significant differences in the primary gradient but showed a state of compression in the second and third gradients. At the regional level, sudden sensorineural hearing loss patients exhibited a significant reduction in the primary gradient values in the temporal pole and ventral prefrontal cortex, which were closely related to neuro-scale scores. Regarding the network level, sudden sensorineural hearing loss did not show significant differences in the primary gradient but instead displayed significant changes in the control network and default mode network in the second and third gradients. This study revealed disruptions in the functional hierarchy of sudden sensorineural hearing loss, and the alterations in functional connectivity gradients were closely associated with cognitive and emotional disturbances in patients. These findings provide new evidence for understanding the functional remodelling that occurs in sudden sensorineural hearing loss.

SlBTB19 interacts with SlWRKY2 to suppress cold tolerance in tomato via the CBF pathway.

Cold stress restricts the metabolic and physiological activities of plants, thereby affecting their growth and development. Although broad-complex, tramtrack, and bric-à-brac (BTB) proteins are essential for diverse biological processes and stress responses, the mechanisms underlying BTB-mediated cold responses remain not fully understood. Here, we characterize the function of the cold-induced SlBTB19 protein in tomato (Solanum lycopersicum). Overexpression of SlBTB19 resulted in increased plant sensitivity to cold stress, whereas SlBTB19 knockout mutants exhibited a cold-tolerance phenotype. Further analyses, including protein-protein interaction studies and cell-free degradation assays, revealed that SlBTB19 interacts with and destabilizes the transcription factor SlWRKY2. Using virus-induced gene silencing (VIGS) to silence SlWRKY2 in both wild-type and slbtb19 mutants, we provided genetic evidence that SlWRKY2 acts downstream of SlBTB19 in regulating cold tolerance. Importantly, we demonstrated that SlWRKY2 positively regulates cold tolerance in a CRT/DRE binding factor (CBF)-dependent manner. Under cold stress, SlWRKY2 binds to the W-box in the CBF1 and CBF3 promoters, directly activating their expression. In summary, our findings identify a SlBTB19-SlWRKY2 module that negatively regulates the CBF-dependent cold tolerance pathway in tomato.