Topoisomerase 1 inhibition modulates pyroptosis to improve recovery after spinal cord injury.

Excessive neuroinflammation and neuronal loss contribute to mechanisms of spinal cord injury (SCI). Accumulating evidence has suggested that topoisomerase 1 (Top1) inhibition can suppress exacerbated immune responses and protect against lethal inflammation. Pyroptosis is a recently identified pro-inflammatory programmed mode of cell death. However, the effects and underlying mechanisms of Top1 inhibition in SCI remains unclear. Locomotor functional recovery in mice was evaluated through Basso Mouse Scale (BMS). Neuronal loss was evaluated by immunochemistry staining of NeuN. Pyroptosis was determined by immunofluorescence staining, western blot, flow cytometry, cell viability, and cytotoxicity assays. In the present study, we estimated the effects of chemical inhibition of Top1 in an SCI model. Administration of Top1 inhibitor camptothecin (CPT) to mice significantly improved locomotor functional recovery after SCI. Moreover, CPT reduced Top1 level, inhibited nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome activation and pyroptosis, attenuated proinflammatory cytokines levels, diminished the number of neutrophil and neuronal loss in mice. Furthermore, CPT in oxygen-glucose deprivation neurons down-regulated Top1 level, attenuated NLRP3 inflammasome activation, and suppressed pyroptosis and inflammatory response. Together, our findings indicate that inhibition of Top1 with CPT can inhibit pyroptosis, control neuroinflammation, and improve functional recovery after SCI.

The Potency of Serum Omentin-1 Quantification in Predicting Major Adverse Cardiac and Cerebrovascular Events Risk in Patients Receiving Hemodialysis.

Omentin-1 regulates inflammation, lipid accumulation, endothelial dysfunction, and atherosclerosis; the latter factors contribute to the occurrence of major adverse cardiac and cerebrovascular events (MACCE). This study aimed to explore the predictive implication of serum omentin-1 for MACCE risk in patients receiving hemodialysis. A total of 319 patients receiving hemodialysis and 160 healthy controls were prospectively enrolled in this study. Omentin-1 from serum was detected by enzyme-linked immunosorbent assay. MACCE was recorded during follow-up (median 18.9 months; range 1.9-62.9 months) in patients receiving hemodialysis. Omentin-1 was reduced in patients receiving hemodialysis versus healthy controls (P < 0.001). In patients receiving hemodialysis, omentin-1 was negatively related to C-reactive protein, total cholesterol, and low-density lipoprotein cholesterol (all P < 0.05); whereas omentin-1 was not related to other clinical characteristics. Notably, the 1-year, 2-year, 3-year, 4-year, and 5-year accumulating MACCE rates in patients receiving hemodialysis were 7.9%, 18.3%, 25.9%, 36.1%, and 41.4%, respectively. Interestingly, high omentin-1 related to decreased accumulating MACCE rate (P = 0.003), which was further validated by multivariate Cox regression analysis (hazard ratio = 0.458, P = 0.006). Additionally, by direct comparison, omentin-1 was reduced in hemodialysis patients who experienced MACCE compared to those who did not (P < 0.001); meanwhile, the receiver operator characteristic curve displayed that omentin-1 had an acceptable ability to estimate MACCE risk with an area under the curve (95% confidence interval) of 0.703 (0.628-0.777). Serum omentin-1 reflects reduced inflammation and lipid accumulation, as well as predicts decreased MACCE risk in patients receiving hemodialysis.

Longitudinal change in microRNA-130a expression and its correlation with the risk of developing major adverse cardiovascular and cerebral events in patients undergoing continuous ambulatory peritoneal dialysis.

BACKGROUND: MicroRNA-130a (miR-130a) regulates angio-cellular dysregulation, atherosclerosis, and cardiocerebral injuries, serving as a biomarker for major adverse cardiovascular and cerebral events (MACCE) in several chronic diseases. However, its clinical application in patients with end-stage renal disease (ESRD) undergoing continuous ambulatory peritoneal dialysis (CAPD), who are at a high risk of developing MACCE, has not been reported. Therefore, this study aimed to explore this aspect. METHODS: miR-130a expression in peripheral blood mononuclear cells obtained from 50 healthy controls (HCs) at recruitment and 257 ESRD patients undergoing CAPD at month (M)0, M12, M24, and M36 was determined by reverse transcription-quantitative polymerase chain reaction. ESRD patients undergoing CAPD were followed up until MACCE occurred or M36. Then, MACCE were recorded, and MACCE-free survival was calculated. RESULTS: miR-130a expression was significantly lower in ESRD patients undergoing CAPD than in HCs (p < 0.001). In addition, miR-130a expression significantly decreased from M0 to M36 in ESRD patients undergoing CAPD (p < 0.001). Moreover, miR-130a expression at M0, M12, and M24 was significantly lower in patients with MACCE than in those without MACCE (all p < 0.05). Furthermore, high miR-130a expression at M0, M12, and M36 was significantly correlated with prolonged MACCE-free survival in ESRD patients undergoing CAPD (all p < 0.05), and high miR-130a expression at M0 was an independent factor for improved MACCE-free survival (p = 0.015; hazard ratio (HR) (95% confidential interval): 0.456 (0.243-0.857)). CONCLUSION: miR-130a expression decreases continuously with disease progression in patients with ESRD undergoing CAPD. Additionally, this expression is negatively correlated with MACCE risk in these patients.

Dopamine inhibits pyroptosis and attenuates secondary damage after spinal cord injury in female mice.

BACKGROUND: An excessive inflammatory response accompanies the pathogenesis of spinal cord injury (SCI) and has been found to be promoted by inflammasomes in a variety of disease models. Dopamine is a neurotransmitter that also regulates nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome-dependent neuroinflammation. However, little is known regarding the effects and molecular mechanisms underlying the role of dopamine in SCI. METHODS: Functional recovery in mice was assessed with the Basso Mouse Scale (BMS). Neuronal loss was evaluated with immunochemical staining of NeuN. Pyroptosis was assessed with immunofluorescence staining, flow cytometry, western blotting, and cell viability and cytotoxicity assays. RESULTS: Dopamine was significantly associated with enhanced locomotor recovery after SCI, and with decreased NLRP3 inflammasome activation, pyroptosis, neuronal loss and pro-inflammatory cytokine levels. In vitro data suggested that dopamine suppressed NLRP3 inflammasome activation and pyroptosis, and decreased pro-inflammatory cytokine levels. CONCLUSIONS: Dopamine may be a novel approach for alleviating secondary damage after SCI.

Elamipretide reduces pyroptosis and improves functional recovery after spinal cord injury.

AIMS: Elamipretide (EPT), a novel mitochondria-targeted peptide, has been shown to be protective in a range of diseases. However, the effect of EPT in spinal cord injury (SCI) has yet to be elucidated. We aimed to investigate whether EPT would inhibit pyroptosis and protect against SCI. METHODS: After establishing the SCI model, we determined the biochemical and morphological changes associated with pyroptosis, including neuronal cell death, proinflammatory cytokine expression, and signal pathway levels. Furthermore, mitochondrial function was assessed with flow cytometry, quantitative real-time polymerase chain reaction, and western blot. RESULTS: Here, we demonstrate that EPT improved locomotor functional recovery following SCI as well as reduced neuronal loss. Moreover, EPT inhibited nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome activation and pyroptosis occurrence and decreased pro-inflammatory cytokines levels following SCI. Furthermore, EPT alleviated mitochondrial dysfunction and reduced mitochondrial reactive oxygen species level. CONCLUSION: EPT treatment may protect against SCI via inhibition of pyroptosis.

Visualizing the Scripts of Data Wrangling With Somnus.

Data workers use various scripting languages for data transformation, such as SAS, R, and Python. However, understanding intricate code pieces requires advanced programming skills, which hinders data workers from grasping the idea of data transformation at ease. Program visualization is beneficial for debugging and education and has the potential to illustrate transformations intuitively and interactively. In this article, we explore visualization design for demonstrating the semantics of code pieces in the context of data transformation. First, to depict individual data transformations, we structure a design space by two primary dimensions, i.e., key parameters to encode and possible visual channels to be mapped. Then, we derive a collection of 23 glyphs that visualize the semantics of transformations. Next, we design a pipeline, named Somnus, that provides an overview of the creation and evolution of data tables using a provenance graph. At the same time, it allows detailed investigation of individual transformations. User feedback on Somnus is positive. Our study participants achieved better accuracy with less time using Somnus, and preferred it over carefully-crafted textual description. Further, we provide two example applications to demonstrate the utility and versatility of Somnus.

Topotecan Reduces Neuron Death after Spinal Cord Injury by Suppressing Caspase-1-Dependent Pyroptosis.

Neuronal loss and excessive inflammatory response mediate the pathogenesis of spinal cord injury (SCI). Topotecan (TPT), a topoisomerase 1 (Top 1) inhibitor, is recently revealed to control lethal inflammation. Top 1 is an essential enzyme in mammalian cells and acts as a key role in the DNA replication, transcription, and repair. However, the effects and underlying mechanisms of TPT in SCI remain unclear. Here, we report that topotecan (TPT), a Top 1 inhibitor, led to a significant recovery of hindlimb locomotor function in mice. Moreover, TPT reduced Top 1 level, prevented nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasome activation, reduced caspase-1 expression and pyroptosis, and decreased the levels of pro-inflammatory cytokines and the number of neutrophils in mice. Furthermore, TPT suppressed NLRP3 inflammasome activation, diminished caspase-1 expression and pyroptosis, and reduced pro-inflammatory cytokines levels in neurons. In addition, inhibition of caspase-1 by VX-765 inhibited pyroptosis and reduced proinflammatory cytokine levels in mice. Furthermore, administration of VX-765 suppressed pyroptosis and alleviated cell damage in primary cultured neurons. Our findings suggest that TPT with specific dose and duration reduces neuron death and improves functional recovery after SCI presumably depends on inhibition of caspase-1-dependent pyroptosis.

Effect of tumor-associated macrophages on lncRNA PURPL/miR-363/PDZD2 axis in osteosarcoma cells.

Tumor-associated macrophages (TAMs) are known to participate in osteosarcoma (OS) progression. As demonstrated in our previous research, miR-363 played a tumor inhibitory effect in OS cells via lowering the PDZ domain containing 2 (PDZD2) expression. The regulatory roles of TAMs on miR-363/PDZD2 and the internal mechanism relating to long noncoding RNA p53 upregulated regulator of P53 levels (lncRNA PURPL) are examined in this study. TAM-like macrophages were formed by inducing CD14+ peripheral blood mononuclear cells (PBMCs). The TAMs migration was detected after MG-63 cells transfected with miR-363 mimics or inhibitors. We then analyzed the regulatory activity of PURPL on miR-363 expression. We also tested the influences of PURPL overexpression/knockdown on MG-63 cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), as well as TAMs migration. Silence in PDZD2 expression was used to confirm the effects of PURPL on MG-63 cells. We successfully induced TAM-like macrophages. MG-63 cells transfecting miR-363 mimics suppressed TAMs migration while transfecting a converse effect was seen in miR-363 inhibitor. TAMs raised PURPL expression in MG-63 cells, which was an upstream regulator of miR-363. Along with TAMs migration, PURPL overexpression promoted MG-63 cell proliferation, migration, invasion, and EMT. An opposite influence was seen due to the PURPL knockdown. The silence of PDZD2 weakened the influences of PURPL overexpression on MG-63 cells and TAMs migration. On modulating the PURPL/miR-363/PDZD2 axis, TAMs-promoted OS development might be achieved.

Efficacy and safety of ifosfamide-based chemotherapy for osteosarcoma: a meta-analysis.

BACKGROUND: The efficacy of ifosfamide-based chemotherapy in the treatment of osteosarcoma has been investigated; however, results are inconsistent. Therefore, we reviewed the relevant studies and conducted a meta-analysis to assess the efficacy of ifosfamide-based chemotherapy in patients with osteosarcoma. METHODS: A systematic literature search on PubMed, Embase, and Web of Science databases was performed. Eligible studies were clinical trials of patients with osteosarcoma who received ifosfamide-based chemotherapy. Hazard ratios (HRs) were pooled to compare event-free survival (EFS) and overall survival (OS). Risk ratios (RRs) were pooled to compare good histologic response rates and adverse event incidence. Meta-analysis was performed using a fixed-effects model or a random-effects model according to heterogeneity. RESULTS: A total of seven randomized controlled trials were included in this meta-analysis. Pooled results showed that ifosfamide-based chemotherapy significantly improved EFS (HR=0.72, 95% confidence interval [CI]: 0.63, 0.82; P=0.000) and OS (HR=0.83, 95% CI: 0.70, 0.99; P=0.034); furthermore, this form of chemotherapy increased good histologic response rate (RR=1.27, 95% CI: 1.10, 1.46; P=0.001). In addition, patients in the ifosfamide group exhibited a significantly higher incidence of fever (RR=2.23, 95% CI: 1.42, 3.50; P=0.000) and required more frequent platelet transfusion (RR=1.92, 95% CI: 1.23, 3.01; P=0.004). CONCLUSION: This meta-analysis confirmed that ifosfamide-based chemotherapy can significantly improve EFS and OS; this chemotherapy can also increase good histologic response rate in patients with osteosarcoma. However, evidence may be limited by potential biases and confounders. Thus, large-scale well-designed randomized controlled trials are needed to verify current findings.