Reversal of atherosclerosis by restoration of vascular copper homeostasis.

Atherosclerosis has traditionally been considered as a disorder characterized by the accumulation of cholesterol and thrombotic materials within the arterial wall. However, it is now understood to be a complex inflammatory disease involving multiple factors. Central to the pathogenesis of atherosclerosis are the interactions among monocytes, macrophages, and neutrophils, which play pivotal roles in the initiation, progression, and destabilization of atherosclerotic lesions. Recent advances in our understanding of atherosclerosis pathogenesis, coupled with results obtained from experimental interventions, lead us to propose the hypothesis that atherosclerosis may be reversible. This paper outlines the evolution of this hypothesis and presents corroborating evidence that supports the potential for atherosclerosis regression through the restoration of vascular copper homeostasis. We posit that these insights may pave the way for innovative therapeutic approaches aimed at the reversal of atherosclerosis.

The combination of temozolomide and perifosine synergistically inhibit glioblastoma by impeding DNA repair and inducing apoptosis.

Temozolomide (TMZ) is widely utilized as the primary chemotherapeutic intervention for glioblastoma. However, the clinical use of TMZ is limited by its various side effects and resistance to chemotherapy. The present study revealed the synergistic inhibition of glioblastoma through the combined administration of TMZ and perifosine. This combination therapy markedly diminished BRCA1 expression, resulting in the suppression of DNA repair mechanisms. Furthermore, the combination of TMZ and perifosine elicited caspase-dependent apoptosis, decreasing glioblastoma cell viability and proliferation. The observed synergistic effect of this combination therapy on glioblastoma was validated in vivo, as evidenced by the substantial reduction in glioblastoma xenograft growth following combined treatment with TMZ and perifosine. In recurrent glioma patients, higher BRCA1 expression is associated with worse prognosis, especially the ones that received TMZ-treated. These findings underscore the potent antitumor activity of the AKT inhibitor perifosine when combined with TMZ and suggest that this approach is a promising strategy for clinical glioblastoma treatment.

Proteomic Profiling of Serum Extracellular Vesicles Identifies Diagnostic Signatures and Therapeutic Targets in Breast Cancer.

Analysis of extracellular vesicles (EVs) is a promising noninvasive liquid biopsy approach for breast cancer (BC) detection, prognosis, and therapeutic monitoring. A comprehensive understanding of the characteristics and proteomic composition of BC-specific EVs from human samples is required to realize the potential of this strategy. In this study, we applied a mass spectrometry-based, data-independent acquisition (DIA) proteomic approach to characterize human serum EVs derived from patients with BC (n = 126) and healthy donors (HDs, n = 70) in a discovery cohort and validated the findings in five independent cohorts. Examination of the EV proteomes enabled construction of specific EV protein classifiers for diagnosing BC and distinguishing patients with metastatic disease. Of note, TALDO1 was found to be an EV biomarker of distant metastasis of BC. In vitro and in vivo analysis confirmed the role of TALDO1 in stimulating BC invasion and metastasis. Finally, high-throughput molecular docking and virtual screening of a library consisting of 271,380 small molecules identified a potent TALDO1 allosteric inhibitor, AO-022, which could inhibit BC migration in vitro and tumor progression in vivo. Together, this work elucidates the proteomic alterations in the serum EVs of BC patients to guide development of improved diagnosis, monitoring, and treatment strategies.

Energy strategy alteration, rather than toxicity itself, interferes with the population fluctuation of Brachionus plicatilis exposed to water-accommodated fractions (WAFs) of crude oil.

Oil spills are reported to have conflicting impacts of either injury or resilience on zooplankton communities, and physiological plasticity is speculated to be the possible causative factor. But how? An explanation was sought by exposing the marine rotifer Brachionus plicatilis to a series of water-accommodated fractions (WAFs) of crude oil under controlled laboratory conditions, and population dynamics, which is the core issue for zooplankton facing external stress, were analyzed. The total hydrocarbon concentration of WAFs was quickly degraded from a concentration of 5.0 mg L-1 to half within 24 h and then remained stable. No acute lethality was observed; only motion inhibition was observed in the group treated with 10 %, 50 % and 100 % WAFs, which occurred simultaneously with inhibition of feeding and filtration. However, sublethal exposure to the WAFs concentration series presented stimulation impacts on reproduction and even the population of B. plicatilis. The negative correlation between motion and reproduction seemed to indicate that a shift in the distribution of individual energy toward reproduction rather than motion resulted in increased reproduction after exposure to WAFs. More evidence from transmission electron microscopy (TEM) revealed ultrastructural impairment in both the ovaries and cilia in each treated group, and imbalance in mitochondrial numbers was one of the distinct features of alteration. WAFs stress may alter the energy utilization and storage paradigm, as indicated by the significant elevation in glycogen and the significant decrease in lipid content after WAFs exposure. Further evidence from metabolomics analysis showed that WAFs stress increased the level of lipid metabolism and inhibited some of the pathways in glucose metabolism. Sublethal acute toxicity was observed only in the first 24 h with WAFs exposure, and an energy strategy consisting of changes in the utilization and storage paradigm and reallocation is responsible for the population resilience of B. plicatilis during oil spills.

Intraoperative quantitative crystalline lens nuclear opacities analysis based on crystalline lenSx platform.

PURPOSE: The main objective is to quantify the lens nuclear opacity using spectral-domain optical coherence tomography (SD-OCT) and to evaluate its association with Lens Opacities Classification System III (LOCS-III) system, lens thickness (LT), and surgical parameters. The secondary objective is to assess the diagnostic model performance for hard nuclear cataract. METHODS: This study included 70 eyes of 57 adults with cataract, with 49 (70%) and 21 (30%) in training and validation cohort, respectively. Correlations of the average nuclear density (AND) /maximum nuclear density (MND) with LOCS-III scores, LT, and surgical parameters were analyzed. Univariate and multivariate logistic regression analysis, receiver operating characteristic curves and calibration curves were performed for the diagnostic of hard nuclear cataract. RESULTS: The pre-operative uncorrected distance visual acuity (UDVA), intraocular pressure (IOP), mean axial length (AL), and LT were 1.20 ± 0.47 log MAR, 15.50 ± 2.87 mmHg, 27.34 ± 3.77 mm and 4.32 ± 0.45 mm, respectively. The average nuclear opalescence (NO) and nuclear colour (NC) scores were 3.61 ± 0.94 and 3.50 ± 0.91 (ranging from 1.00 to 6.90), respectively. The average AND and MND were 137.94 ± 17.01 and 230.01 ± 8.91, respectively. NC and NO scores both significantly correlated with the AND (rNC = 0.733, p = 0.000; rNO = 0.755, p = 0.000) and MND (rNC = 0.643, p = 0.000; rNO = 0.634, p = 0.000). In the training cohort, the area under the curve (AUC) of the model was 0.769 (P < 0.001, 95%CI 0.620-0.919), which had a good degree of differentiation (Fig. 2a). The calibration curve showed good agreement between predicted and actual probability. CONCLUSION: The nuclear density measurement on SD-OCT images can serve as an objective and reliable indicator for quantifying nuclear density.

Hexabromocyclododecane-induced reproductive toxicity in Brachionus plicatilis: Impacts and assessment.

Hexabromocyclododecane (HBCD), third-generation brominated flame retardants (BRFs), has aroused worldwide concern because of its wide application and potentially negative impacts on marine ecosystems, but an information gap still exists regarding marine low-trophic organisms. Brachionus plicatilis, the model marine zooplankton, was used in the present study, and its reproductive responses were used as the endpoint to indicate HBCD-induced toxicity. HBCD was suggested to be extremely highly toxic compounds regarding the 96 h-LC50 of 0.58 mg L-1. The sublethal exposure of HBCD injured the reproduction of B. plicatilis: The total number of offspring per female and the key population index calculated from the life table, including the intrinsic rate of population increase (rm) and net reproductive rate (R0), were significantly influenced in a concentration-dependent manner. The reproductive process was also altered, as indicated by the first spawning time, first hatching time and oocyst development time. At the same time, individual survival and growth (body length) were also negatively affected by HBCD. Reactive oxygen species (ROS) were suggested to be responsible for reproductive toxicity mainly because the total ROS contents as well as the main components of •OH and H2O2 greatly increased and resulted in the oxidative imbalance that presented as malondialdehyde (MDA) elevation. Simultaneous activation of the glutathione antioxidant system was accompanied by the apoptosis marker enzymes Caspase-3 and 9, as well as the correlation between ROS content, physiological alteration and cell apoptosis, providing further evidence for this. The integrated biomarker response (IBR) and adverse outcome pathway (AOP) showed that HBCD had a significant toxic effect on B. plicatilis near the concentration range of 96 h-LC50. The establishment of this concentration range will provide a reliable reference for future environmental concentration warning of HBCD in marine.

Is dancing an effective intervention for fat loss? A systematic review and meta-analysis of dance interventions on body composition.

OBJECTIVE: The systematic review aimed to review the research on the effects of dance interventions, relative to normal lifestyles, on body composition in people with overweight and obesity. METHODS: 7 databases were searched from their inception to 3 July 2023 for studies with dance interventions and normal lifestyles groups. Only studies investigating dance interventions in people with overweight and obesity(body mass index (BMI)>24kg/m2 and percent fat mass (Fat(%)) abnormal(male>20%, female>25%)) were included in the meta-analysis. There were no restrictions on dance forms. RESULTS: 654 studies were identified from the databases, and 10 studies were evaluated to be eligible. The meta-analysis revealed that compared to normal lifestyles dance had meaningful improvements in body mass(BM), BMI, waist circumference(WC), Fat(%), and fat mass(Fat(kg)). No significant differences were found in the waist-to-hip ratio(WHR). CONCLUSIONS: Dance is effective on fat loss in people with overweight and obesity, and has a significant improvement on body composition and morphology. For its high efficiency and greater sense of enjoyment, dance can be a beneficial exercise intervention for fat loss.

Correction: Sugarcane stem node identification algorithm based on improved YOLOv5.

[This corrects the article DOI: 10.1371/journal.pone.0295565.].

Implantation of Adipose-Derived Mesenchymal Stromal Cells (ADSCs)-Lining Prosthetic Graft Promotes Vascular Regeneration in Monkeys and Pigs.

BACKGROUND: Current replacement procedures for stenosis or occluded arteries using prosthetic grafts have serious limitations in clinical applications, particularly, endothelialization of the luminal surface is a long-standing unresolved problem. METHOD: We produced a cell-based hybrid vascular graft using a bioink engulfing adipose-derived mesenchymal stromal cells (ADSCs) and a 3D bioprinting process lining the ADSCs on the luminal surface of GORE-Tex grafts. The hybrid graft was implanted as an interposition conduit to replace a 3-cm-long segment of the infrarenal abdominal aorta in Rhesus monkeys. RESULTS: Complete endothelium layer and smooth muscle layer were fully developed within 21 days post-implantation, along with normalized collagen deposition and crosslinking in the regenerated vasculature in all monkeys. The regenerated blood vessels showed normal functionality for the longest observation of more than 1650 days. The same procedure was also conducted in miniature pigs for the interposition replacement of a 10-cm-long right iliac artery and showed the same long-term effective and safe outcome. CONCLUSION: This cell-based vascular graft is ready to undergo clinical trials for human patients.

Sugarcane stem node identification algorithm based on improved YOLOv5.

Identification of sugarcane stem nodes is generally dependent on high-performance recognition equipment in sugarcane seed pre-cutting machines and inefficient. Accordingly, this study proposes a novel lightweight architecture for the detection of sugarcane stem nodes based on the YOLOv5 framework, named G-YOLOv5s-SS. Firstly, the study removes the CBS and C3 structures at the end of the backbone network to fully utilize shallow-level feature information. This enhances the detection performance of sugarcane stem nodes. Simultaneously, it eliminates the 32 times down-sampled branches in the neck structure and the 20x20 detection heads at the prediction end, reducing model complexity. Secondly, a Ghost lightweight module is introduced to replace the conventional convolution module in the BottleNeck structure, further reducing the model's complexity. Finally, the study incorporates the SimAM attention mechanism to enhance the extraction of sugarcane stem node features without introducing additional parameters. This improvement aims to enhance recognition accuracy, compensating for any loss in precision due to lightweight modifications. The experimental results showed that the average precision of the improved network for sugarcane stem node identification reached 97.6%, which was 0.6% higher than that of the YOLOv5 baseline network. Meanwhile, a model size of 2.6MB, 1,129,340 parameters, and 7.2G FLOPs, representing respective reductions of 82%, 84%, and 54.4%. Compared with mainstream one-stage target detection algorithms such as YOLOv4-tiny, YOLOv4, YOLOv5n, YOLOv6n, YOLOv6s, YOLOv7-tiny, and YOLOv7, G-YOLOv5s-SS achieved respective average precision improvements of 12.9%, 5.07%, 3.6%, 2.1%, 1.2%, 3%, and 0.4% in sugarcane stem nodes recognition. Meanwhile, the model size was compressed by 88.9%, 98.9%, 33.3%, 72%, 92.9%, 78.8% and 96.3%, respectively. Compared with similar studies, G-YOLOv5s-SS not only enhanced recognition accuracy but also considered model size, demonstrating an overall excellent performance that aligns with the requirements of sugarcane seed pre-cutting machines.

Obesity and Cardiac Conduction Block Disease in China.

Importance: Although a high body mass index (BMI) has been found to be associated with increased risk of cardiac conduction block (CCB) in older adults, no further studies have investigated the association between obesity and CCB in the general population. Objective: To investigate the association between obesity and CCB, including its subtypes. Design, Setting, and Participants: This cohort study used data from participants in the Kailuan Study in China (2006-2018) who had completed a physical examination in 2006 (baseline) and had not experienced CCB before baseline. Data analysis was conducted from March to September 2023. Exposures: Obesity status was defined by BMI in 3 groups: normal weight (18.5 to <24), overweight (24 to <28), and obesity (≥28). Main Outcome and Measures: The primary outcome was CCB, which was diagnosed from standard 12-lead electrocardiography. The primary end point included high-grade atrioventricular block (HAVB), complete right bundle branch block, complete left bundle branch block, left anterior fascicular block (LAFB), and left posterior fascicular block. First-degree atrioventricular block (FAVB), second-degree type 1 AVB, HAVB, complete and incomplete right and left bundle branch block, LAFB, and left posterior fascicular block were considered separately as secondary end points. Results: Among 86 635 participants (mean [SD] age, 50.8 [11.9] years; 68 205 males [78.7%]), there were 33 259 individuals with normal weight (38.4%), 37 069 individuals with overweight (42.8%), and 16 307 individuals with obesity (18.8%). The mean (SD) follow-up was 10.6 (3.07) years. In the multivariable Cox proportional hazards regression analysis, obesity was associated with an increased risk of incident CCB (hazard ratio [HR], 1.21; 95% CI, 1.04-1.42) vs normal BMI. In secondary analysis, obesity was associated with an increased risk of FAVB (HR, 1.44; 95% CI, 1.21-1.73), HAVB (HR, 1.99; 95% CI, 1.03-3.82), and LAFB (HR, 1.29; 95% CI, 1.03-1.62) vs normal BMI. There was no association between obesity and other CCB subtypes. Obesity was associated with a greater increase in risk of CCB vs normal BMI in older (aged ≥65 years; HR, 1.44; 95% CI, 1.05-1.96) vs younger (aged <65 years; HR, 1.13; 95% CI, 0.96-1.34) participants (P for interaction < .001) and those with diabetes (HR, 2.16; 95% CI, 1.24-3.76) vs without diabetes (HR, 1.19; 95% CI, 1.02-1.39) (P for interaction = .02). Conclusions and Relevance: This study found that obesity was associated with an increased risk of CCB, with greater increases in risk for FAVB, HAVB, and LAFB. Individuals who were older and those who had diabetes had larger increases in risk.

Mesenchymal Stem Cell-Derived Exosomes are Effective for Radiation Enteritis and Essential for the Proliferation and Differentiation of Lgr5+ Intestinal Epithelial Stem Cells by Regulating Mir-195/Akt/ß-Catenin Pathway.

BACKGROUND: Radiation enteritis (RE) is a common complication of abdominal or pelvic radiotherapy, which when severe, could be life-threatening. Currently, there are no effective treatments. Studies have shown that mesenchymal stem cells (MSCs)-derived exosomes (MSC-exos) exhibit promising therapeutic effects in inflammatory diseases. However, the specific role of MSC-exos in RE and the regulatory mechanisms remain elusive. METHODS: In vivo assay was carried out by injecting MSC-exos into the total abdominal irradiation (TAI)-induced RE mouse model. For in vitro assay, Lgr5-positive intestinal epithelial stem cells (Lgr5+ IESC) were extracted from mice, followed by irradiation along with MSC-exos treatment. HE staining was performed to measure histopathological changes. mRNA expression of inflammatory factors TNF-α and IL-6 and stem cell markers LGR5, and OCT4 were quantified by RT-qPCR. EdU and TUNEL staining was performed to estimate cell proliferation and apoptosis. MiR-195 expression in TAI mice and radiation-induced Lgr5+ IESC was tested. RESULTS: We found that the injection of MSC-exos inhibited inflammatory reaction, increased stem cell marker expression, and maintained intestinal epithelial integrity in TAI mice. Furthermore, MSC-exos treatment increased the proliferation and simultaneously suppressed apoptosis in radiation-stimulated Lgr5+ IESC. MiR-195 expression increased by radiation exposure was decreased by MSC-exos therapy. MiR-195 overexpression facilitated the progress of RE by counteracting the effect of MSC-exos. Mechanistically, the Akt and Wnt/ß-catenin pathways inhibited by MSC-exos were activated by miR-195 upregulation. CONCLUSION: MSC-Exos are effective in treating RE and are essential for the proliferation and differentiation of Lgr5+ IESCs. Moreover, MSC-exos mediates its function by regulating miR-195 Akt ß-catenin pathways.

The role of social network embeddedness and collective efficacy in encouraging farmers' participation in water environmental management.

Water environmental management (WEM) has a significant influence on the global ecological balance. As an institutional innovation, the River Chief System (RCS) in China has achieved a positive short-term impact on addressing water environmental problems. However, its effects are limited in rural China. As a type of public good, the rural WEM demands the active participation not only of government but also of farmers. Based on the social cognitive and social network theory, this study empirically investigates how rural social networks promote farmers' participation in WEM. Using the survey of 860 farmers in the Yellow and Yangtze River Basin, we employ the double-hurdle model (D-H-M) to craft the primary assessment. The results show that the social network embeddedness facilitates farmers' participation in WEM directly. Collective efficacy plays a full mediation role in the relationship between social network embeddedness and farmers' participation. Moreover, the perceived role of village leaders affects the relationship between social networks and farmers' participation. Our research enriches the application of social network theory in the rural social context and offers an innovative approach to solving farmers' participation problems in WEM.

Isoliensinine suppresses bone loss by targeted inhibition of RANKL-RANK binding.

BACKGROUND: Osteoporosis, a systemic metabolic bone disease, is often caused by the disruption of dynamic equilibrium between osteoclasts and osteoblasts. Overactive bone resorption, in which osteoclasts play a major role, is one of the most common and major causes of osteoporosis. Less costly and more effective drug treatments for this disease are needed. Based on the combination of molecular docking techniques and in vitro cell assays, this study aimed to explore the mechanism by which Isoliensinine (ILS) protects the bone loss by inhibiting osteoclast differentiation. METHODS: A virtual docking model based on molecular docking technology was used to investigate the interactions between ILS and the Receptor Activator of Nuclear Kappa-B (RANK)/Receptor Activator of Nuclear Kappa-B Ligand (RANKL).In this study, we determined the effective dose of action of ILS to inhibit osteoclast differentiation in vitro and, using bone resorption experiments, RT-CPR and Western Blot investigated the effects of ILS on bone resorption function and normal expression of osteoclast-associated genes and proteins, and validated potential mechanistic pathways. In vivo experiments revealed that ILS could inhibit bone loss through Micro-CT results. Finally, the molecular interaction between ILS and RANK/RANKL was investigated using biomolecular interaction experiments to verify the correctness and accuracy of the computational results. RESULTS: ILS binds to RANK and RANKL proteins, respectively, through virtual molecular docking. The Surface Plasmon Resonance (SPR) experiment results revealed that phosphorylated JNK, ERK, P38, and P65 expression was significantly downregulated when ILS were targeted to inhibit RANKL/RANK binding. At the same time, the expression of IKB-a was significantly increased under the stimulation of ILS, which rescued the degradation of IKB-a. ILS can significantly inhibit the levels of Reactive Oxygen Species (ROS) and Ca2 + concentration in vitro. Finally, the results of Micro-CT showed that ILS can significantly inhibit bone loss in vivo, indicating that ILS has a potential role in the treatment of osteoporosis. CONCLUSION: ILS inhibits osteoclast differentiation and bone loss by preventing the normal binding of RANKL/RANK, affecting downstream signaling pathways, including MAPK.NF-KB, ROS, Ca2+, genes, and proteins.

Trajectories of lipids around the menopause transition in Chinese women: results of the Kailuan cohort study.

OBJECTIVE: To investigate changes in lipid parameters around the final menstrual period (FMP) in Chinese women. DESIGN: A prospective community-based cohort study. PATIENT(S): Three thousand seven hundred fifty six Chinese women from the Kailuan cohort study who participated in the first examination and reached their FMP by the end of the seventh examination. Health examinations were performed every 2 years. Multivariable piece-wise linear mixed-effect models were used for repeated measures of lipids as a function of time around FMP. INTERVENTION(S): Number of years before or after FMP at each examination. MAIN OUTCOME MEASURE(S): Lipids at each examination, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs). RESULT(S): Total cholesterol, LDL-C, and TGs began to increase in early transition, regardless of baseline age. Moreover, TC and LDL-C had a maximum annual increase from 1 year before to 2 years after FMP; TGs had a maximum annual increase from early transition to the fourth-year after menopause. The trajectories in other postmenopause segments differed across subgroups of different baseline ages. Furthermore, HDL-C remained stable around FMP if baseline age was <45 years, whereas if baseline age was ≥45 years, HDL-C would first decline and then rise during postmenopause. Women with a higher body mass index (BMI) underwent less adverse changes in TC and TGs during postmenopause and had decline in HDL-C before menopause. A later FMP age was associated with less adverse changes in TC, LDL-C, and TGs and greater increase in HDL-C during postmenopause; it was associated with a greater increase in LDL-C during early transition. CONCLUSION(S): This repeated measurement cohort study of indigenous Chinese women demonstrated that, regardless of baseline age, the adverse effect of menopause on lipids was since early transition, and the most adverse change time was from 1 year before to 2 years after FMP; HDL-C decreased first and then increased during postmenopause in older women; BMI and FMP age affected lipid trajectory mainly during postmenopause. We highlighted positive lipid management during menopause to reduce the burden of postmenopausal dyslipidemia. For lipid stratification management in postmenopausal women, BMI and FMP age are important factors.

A clinical feasible stem cell encapsulation ensures an improved wound healing.

Cell encapsulation has proven to be promising in stem cell therapy. However, there are issues needed to be addressed, including unsatisfied yield, unmet clinically friendly formulation, and unacceptable viability of stem cells after cryopreservation and thawing. We developed a novel biosynsphere technology to encapsulate stem cells in clinically-ready biomaterials with controlled microsphere size. We demonstrated that biosynspheres ensure the bioviability and functionality of adipose-derived stromal cells (ADSCs) encapsulated, as delineated by a series of testing procedures. We further demonstrated that biosynspheres protect ADSCs from the hardness of clinically handling such as cryopreservation, thawing, high-speed centrifugation and syringe/nozzle injection. In a swine full skin defect model, we showed that biosynspheres were integrated to the destined tissues and promoted the repair of injured tissues with an accelerating healing process, less scar tissue formation and normalized deposition of collagen type I and type III, the ratio similar to that found in normal skin. These findings underscore the potential of biosynsphere as an improved biofabrication technology for tissue regeneration in clinical setting.

The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor with a poor median survival of less than 15 months. However, clinical strategies and effective therapies are limited. Here, we found that the second-generation small molecule multi-CDK inhibitor AT7519 is a potential drug for GBM treatment according to high-throughput screening via the Approved Drug Library and Clinical Compound Library (2718 compounds). We found that AT7519 significantly inhibited the cell viability and proliferation of U87MG, U251, and patient-derived primary GBM cells in a dose-dependent manner. Furthermore, AT7519 also inhibited the phosphorylation of CDK1/2 and arrested the cell cycle at the G1-S and G2-M phases. More importantly, AT7519 induced intrinsic apoptosis and pyroptosis via caspase-3-mediated cleavage of gasdermin E (GSDME). In the glioblastoma intracranial and subcutaneous xenograft assays, tumor volume was significantly reduced after treatment with AT7519. In summary, AT7519 induces cell death through multiple pathways and inhibits glioblastoma growth, indicating that AT7519 is a potential chemical available for GBM treatment.

A simulated toxic assessment of cesium on the blue mussel Mytilus edulis provides evidence for the potential impacts of nuclear wastewater discharge on marine ecosystems.

The toxic effects of cesium (Cs) on the blue mussel Mytilus edulis were experimentally investigated to assess the potential environmental consequences of the discharge of nuclear wastewater containing radionuclides. A simulated experimental system of stable cesium (133Cs) was set up to mimic the impacts of radiocesium, and its heavy metal property was emphasized. The mussels were exposed to a concentration gradient of 133Cs for 21 days, followed by another 21-day elimination period. 133Cs exposure resulted in effective bioaccumulation with distinct features of concentration dependence and tissue specificity, and hemolymph, gills and digestive glands were recognized as the most target tissues for accumulation. Although the elimination period was helpful in reducing the accumulated 133Cs, the remaining concentrations of tissues were still significant. 133Cs exposure presented little effect on growth status at the individual level but had distinct interference on feeding and metabolism indicated by the oxygen consumption rate, ammonia-N excretion rate and O:N ratio, simultaneously with the impairment of digestive glands. Regarding hemocytes in the hemolymph, the cell mortality increment, micronucleus promotion, lysosomal membrane stability disruption and phagocytic ability inhibition suggested that the immune function was injured. The cooccurrence of reactive oxygen species overproduction had a close relationship with the observed damages and was thought to be the possible explanation for the immune toxicity. The assay based integrated biomarker response (IBR) presented a good linear relation with the exposure concentrations, suggesting that it was a promising method for assessing the risk of 133Cs. The results indicated that 133Cs exposure damaged M. edulis at the tissue and cell before at the macroscopic individual, evidencing the potentially detrimental impacts of nuclear wastewater discharge on marine ecosystems.

Defense against oxidative stress in Caenorhabditis elegans by dark tea.

Dark tea, rich in nutricines including tea polyphenols and free amino acids, is a kind of post-fermented tea. The potential application of nutricines against oxidative damage and senescence, which drives animal health maintenance and disease prevention, has attracted considerable interest. In this study, the effect of dark tea and its effects on longevity and defense against oxidative stress was investigated in the Caenorhabditis elegans (C. elegans) model. Under normal conditions, dark tea extended the lifespan without significant impairment of propagation. It also improved the motility, alleviated the fat accumulation and apoptosis. Additionally, orally administered dark tea could significantly decrease the level of reactive oxygen species (ROS) and resulted in a superior lifespan in H2O2-induced oxidative stressed C. elegans. In antioxidant assays in vitro, dark tea was found to be rich in strong hydroxyl, DPPH and ABTS+ free radical scavenging capacity. Interestingly, mRNA sequence analyses further revealed that dark tea may catalyze intracellular relevant oxidative substrates and synthesize antioxidants through synthetic and metabolic pathways. These results suggest that dark tea is worth further exploration as a potential dietary supplement for the maintenance of animal health and the prevention of related diseases.

Ultrasound deep brain stimulation decelerates telomere shortening in Alzheimer's disease and aging mice.

Telomere length is a reliable biomarker for health and longevity prediction in both humans and animals. The common neuromodulation techniques, including deep brain stimulation (DBS) and optogenetics, have excellent spatial resolution and depth penetration but require implementation of electrodes or optical fibers. Therefore, it is important to develop methods for noninvasive modulation of telomere length. Herein, we reported on a new method for decelerating telomere shortening using noninvasive ultrasound deep brain stimulation (UDBS). Firstly, we found that UDBS could activate the telomerase-associated proteins in normal mice. Then, in the Alzheimer's disease mice, UDBS was observed to decelerate telomere shortening of the cortex and myocardial tissue and to effectively improve spatial learning and memory abilities. Similarly, UDBS was found to significantly slow down telomere shortening of the cortex and peripheral blood, and improve motor and cognitive functions in aging mice. Finally, transcriptome analysis revealed that UDBS upregulated the neuroactive ligand-receptor interaction pathway. Overall, the present findings established the critical role of UDBS in delaying telomere shortening and indicated that ultrasound modulation of telomere length may constitute an effective therapeutic strategy for aging and aging-related diseases.