Oxymatrine and Gut Microbiota Modulation: A Potential Therapeutic Strategy for Bone Cancer Pain Management.

Chronic pain often coincides with changes in gut microbiota composition. Yet, the role of gut microbiota in bone cancer pain(BCP) is still not fully understood. This study investigated the role of gut microbiota in BCP and the effect of oxymatrine(OMT) on gut microbiota in BCP. A BCP mice model was developed to assess gut microbiota composition, serum and brain tissue butyric acid levels, and blood-brain barrier(BBB) permeability. Microbiota transplantation was used to restore gut microbiota, and the effect of Clostridium butyricum (C. butyricum) or sodium butyrate(NaB) supplementation on pain-related behaviors and BBB integrity was evaluated. The potential benefits of OMT on gut microbiota composition, PPARγ/COX-2 signaling, BBB integrity, and pain-related behaviors were also explored. BCP significantly altered gut microbiota composition and reduced serum and brain tissue butyric acid levels. Additionally, BBB permeability increased considerably in the BCP group compared to sham and control mice. Microbiota transplantation, as well as C. butyricum or NaB supplementation, ameliorated pain-related behaviors and BBB integrity; the supplementation of C. butyricum or NaB boosted brain tight junction protein expression, potentially through modulating PPARγ/COX-2 signaling. OMT influenced gut microbiota composition and regulated PPARγ/COX-2 signaling in the BCP model, improving pain-related behaviors and BBB integrity. BCP affects gut microbiota composition and butyric acid levels. Modulating gut microbiota and butyric acid levels through transplantation or supplementation may alleviate BCP. OMT shows potential as a treatment by altering gut microbiota composition and regulating PPARγ/COX-2 signaling. These findings provide new insights into BCP pathophysiology and possible treatments. PERSPECTIVE: This study explores the impact of gut microbiota on bone cancer pain (BCP). Microbiota transplantation alleviates BCP and enhances BBB integrity. Also, Clostridium butyricum or sodium butyrate improves BBB via PPARγ/COX-2. Oxymatrine (OMT), a BCP treatment, modifies microbiota by regulating PPARγ/COX-2, in turn improving pain and BBB integrity. These findings suggest a therapeutic approach, emphasizing clinical relevance in targeting gut microbiota and restoring butyric acid levels.

Towards an Optimal KELM Using the PSO-BOA Optimization Strategy with Applications in Data Classification.

The features of the kernel extreme learning machine-efficient processing, improved performance, and less human parameter setting-have allowed it to be effectively used to batch multi-label classification tasks. These classic classification algorithms must at present contend with accuracy and space-time issues as a result of the vast and quick, multi-label, and concept drift features of the developing data streams in the practical application sector. The KELM training procedure still has a difficulty in that it has to be repeated numerous times independently in order to maximize the model's generalization performance or the number of nodes in the hidden layer. In this paper, a kernel extreme learning machine multi-label data classification method based on the butterfly algorithm optimized by particle swarm optimization is proposed. The proposed algorithm, which fully accounts for the optimization of the model generalization ability and the number of hidden layer nodes, can train multiple KELM hidden layer networks at once while maintaining the algorithm's current time complexity and avoiding a significant number of repeated calculations. The simulation results demonstrate that, in comparison to the PSO-KELM, BBA-KELM, and BOA-KELM algorithms, the PSOBOA-KELM algorithm proposed in this paper can more effectively search the kernel extreme learning machine parameters and more effectively balance the global and local performance, resulting in a KELM prediction model with a higher prediction accuracy.

Bio-Inspired Swarm Intelligence Optimization Algorithm-Aided Hybrid TDOA/AOA-Based Localization.

A TDOA/AOA hybrid location algorithm based on the crow search algorithm optimized by particle swarm optimization is proposed to address the challenge of solving the nonlinear equation of time of arrival (TDOA/AOA) location in the non-line-of-sight (NLoS) environment. This algorithm keeps its optimization mechanism on the basis of enhancing the performance of the original algorithm. To obtain a better fitness value throughout the optimization process and increase the algorithm's optimization accuracy, the fitness function based on maximum likelihood estimation is modified. In order to speed up algorithm convergence and decrease needless global search without compromising population diversity, an initial solution is simultaneously added to the starting population location. Simulation findings demonstrate that the suggested method outperforms the TDOA/AOA algorithm and other comparable algorithms, including Taylor, Chan, PSO, CPSO, and basic CSA algorithms. The approach performs well in terms of robustness, convergence speed, and node positioning accuracy.

Fabrication of Ti3Al-Based Intermetallic Alloy by Laser Powder Bed Fusion Using a Powder Mixture.

Due to their light weight and outstanding mechanical properties at high temperatures, Ti3Al-based intermetallic alloys have driven increasing interest from both academia and industry; however, when additive manufacturing (AM) is applied to them, the outcome is hardly satisfying. In this work, we report a crack-free Ti3Al-based alloy fabrication by laser powder bed fusion (LPBF) using a mixture of a commercial Ti-48Al-2Cr-2Nb powder and a pure Ti powder. With the aid of a high cooling rate during LPBF, the as-built sample shows a ductile ß phase with some partially-melted particles. After the heat treatment, partially-melted particles were dissolved, and the sample showed equiaxed α2 precipitates in the ß matrix. The hardness was 515 ± 38 HV in the as-built sample and 475 ± 37 HV in the heat-treated sample. This study shows a novel strategy to fabricate crack-free Ti3Al-based alloy using LPBF from powder blends.

Arecoline promotes proliferation and migration of human HepG2 cells through activation of the PI3K/AKT/mTOR pathway.

BACKGROUND: Arecoline is a well-known risk factor for oral submucosal fibrosis and cancer. However, the mechanistic correlation between arecoline and hepatocellular cancer remains elusive. Here, we investigated the effect of arecoline on the proliferation and migration of human HepG2 hepatoma cells and its potential oncogenic mechanisms. METHODS: Bioinformatic technologies were used to identify the deferentially expressed miRNAs (DE-miRNAs) and hub target genes of arecoline-induced cancers. These DE-miRNAs, hub genes and pathway were proved in arecoline-treated HepG2 cells. RESULTS: A total of 86 DE-miRNAs and 460 target genes were identified. These target genes are associated with DNA-templated regulation of transcription and other biological processes. Significant molecular functions were protein binding, calcium ion binding, and enrichment in the nucleus and cytoplasm. These genes are involved in the PI3K-AKT pathway. CDK1, CCND1, RAF1, CDKN1B and BTRC were defined as the top 5 hub target genes, and patients with high expression of CDK1 showed poor prognosis. Compared with control group, 2.5 µM arecoline treatment increased the proliferation and migration ability of the HepG2 cells. Treatment with 2.5 µM arecoline increased the levels of miR-21-3p, miR-21-5p and miR-1267, upregulated the expression of PI3K-AKT pathway factors, CDK1, CCND1 but decreased RAF1 expression. CONCLUSION: A low concentration arecoline can induce the proliferation and migration of HepG2 cells, with the potential mechanism of action linked to high levels of exosomal miR-21 and miR-1267, activation of the PI3K-AKT pathway, upregulation of CDK1 and CCND1, and downregulation of RAF1.

Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways.

Rationale: Disruption of intracellular calcium (Ca2+) homeostasis is implicated in inflammatory responses. Here we investigated endoplasmic reticulum (ER) Ca2+ efflux through the Inositol 1,4,5-trisphosphate receptor (IP3R) as a potential mechanism of inflammatory pathophysiology in a ventilator-induced lung injury (VILI) mouse model. Methods: C57BL/6 mice were exposed to mechanical ventilation using high tidal volume (HTV). Mice were pretreated with the IP3R agonist carbachol, IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) or the Ca2+ chelator BAPTA-AM. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected to measure Ca2+ concentrations, inflammatory responses and mRNA/protein expression associated with ER stress, NLRP3 inflammasome activation and inflammation. Analyses were conducted in concert with cultured murine lung cell lines. Results: Lungs from mice subjected to HTV displayed upregulated IP3R expression in ER and mitochondrial-associated-membranes (MAMs), with enhanced formation of MAMs. Moreover, HTV disrupted Ca2+ homeostasis, with increased flux from the ER to the cytoplasm and mitochondria. Administration of carbachol aggravated HTV-induced lung injury and inflammation while pretreatment with 2-APB or BAPTA-AM largely prevented these effects. HTV activated the IRE1α and PERK arms of the ER stress signaling response and induced mitochondrial dysfunction-NLRP3 inflammasome activation in an IP3R-dependent manner. Similarly, disruption of IP3R/Ca2+ in MLE12 and RAW264.7 cells using carbachol lead to inflammatory responses, and stimulated ER stress and mitochondrial dysfunction. Conclusion: Increase in IP3R-mediated Ca2+ release is involved in the inflammatory pathophysiology of VILI via ER stress and mitochondrial dysfunction. Antagonizing IP3R/Ca2+ and/or maintaining Ca2+ homeostasis in lung tissue represents a prospective treatment approach for VILI.

TLR4/TRAF6/NOX2 signaling pathway is involved in ventilation-induced lung injury via endoplasmic reticulum stress in murine model.

In ventilation-induced lung injury (VILI), prolonged nonpathogen-mediated inflammation is triggered as a result of alveolar hyperinflation. In our previous study, we suggested that endoplasmic reticulum (ER) stress-mediated inflammation was involved in VILI, but how ER stress is triggered remains unknown. Toll-like receptor 4 (TLR4) activation plays an important role in mechanical ventilation (MV)-induced lung inflammation, however, it is unknown whether ER stress is activated by TLR4 to participate in VILI. In this study, C57BL/6 mice were exposed to MV with high tidal volumes (HTV 20 ml/kg). Mice were pretreated with TAK-242 the TLR4 inhibitor, C25-140, the TRAF6 inhibitor, or GSK2795039, the NOX2 inhibitor. Lung tissue and bronchoalveolar lavage fluid (BALF) were collected to measure lung injury, inflammatory responses and mRNA/protein expression associated with ER stress and the TLR4/TRAF6/NOX2 signaling pathway. Our results indicate that MV with HTV caused the TLR4/TRAF6/NOX2 signaling pathway activation and production of large amounts of ROS, which led to ER stress and NF-κB mediated inflammation in VILI. Furthermore, TLR4/TRAF6/NOX2 signaling pathway inhibition attenuated ER stress response and alleviate lung injury in mice.