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Effective prevention and treatment options for bone cancer-related pain (BCP) are lacking. In recent years, numerous studies have investigated the association between m6A epigenetic modifications and pain, revealing their significant role in pain initiation and maintenance. This study aimed to provide theoretical support for the treatment of BCP and to identify target drugs for future development. Specifically, we investigated the involvement of fat mass and obesity-related protein (FTO) in rat models of BCP by administering varying doses (1/5/10 mg/kg) of the FTO inhibitor meclofenamic acid (MA) and assessing changes in mechanical sensitivity through domain analysis, gait analysis, and open-field experiments. After successfully establishing the BCP model, we verified it by performing mechanical sensitivity assessments. We observed significantly increased expression levels of the demethylase FTO within the spinal dorsal horn accompanied by decreased m6A methylation levels in the model. Compared with untreated BCP rats, remarkably improved behavioral responses indicative of reduced pain were observed in the model rats after administration of 10 mg/kg MA, concomitant with decreased expression levels of FTO and increased m6A methylation levels. Compared with untreated BCP rats, the expression levels of p-ERK and pro-inflammatory cytokines were also significantly decreased after MA administration. Taken together, FTO can downregulate m6A methylation level and activate ERK/inflammatory cytokines signaling pathway to maintain BCP in rats. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a severe complication of acute respiratory distress syndrome (ARDS). Emerging studies have revealed the effects of pyrrolidine dithiocarbamate (PDTC) on improving surgery-induced cognitive impairment. The major aim of the study was to investigate whether PDTC protected against ARDS-induced cognitive dysfunction and to identify the underlying mechanisms involved. The rat model of ARDS was established by intratracheal instillation of lipopolysaccharide (LPS), followed by treatment with PDTC. The cognitive function of rats was analyzed by the Morris Water Maze, and pro-inflammatory cytokines were assessed by quantitative real-time PCR, enzyme-linked immunosorbent assay, and western blot assays. A dual-luciferase reporter gene assay was performed to identify the relationship between miR-181c and its target gene, TAK1 binding protein 2 (TAB2). The results showed that PDTC improved cognitive impairment and alleviated neuroinflammation in the hippocampus in LPS-induced ARDS model. Furthermore, we demonstrated that miR-181c expression was downregulated in the hippocampus of the ARDS rats, which was restored by PDTC treatment. In vitro studies showed that miR-181c alleviated LPS-induced pro-inflammatory response by inhibiting TAB2, a critical molecule in the nuclear factor (NF)-κB signaling pathway. PDTC improves cognitive impairment in LPS-induced ARDS by regulating miR-181c/NF-κB axis-mediated neuroinflammation, providing a potential opportunity for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Notch signal plays an important role in regulating cell–cell interactions with the adjacent cells. However, it remains unknown whether Jagged1 (JAG‐1) mediated Notch signaling regulates bone cancer pain (BCP) via the spinal cell interactions mechanism. Here, we showed that intramedullary injection of Walker 256 breast cancer cells increased the expression of JAG‐1 in spinal astrocytes and knockdown of JAG‐1 reduced BCP. The supplementation of exogenous JAG‐1 to the spinal cord induced BCP‐like behavior and promoted expression of c‐Fos and hairy and enhancer of split homolog‐1 (Hes‐1) in the spinal cord of the naïve rats. These effects were reversed when the rats were administered intrathecal injections of N‐[N‐(3,5‐difluorophenacetyl)‐l‐alanyl]‐S‐phenylglycine t‐butyl ester (DAPT). The intrathecal injection of DAPT reduced BCP and inhibited Hes‐1 and c‐Fos expression in the spinal cord. Furthermore, our results showed that JAG‐1 up‐regulated Hes‐1 expression by inducing the recruitment of Notch intracellular domain (NICD) to the RBP‐J/CSL‐binding site located within the Hes‐1 promoter sequence. Finally, the intrathecal injection of c‐Fos‐antisense oligonucleotides (c‐Fos‐ASO) and administration of sh‐Hes‐1 to the spinal dorsal horn also alleviated BCP. The study indicates that inhibition of the JAG‐1/Notch signaling axis may be a potential strategy for the treatment of BCP. [ABSTRACT FROM AUTHOR]