Palladium/Platinum/Ruthenium Trimetallic Dendritic Nanozymes Exhibiting Enhanced Peroxidase-like Activity for Signal Amplification of Lateral Flow Immunoassays.

Developing ultrasensitive lateral flow immunoassays (LFIAs) has garnered significant attention in the field of point-of-care testing. In this study, a trimetallic dendritic nanozyme (Pd@Pt-Ru) was synthesized through Ru deposition on a Pd@Pt core and utilized to enhancing the sensitivity of LFIAs. Pd@Pt-Ru exhibited a Km value of 5.23 mM for detecting H2O2, which indicates an H2O2 affinity comparable with that of horseradish peroxidase. The Ru surface layer reduces the activation energy barrier, which increases the maximum reaction rate. As a proof of concept, the proposed Pd@Pt-Ru nanozyme was incorporated into LFIAs (A-Pd@Pt-Ru-LFIAs) for detecting human chorionic gonadotropin (hCG). Compared with conventional gold nanoparticle (AuNP)-LFIAs, A-Pd@Pt-Ru-LFIAs demonstrated 250-fold increased sensitivity, thereby enabling a visible detection limit as low as 0.1 IU/L. True positive and negative rates both reached 100%, which renders the proposed Pd@Pt-Ru nanozyme suitable for detecting hCG in clinical samples.

Enhancing the Performance of Tyndall-Powell Gate Ion Mobility Spectrometry by Combining Ion Enrichment, Discrimination Reduction, and Temporal Compression into a Single Gating Process.

The broad applications of ion mobility spectrometry (IMS) demand good sensitivity and resolving power for ion species with different reduced mobilities (K0). In this work, a new Tyndall-Powell gate (TPG) gating method for combining ion enrichment, mobility discrimination reduction, and temporal compression into a single gating process is proposed to improve IMS analysis performance. The two-parallel-grid structure and well-confined gate region of the TPG make it convenient to spatiotemporally vary the electric fields within and around the gate region. Under the new gating method, a potential wave is applied on TPG grid 1 to enrich ions within the ionization region adjacent to the TPG during the gate-closed state; meanwhile, a potential wave is applied on TPG grid 2 to enhance mobility discrimination reduction and temporal compression simultaneously during the gate-open state. For triethyl phosphate (TEP) and dimethyl methylphosphonate mixtures, product ion peaks within K0 of 1.9 to 1.1 cm2/V·s exhibit a 19-fold increase in ion current compared to the traditional TPG gating method, while maintaining a resolving power of 85. The estimated limit of detection for the TEP dimer is lowered from 8 ppb to 135 ppt. The new gating method can be applied to other TPG-based IMS systems to enhance their performance in analyzing complex samples.

Bruceantinol targeting STAT3 exerts promising antitumor effects in in vitro and in vivo osteosarcoma models.

Bruceantinol (BOL) is a quassinoid compound found in the fruits of Brucea javanica. Previous research has highlighted the manifold physiological and pharmacological activities of BOL. Notably, BOL has demonstrated antitumor cytotoxic and antibacterial effects, lending support to its potential as a promising therapeutic agent for various diseases. Despite being recognized as a potent antitumor inhibitor in multiple cancer types, its efficacy against osteosarcoma (OS) has not been elucidated. In this work, we investigated the antitumor properties of BOL against OS. Our findings showed that BOL significantly decreased the proliferation and migration of OS cells, induced apoptosis, and caused cell death without affecting the cell cycle. We further confirmed that BOL potently suppressed tumor growth in vivo. Mechanismly, we discovered that BOL directly bound to STAT3, and prevent the activation of STAT3 signaling at low nanomolar concentrations. Overall, our study demonstrated that BOL potently inhibited the growth and metastasis of OS, and efficiently suppressed STAT3 signaling pathway. These results suggest that BOL could be a promising therapeutic candidate for OS.

Natural pyrethrins induce cytotoxicity in SH-SY5Y cells and neurotoxicity in zebrafish embryos (Danio rerio).

Natural pyrethrins are widely used in agriculture because of their good insecticidal activity. Meanwhile, natural pyrethrins play an important role in the safety evaluation of pyrethroids as precursors for structural development of pyrethroid insecticides. However, there are fewer studies evaluating the neurological safety of natural pyrethrins on non-target organisms. In this study, we used SH-SY5Y cells and zebrafish embryos to explore the neurotoxicity of natural pyrethrins. Natural pyrethrins were able to induce SH-SY5Y cells damage, as evidenced by decreased viability, cycle block, apoptosis and DNA damage. The apoptotic pathway may be related to the involvement of mitochondria and the results showed that natural pyrethrins induced a rise in Capase-3 viability, Ca2+ overload, a decrease in adenosine triphosphate (ATP) and a collapse of mitochondrial membrane potential in SH-SY5Y cells. Natural pyrethrins may mediate DNA damage in SH-SY5Y cells through oxidative stress. The results showed that natural pyrethrins induced an increase in reactive oxygen species (ROS) levels, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and catalase (CAT) activity, and induced a decrease in glutathione peroxidase (GPx) activity in SH-SY5Y cells. In vivo, natural pyrethrins induced developmental malformations in zebrafish embryos, which were mainly characterized by pericardial edema and yolk sac edema. Meanwhile, the results showed that natural pyrethrins induced damage to the Huc-GFP axis and disturbed lipid metabolism in the head of zebrafish embryos. Further results showed elevated ROS levels and apoptosis in the head of zebrafish embryos, which corroborated with the results of the cell model. Finally, the results of mRNA expression assay of neurodevelopment-related genes indicated that natural pyrethrins exposure interfered with their expression and led to neurodevelopmental damage in zebrafish embryos. Our study may raise concerns about the neurological safety of natural pyrethrins on non-target organisms.

Clinical characteristics analysis of pediatric spinal cord injury without radiological abnormality in China: a retrospective study.

PURPOSE: This study aims to analyze the clinical characteristics of Chinese children with spinal cord injury (SCI) without radiographic abnormality (SCIWORA) and explore their contributing factors and mechanisms of occurrence. METHODS: A retrospective analysis was conducted on the clinical data of pediatric patients diagnosed with SCIWORA from January 2005 to May 2020. Epidemiological, etiological, mechanistic, therapeutic, and outcome aspects were analyzed. RESULTS: A total of 47 patients with SCIWORA were included in this study, comprising 16 males and 31 females. The age range was 4 to 12 years, with an average age of 7.49 ± 2.04 years, and 70% of the patients were below eight. Sports-related injuries constituted 66%, with 70% attributed to dance backbend practice. Thoracic segment injuries accounted for 77%. In the American Spinal Injury Association (ASIA) classification, the combined proportion of A and B grades accounted for 88%. Conservative treatment was chosen by 98% of the patients, with muscle atrophy, spinal scoliosis, hip joint abnormalities, and urinary system infections being the most common complications. CONCLUSION: SCIWORA in Chinese children is more prevalent in those under eight years old, with a higher incidence in females than males. Thoracic spinal cord injuries are predominant, dance backbend as a primary contributing factor, and the social environment of "neijuan" is a critical potential inducing factor. Furthermore, the initial severity of the injury plays a decisive role in determining the prognosis of SCIWORA.

Association between cup orientation and low back pain after total hip arthroplasty in patients with osteonecrosis of the femoral head.

BACKGROUND: Postoperative low back pain (LBP) following total hip arthroplasty (THA) is classified as secondary hip-spine syndrome. The purpose of this study was to explore the correlations between cup orientation of THA and postoperative LBP in patients with osteonecrosis of the femoral head (ONFH). METHODS: A retrospective cohort study included 364 ONFH patients who underwent bilateral THA between January 2011 and December 2020. Among them, 53 patients (14.6%) experienced postoperative LBP at the end of follow-up and were designated as pain group (PG). A control group (CG) consisting of 106 patients with similar age, sex, and body mass index (BMI) to those in the PG was selected. Postoperative LBP in the PG was assessed using the visual analogue scale (VAS). Demographic data, clinical information, and radiographic criteria were evaluated as potential predictors of LBP. RESULTS: Patients in PG (mean age, 47.3 years [range, 27 to 75 years]; 42 [79%] male) had a mean VAS score of 4.6 (range, 1 to 9) compared with 0 for the patients in CG (mean age, 47.6 years [range, 19 to 77 years]; 84 [79%] male). There were no significant differences in clinical data between the two groups (p > 0.05). Preoperative radiographic variables also showed no significant differences between the PG and CG (p > 0.05). However, the postoperative inclination, anteversion, and standing ante-inclination (AI) were significantly lower in the PG compared to the CG, whereas the sitting and standing sacral slope (SS) were significantly higher (p < 0.05). Moreover, the variations in standing AI, standing and sitting pelvic tilt (PT) were significantly lower in the PG compared to the CG, while the variations in standing and sitting SS and lumbar lordosis (LL) were significantly higher (p < 0.05). The variation in standing AI in the PG showed a significantly correlation with the variation of standing SS, standing PT, and LL (p < 0.05). CONCLUSION: Postoperative LBP in ONFH patients after bilateral THA is significantly associated with the intraoperative cup orientation. The variation in standing AI is correlated with the variations in standing SS, standing PT, and LL, potentially contributing to the development of postoperative LBP.

Intrauterine Device Migrated into the Urachus: A Case Report.

Background: The intrauterine device is the most commonly used female contraceptive device, but the related complications of intrauterine devices are also common. Sometimes, intrauterine devices can cause uterine perforation, migrating into the abdominal cavity or other organs. At the same time, the intrauterine device may break into several small segments, migrate to distant organs, and even cause misdiagnosis. Objective: This study assessed the role of laparoscopy in treating intrauterine device migration. Design: This was a retrospective study involving in a review of a single case. Setting: This study was conducted at Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University. Participants: This study focued on a single case acout a 64-year-old female patient presented with repeated painless gross hematuria. She had a history of placing an intrauterine device and "removed the intrauterine device" in a local hospital for 20 years. Interventions: Laparoscopic ureterectomy was chosen based on the specific findings from the computerized tomography scan and cystoscopy. Abdominal computerized tomography showed high-density foreign body under the abdominal wall, size 2.29×0.51 cm, showed signs of edema in the surrounding tissue, and it was connected to the bladder wall. High-density lesions in the urachus and urachus calculi were considered. Cystoscopy showed the bubble position on the top of the bladder was depressed, a dark foreign body seemed to be seen inside, and the local mucosa was congested. The urachus foreign body, the urachus stone, was considered. Results: Computerized tomography examination showed a high-density space-occupying lesion at the position of the bladder and urachus tube. Cystoscopy showed local congestion at the top of the bladder, like urachus and dark foreign bodies, and no obvious abnormality in other parts of the bladder. Laparoscopy showed the urachus position was congested and edema, with local adhesion of the greater omentum and foreign bodies. The foreign bodies and surrounding tissues were removed by laparoscopic ureterectomy. Pathology showed tubular tissue, metal and plastic foreign bodies, fibrous tissue proliferation, and chronic inflammatory cell infiltration around the foreign bodies. Conclusion: The intrauterine device is a common contraceptive tool, and intrauterine device rupture and migration are normal. Migration to rare locations can lead to misdiagnosis. It can be removed by endoscopy, and combined with imaging and pathological examination, a correct diagnosis can finally be obtained. The patients should be advised to undergo regular check-ups after the procedure. These cases may provide diagnostic reference for similar symptoms of intrauterine device migration.

Studies on immunotoxicity induced by emamectin benzoate in zebrafish embryos based on metabolomics.

Emamectin benzoate (EMB) is an insecticide for the control of agricultural lepidoptera pests, and also an anti-parasiticide for the control of exoparasites in aquaculture industry. Increased studies suggest that EMB could cause toxicity to non-targeted organisms, but its immunotoxicity to human remains unclear. In this study, zebrafish were used to investigate the immunotoxic effects induced by environmentally relevant doses of EMB. We observed that EMB exposure led to embryo mortality and delayed hatching, as well as increased malformations. Meanwhile, zebrafish exposed to EMB exhibited a significant decrease in the number of neutrophils and macrophages. In addition, untargeted metabolomics approach was developed to elucidate the mechanism of EMB-induced immunotoxicity. We found that a total of 10 shared biomarkers were identified in response to EMB exposure. Furthermore, pathway analysis identified glycerophospholipid metabolism was the most relevant pathway. Within this pathway, it was observed abnormal increases in glycerol 3-phosphate content, which could be attributed to the increased expression of GK5 and decreased expression of GPAT3. Our study provided novel and robust perspectives, which showed that EMB exposure to zebrafish embryos could cause metabolic disturbances that adversely affected development and immune system.

Association of foods consumption and physical activity with prefrailty and frailty among Chinese older adults in urban communities: A cross-sectional study.

BACKGROUND AND OBJECTIVES: Frailty has become a public health challenge in China. To investigate the association of foods consumption and physical activity with prefrailty and frailty among older Chinese adults in urban communities. METHODS AND STUDY DESIGN: In a cross-sectional study from February to July 2023, 1183 older adults aged between 65y-88y were enrolled from urban communities in Chongqing and Shandong province, China. Frailty Index (FI) was applied to measure prefrailty and frailty. Partial proportional odds model was used to assess the association between foods consumption, physical activity and prefrailty/frailty. RESULTS: Higher Dietary Diversity Score (DDS), (OR=0.61, 95% CI=0.46-0.80; OR=0.47, 95% CI=0.28-0.79), Consuming animal-based foods ≥2 times/day (OR=0.62, 95% CI=0.47-0.82; OR=0.54, 95% CI=0.33-0.88), soy products ≥2 times/week (OR=0.69, 95% CI=0.53-0.89; OR=0.51, 95% CI=0.31-0.84), fresh vegetables ≥2 times/day (OR=0.42, 95% CI=0.31-0.57; OR=0.41, 95% CI=0.23-0.72), and nuts ≥2 times/week (OR=0.71, 95% CI=0.55-0.91; OR=0.52, 95% CI=0.32-0.85) was associated with a lower risk of prefrailty and frailty. In addition, higher frequency and longer duration of walking (OR=0.61, 95% CI=0.42-0.88; OR=0.63, 95% CI=0.48-0.81), exercise (OR=0.48, 95% CI=0.35-0.64; OR=0.44, 95% CI=0.32-0.61) per week were significantly associated with lower risk of prefrailty. Furthermore, higher frequency and longer duration of walking (OR=0.42, 95% CI=0.25-0.72; OR=0.46, 95% CI=0.29-0.74), and housework (OR=0.39, 95% CI=0.24-0.65; OR=0.57, 95% CI=0.34-0.96) per week, were significantly associated with lower frailty. CONCLUSIONS: Higher DDS and higher frequency of animal-based foods, soy products, fresh vegetables, and nuts consumption is significantly associated with lower risk of prefrailty and frailty. Additionally, walking and exercising are significantly associated with lower risk of prefrailty, while walking and doing housework is significantly associated with lower frailty.

Osseous factors influencing distal tibial rotation in biplane medial opening wedge high tibial osteotomy.

PURPOSE: There is a lack of studies investigating the distal tibial rotation (DTR) during medial opening wedge high tibial osteotomy (MOWHTO). This study was designed to evaluate osseous factors influencing DTR in patients who underwent biplane MOWHTO. METHODS: A total of 106 knee joints in 69 patients who underwent surgery for varus malalignment of knee were reviewed. Based on several software, standard and actual hinge positions were defined in pre-operative and post-operative CT data. Pearson's correlation and Spearman's correlation analysis were performed with DTR change as the dependent variable. Independent variables included angles between standard and actual hinge in the sagittal (ASAHS) and axial (ASAHA) planes, pre-operative and post-operative medial proximal tibial angle, opening width (OW), tuberosity osteotomy angle, flange angle (FA), gap ratio, and hinge fracture. RESULTS: The distal tibia rotated approximately 0.35° internally. Pearson's and Spearman's correlation analysis showed that DTR change was associated with ASAHS, OW, and FA. Larger OW and FA resulted in higher external rotation angles. CONCLUSIONS: DTR change was significantly associated with ASAHS, followed by OW and FA rather than ASAHA if only considering osseous factors in biplane MOWHTO. The distal tibia tended to rotate externally when the actual hinge was inclined posteriorly to the standard hinge in the sagittal planes, but rotate externally or internally when the actual hinge was inclined anteriorly.

Preoperative evaluation of femoral and tibial sagittal alignment in robotic-assisted and conventional total knee arthroplasty and consequences for practice.

PURPOSE: Robot-assisted total knee arthroplasty (TKA) was developed to improve the precision and accuracy of implant placement in conventional TKA. However, the angular differences between referenced axes in robot-assisted TKA and conventional TKA remain unclear. The aim of this study was to investigate the angular differences in sagittal alignment between robot-assisted TKA and conventional TKA for both the femur and the tibia and to discuss their clinical implications. METHODS: We conducted a retrospective analysis of data from 100 patients (97 patients) who underwent computed tomography (CT) for Mako TKA. We measured the angle between the robot femoral axis (RFA) and conventional femoral axis (CFA) in the sagittal plane and the angle between the robot tibial axis (RTA) and the conventional tibial axis (CTA). Angles were compared between the sexes. Correlation analysis was conducted between the angles and height. RESULTS: In the sagittal plane, the mean RFA-CFA angle was 2.2° ± 1.6°, and the mean RTA-CTA angle was 2.3° ± 1.6°. There were no significant differences between the two angles among males and females (p > 0.05). There was a correlation between the RFA-CFA angle and RTA-CTA angle (p < 0.001, r = 0.33), and there was a correlation between height and the combination of the RFA-CFA angle and RTA-CTA angle (p = 0.03, r = 0.22). CONCLUSION: There are angular differences between the axes referenced by robot-assisted TKA and those referenced by conventional TKA, which may be influenced by patient height. Correctly understanding these differences is crucial when evaluating the implant position and surgical outcomes after robot-assisted TKA. Furthermore, caution should be taken when assessing the flexion-extension angle of the knee since the angles displayed in the Mako system are different from the angles measured with intramedullary anatomical axes. After all, sagittal alignment principles differ between robot-assisted and conventional TKA; however, further studies are required to determine which principle is more appropriate or to modify these principles.

Does patient-specific instrument or robot improve imaging and functional outcomes in unicompartmental knee arthroplasty? A bayesian analysis.

INTRODUCTION: This study conducted a Bayesian network meta-analysis (NMA) to compare the imaging and functional outcomes of patient-specific instrument-assisted unicompartmental knee arthroplasty (P-UKA), robot-assisted unicompartmental knee arthroplasty (R-UKA), and conventional unicompartmental knee arthroplasty (C-UKA). MATERIALS AND METHODS: A comprehensive search was performed on five electronic databases and major orthopedic journals as of September 24, 2023. We included randomized controlled studies featuring at least two interventions of P-UKA, R-UKA, or C-UKA. Primary outcomes encompassed the deviation angle of hip-knee-ankle angle, as well as the coronal and sagittal plane alignment of femoral and tibial components. Secondary outcomes included patient-reported outcome measures (PROM), surgery time, revision rate, and complication rate. Bayesian framework was employed for risk ratio (RR) or mean deviation (MD) analysis, and treatment hierarchy was established based on rank probabilities. RESULTS: This NMA included 871 knees from 12 selected studies. In sagittal plane, R-UKA exhibited a significantly reduced deviation angle of femoral component compared to P-UKA (MD: 4.16, 95% CI: 0.21, 8.07), and of tibial component in comparison to C-UKA (MD: -2.45, 95% CI: -4.20, -0.68). Notably, the surgery time was significantly longer in R-UKA than in C-UKA (MD: 15.98, 95% CI: 3.11, 28.88). However, no significant differences were observed in other outcomes. CONCLUSION: Compared with P-UKA or C-UKA, R-UKA significantly improves the femoral and tibial component alignment in the sagittal plane, although this does not translate into discernible differences in functional outcomes. Comprehensive considerations of economic and learning costs are imperative for the judicious selection of the appropriate procedure.

Combining Multiple Photosensitizer Modules into One Supramolecular System for Synergetic Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT), as an emerging cancer treatment, requires the development of highly desirable photosensitizers (PSs) with integrated functional groups to achieve enhanced therapeutic efficacy. Coordination-driven self-assembly (CDSA) would provide an alternative approach for combining multiple PSs synergistically. Here, we demonstrate a simple yet powerful strategy of combining conventional chromophores (tetraphenylethylene, porphyrin, or Zn-porphyrin) with pyridinium salt PSs together through condensation reactions, followed by CDSA to construct a series of novel metallo-supramolecular PSs (S1-S3). The generation of reactive oxygen species (ROS) is dramatically enhanced by the direct combination of two different PSs, and further reinforced in the subsequent ensembles. Among all the ensembles, S2 with two porphyrin cores shows the highest ROS generation efficiency, specific interactions with lysosome, and strong emission for probing cells. Moreover, the cellular and living experiments confirm that S2 has excellent PDT efficacy, biocompatibility, and biosafety. As such, this study will enable the development of more efficient PSs with potential clinical applications.

BACH1 promotes intervertebral disc degeneration by regulating HMOX1/GPX4 to mediate oxidative stress, ferroptosis, and lipid metabolism in nucleus pulposus cells.

BACKGROUND: Intervertebral disc degeneration (IDD) is a primary health problem worldwide that involves oxidative stress, ferroptosis, and lipid metabolism. However, the underlying mechanism remains unclear. We investigated whether the transcription factor BTB and CNC homology 1 (BACH1) affected IDD progression by regulating HMOX1/GPX4-mediated ferroptosis and lipid metabolism in nucleus pulposus cells (NPCs). METHODS: A rat IDD model was created to detect BACH1 expression in intervertebral disc tissues. Next, rat NPCs were isolated and treated with tert-butyl hydroperoxide (TBHP). BACH1, HMOX1, and GPX4 were knocked down, and oxidative stress and ferroptosis-related marker levels were examined. The binding of BACH1 to HMOX1 and of BACH1 to GPX4 was verified using chromatin immunoprecipitation (ChIP). Finally, untargeted lipid metabolism analysis was performed. RESULTS: An IDD model was successfully created, and BACH1 activity was found to be enhanced in the rat IDD tissues. BACH1 inhibited TBHP-induced oxidative stress and oxidative stress-induced ferroptosis in NPCs. Simultaneously, ChIP verified that BACH1 protein bound to HMOX1 and targeted the HMOX1 transcription inhibition to affect oxidative stress in NPCs. ChIP also verified that BACH1 bound to GPX4 and targeted the GPX4 inhibition to affect ferroptosis in NPCs. Finally, BACH1 inhibition in vivo improved IDD and affected lipid metabolism. CONCLUSIONS: The transcription factor BACH1 promoted IDD by regulating HMOX1/GPX4 to mediate oxidative stress, ferroptosis, and lipid metabolism in NPCs.

The long non-coding RNA KLF3-AS1/miR-10a-3p/ZBTB20 axis improves the degenerative changes in human nucleus pulposus cells.

Excessive apoptosis of intervertebral disc cells, namely nucleus pulposus (NP) cells, results in decreased cell density and extracellular matrix (ECM) catabolism, hence leading to intervertebral disc degeneration (IVDD). As a cell model in the present study, a commercially available human NP cell line was utilized. Long noncoding RNAs and microRNAs may regulate the proliferation or apoptosis of human NP cells, hence exerting a significant influence on the occurrence of IVDD. KLF3-AS1 was discovered to be abnormally downregulated in IVDD tissues. Overexpression of KLF3-AS1 enhanced NP cell viability, prevented cell apoptosis, boosted ECM synthesis, and lowered MMP-13 and ADAMTS4 levels. ZBTB20 and KLF3-AS1 were co-expressed in IVDD; ZBTB20 overexpression had similar effects on NP cells, ECM production, and MMP-13 and ADAMTS4 levels as KLF3-AS1 overexpression. miR-10a-3p may target KLF3-AS1 and ZBTB20 and inhibit the expression of ZBTB20. Inhibition of miR-10a-3p enhanced NP cell viability, reduced apoptosis, and enhanced ECM synthesis. KLF3-AS1 overexpression increased ZBTB20 expression, whereas miR-10a-3p overexpression decreased ZBTB20 expression; miR-10a-3p overexpression reduced the effects of KLF3-AS1 on ZBTB20. Overexpression of miR-10a-3p consistently decreased the effects of KLF3-AS1 overexpression on NP cell survival, apoptosis, and ECM synthesis. In conclusion, KLF3-AS1 overexpression may ameliorate degenerative NP cell alterations through the miR-10a-3p/ZBTB20 axis.

Glyphosate Causes Vascular Toxicity through Cellular Senescence and Lipid Accumulation.

The health risks associated with glyphosate (GLY) have recently received increasing attention. However, its potential vascular toxic effects in occupationally exposed populations remain unclear. This study assessed the effects of GLY on human aortic vascular smooth muscle cells (HAVSMCs) and the relationship between GLY and atherosclerosis. The results demonstrate that GLY induces a relatively larger and more flattened cell morphology, which is typical of cellular senescence and promotes senescence-associated ß-galactosidase activity, as well as the expression of p53, p21, and p16 proteins in HAVSMCs. Regarding toxic effects, GLY induces the accumulation of reactive oxygen species, DNA damage, and mitochondrial damage in HAVSMCs. Mechanistically, the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 pathway is activated in response to oxidative stress produced by GLY. In an in vivo model, GLY led to dyslipidemia and macrophage recruitment in zebrafish vasculature. In conclusion, our results demonstrate that GLY induces vascular toxicity and may be a potential risk for atherosclerosis. These findings highlight the need for concern about cardiovascular risk in occupational populations chronically exposed to GLY.

Blockade of IL-11 Trans-Signaling or JAK2/STAT3 Signaling Ameliorates the Profibrotic Effect of IL-11.

OBJECTIVES: Systemic sclerosis (SSc) is a rare rheumatic disease characterized by vascular damage, dysregulated immune response, and fibrosis. Interleukin-11 (IL-11) is upregulated in SSc. This study aimed to investigate the pathological and therapeutic role of the IL-11 trans-signaling pathway in SSc. METHODS: Plasma IL-11 level was evaluated in 32 patients with SSc and 15 healthy controls, while the expression levels of ADAM10, ADAM17, IL-11, IL-11 Rα, or IL-11 co-stained with CD3 or CD163 in the skin of SSc patients and healthy controls were analyzed. Fibroblasts were treated with IL-11 and ionomycin to evaluate the profibrotic effect of IL-11 trans-signaling pathway. TJ301 (sgp130Fc) and WP1066 (a JAK2/STAT3 inhibitor) intervention groups were set up to investigate the antifibrotic effect of targeting IL-11. RESULTS: Levels of plasma IL-11 were extremely low in most SSc patients and healthy controls. In contrast, levels of IL-11, IL-11 Rα, and ADAM10, but not ADAM17, were significantly elevated in the skin of SSc patients. Moreover, the numbers of IL-11+ CD3+ cells and IL-11+ CD163+ cells were increased in the skin of SSc patients. Besides, IL-11 and ADAM10 were also elevated in the skin and pulmonary of bleomycin-induced SSc mouse. Fibroblasts co-stimulated with IL-11 and ionomycin showed increased expression of COL3 and phosphorylation of STAT3, which could be inhibited by TJ301 or WP1066. TJ301 also ameliorated skin and lung fibrosis in BLM-induced SSc mouse. CONCLUSIONS: IL-11 induces fibrosis in SSc by regulating the trans-signaling pathway. Blockage of sgp130Fc or inhibition of the JAK2/STAT3 pathway could ameliorate the profibrotic effect of IL-11.

HYOU1 promotes cell proliferation, migration, and invasion via the PI3K/AKT/FOXO1 feedback loop in bladder cancer.

BACKGROUND: Hypoxia up-regulated 1 (HYOU1) was identified as a proto-oncogene and involved in tumorigenesis and progression in several cancer. Nonetheless, the biological function and mechanism of HYOU1 in bladder cancer (BCa) remian unclear. METHODS: The HYOU1 level in BCa tissues and cells was examined using RT-qPCR and western blot methods. The relationship between HYOU1 expression and clinicopathologic characteristics of BCa was analyzed. The biological role of HYOU1 on BCa cell proliferation, apoptosis, migration and invasion were analyzed via counting kit-8 (CCK-8), flow cytometry, wound healing and Transwell assays, respectively. The association between HYOU1 and the PI3K/AKT/Forkhead box O1 (FOXO1) signalling was assessed via western blot assay, meanwhile the the association of FOXO1 with HYOU1 was also investigated. RESULTS: HYOU1 was up-regulated in BCa tissues and cell lines, and the high level of HYOU1 was associated with bladder cancer histological grade and pathologic stage. Moreover, patients with high expression of HYOU1 showed poor overall survival from Kaplan-Meier Plotter. HYOU1 depletion impeded cell proliferation, migration and invasion, and induced cell apoptosis, while HYOU1 overexpression promoted cell proliferation, migration and invasion. Mechanically, our results showed that HYOU1 knockdown repressed PI3K/AKT/FOXO1 pathway and HYOU1 was negative regulated by FOXO1 in BCa. Significantly, we confirmed that the HYOU1/PI3K-AKT/FOXO1 negative feedback loop was involved in BCa cell proliferation, migration and invasion. CONCLUSION: These findings revealed that HYOU1 acted as a pro-oncogene on BCa progression, and it will be a possible target for BCa treatment.

Exposure to environmental concentrations of glyphosate induces cardiotoxicity through cellular senescence and reduced cell proliferation capacity.

Glyphosate (GLY), the preeminent herbicide utilized globally, is known to be exposed to the environment and population on a chronic basis. Exposure to GLY and the consequent health risks are alarming public health problems that are attracting international attention. However, the cardiotoxicity of GLY has been a matter of dispute and uncertainty. Here, AC16 cardiomyocytes and zebrafish were exposed to GLY. This study found that low concentrations of GLY lead to morphological enlargement of AC16 human cardiomyocytes, indicating a senescent state. The increased expression of P16, P21, and P53 following exposure to GLY demonstrated that GLY causes senescence in AC16. Moreover, it was mechanistically confirmed that GLY-induced senescence in AC16 cardiomyocytes was produced by ROS-mediated DNA damage. In terms of in vivo cardiotoxicity, GLY decreased the proliferative capacity of cardiomyocytes in zebrafish through the notch signaling pathway, resulting in a reduction of cardiomyocytes. It was also found that GLY caused zebrafish cardiotoxicity associated with DNA damage and mitochondrial damage. KEGG analysis after RNA-seq shows a significant enrichment of protein processing pathways in the endoplasmic reticulum (ER) after GLY exposure. Importantly, GLY induced ER stress in AC16 cells and zebrafish by activating PERK-eIF2α-ATF4 pathway. Our study has thus provided the first novel insights into the mechanism underlying GLY-induced cardiotoxicity. Furthermore, our findings emphasize the need for increased attention to the potential cardiotoxic effects of GLY.

Investigation on the immunotoxicity induced by Emamectin benzoate on THP-1 macrophages based on metabolomics analysis.

Emamectin benzoate (EMB) is an insecticide extensively used in agricultural area. Assessing the toxic effects of EMB in mammals or humans and its endogenous metabolites alteration are the appropriate means of evaluating its risks to human health. In the study, THP-1 macrophage, a human immune model, was applied to investigate the immunotoxicity of EMB. A global metabolomics approach was developed to analyze metabolic perturbation on macrophages and discover the potential biomarkers of EMB-induced immunotoxicity. The results indicated that EMB could inhibit immune functions of macrophages. Based on metabolomics analysis, our results illustrated that EMB caused significant alterations in metabolic profiles on macrophages. 22 biomarkers associated with immune response were screened by pattern recognition and multivariate statistical analysis. Furthermore, pathway analysis identified purine metabolism was the most relevant pathway in the metabolic process and the abnormal conversion of AMP to xanthosine regulated by NT5E might be a potential mechanism of immunotoxicity induced by EMB. Our study provides important insights for understanding and underlying mechanism of immunotoxicity exposed to EMB.