Naringenin relieves paclitaxel-induced pain by suppressing calcitonin gene-related peptide signalling and enhances the anti-tumour action of paclitaxel.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) commonly causes neuropathic pain, but its pathogenesis remains unclear, and effective therapies are lacking. Naringenin, a natural dihydroflavonoid compound, has anti-inflammatory, anti-nociceptive and anti-tumour activities. However, the effects of naringenin on chemotherapy-induced pain and chemotherapy effectiveness remain unexplored. EXPERIMENTAL APPROACH: Female and male mouse models of chemotherapy-induced pain were established using paclitaxel. Effects of naringenin were assessed on pain induced by paclitaxel or calcitonin gene-related peptide (CGRP) and on CGRP expression in dorsal root ganglia (DRG) and spinal cord tissue. Additionally, we examined peripheral macrophage infiltration, glial activation, c-fos expression, DRG neuron excitability, microglial M1/M2 polarization, and phosphorylation of spinal NF-κB. Furthermore, we investigated the synergic effect and related mechanisms of naringenin and paclitaxel on cell survival of cancer cells in vitro. KEY RESULTS: Systemic administration of naringenin attenuated paclitaxel-induced pain in both sexes. Naringenin reduced paclitaxel-enhanced CGRP expression in DRGs and the spinal cord, and alleviated CGRP-induced pain in naïve mice of both sexes. Naringenin mitigated macrophage infiltration and reversed paclitaxel-elevated c-fos expression and DRG neuron excitability. Naringenin decreased spinal glial activation and NF-κB phosphorylation in both sexes but influenced microglial M1/M2 polarization only in females. Co-administration of naringenin with paclitaxel enhanced paclitaxel's anti-tumour effect, impeded by an apoptosis inhibitor. CONCLUSION AND IMPLICATIONS: Naringenin's anti-nociceptive mechanism involves CGRP signalling and neuroimmunoregulation. Furthermore, naringenin facilitates paclitaxel's anti-tumour action, possibly involving apoptosis. This study demonstrates naringenin's potential as a supplementary treatment in cancer therapy by mitigating side effects and potentiating efficacy of chemotherapy.

Increased postoperative complications after laparoscopic gastrectomy in patients with preserved ratio impaired spirometry.

BACKGROUND: Preserved ratio impaired spirometry (PRISm), defined as decreased forced expiratory volume in the first second in the setting of normal ratio, is associated with an increased risk of respiratory disease and systemic comorbidities. Unlike severe obstructive pulmonary disease, little is known about the impact of PRISm on short-term outcomes in patients undergoing laparoscopic gastrectomy (LG) and its association with small airway dysfunction (SAD). METHODS: This study enrolled 830 patients who underwent preoperative spirometry and LG between January 2021 and August 2023. Of these, 228 patients were excluded. Participants were categorized into 3 groups based on their baseline lung function, and postoperative outcomes were subsequently analyzed. Potential associations between postoperative outcomes and various clinical variables were examined using univariate and multivariate analyses. RESULTS: PRISm was identified in 16.6% of the patients, whereas SAD was present in 20.4%. The incidence of postoperative pulmonary complications (PPCs) was notably higher in the SAD group (20.3% vs 9.8%, P = .002) and the PRISm group (28.0% vs 9.8%, P < .001) than the normal group. Among the 3 groups, pneumonia was the most frequently observed PPC. Multivariate analysis revealed that both SAD (odds ratio [OR], 2.34; 95% CI, 1.30-4.22; P = .005) and PRISm (OR, 3.26; 95% CI, 1.80-5.90; P < .001) independently constituted significant risk factors associated with the occurrence of PPCs. Univariate analysis showed that female was a possible risk factor for PPCs in PRISm group. CONCLUSION: Our study showed that PRISm and SAD were associated with the increased PPCs in patients undergoing LG for gastric cancer.

Small airway dysfunction associated with poor short-term outcomes in patients undergoing thoracoscopic surgery for lung cancer.

BACKGROUND: Although small airway dysfunction is a common respiratory dysfunction, its prognosis after lung cancer surgery is often neglected. This study investigated the relationship between small airway dysfunction and outcomes in patients who underwent thoracoscopic surgery for lung cancer. METHODS: A retrospective cohort study of patients who underwent thoracoscopic surgery was conducted between December 2019 and March 2021 at Ningbo First Hospital. We used univariate and multivariate analyses to assess the possible associations between postoperative outcomes and clinical variables, including small airway dysfunction. To balance the potential confounding factors, propensity score matching was performed to establish 1:1 small airway dysfunction and small airway normal function group matching. RESULTS: In this study, 1,012 patients undergoing thoracoscopic surgery for lung cancer were enrolled. Small airway dysfunction was present in 18.7% of patients (189/1,012). The incidence of postoperative pulmonary complications in the small airway dysfunction group was higher than that of the small airway normal function group (16.4% vs 6.2%, P < .001). The most significant postoperative pulmonary complications were pneumonia (7.4% vs 2.4%, P < .001) in the small airway dysfunction and normal function groups, respectively. In addition, a significantly prolonged median hospital length of stay was observed in the small airway dysfunction group compared to the small airway normal function group (median [interquartile range], 9 [7-12] vs 8 [7-9], P < .001). After 1:1 propensity score matching, 298 patients (149 pairs) were included in the comparison between small airway dysfunction and small airway normal function, and this association remained. Postoperative pulmonary complications (13.4% vs 6.0%, P = .032) were still higher, and length of stay (median [interquartile range] 9 [7-11] vs 8 [6-10] days, P = .001) was still longer in the small airway dysfunction group. Multivariate analysis indicated that small airway dysfunction was the independent risk factor associated with both postoperative pulmonary complications (odds ratio = 2.694, 95% confidence interval: 1.640-4.426, P < .001) and prolonged length of stay (beta = 1.045, standard error = 0.159, 95% confidence interval: 0.733-1.357, P < .001). CONCLUSION: Our study showed that small airway dysfunction increased the incidence of postoperative pulmonary complications and prolonged length of stay in patients undergoing thoracoscopic surgery for lung cancer.

Trimethoxyflavanone relieves Paclitaxel-induced neuropathic pain via inhibiting expression and activation of P2X7 and production of CGRP in mice.

Paclitaxel (PTX) is an anticancer drug used to treat solid tumors, but one of its common adverse effects is chemotherapy-induced peripheral neuropathy (CIPN). Currently, there is limited understanding of neuropathic pain associated with CIPN and effective treatment strategies are inadequate. Previous studies report the analgesic actions of Naringenin, a dihydroflavonoid compound, in pain. Here we observed that the anti-nociceptive action of a Naringenin derivative, Trimethoxyflavanone (Y3), was superior to Naringenin in PTX-induced pain (PIP). An intrathecal injection of Y3 (1 µg) reversed the mechanical and thermal thresholds of PIP and suppressed the PTX-induced hyper-excitability of dorsal root ganglion (DRG) neurons. PTX enhanced the expression of ionotropic purinergic receptor P2X7 (P2X7) in satellite glial cells (SGCs) and neurons in DRGs. The molecular docking simulation predicts possible interactions between Y3 and P2X7. Y3 reduced the PTX-enhanced P2X7 expression in DRGs. Electrophysiological recordings revealed that Y3 directly inhibited P2X7-mediated currents in DRG neurons of PTX-treated mice, suggesting that Y3 suppressed both expression and function of P2X7 in DRGs post-PTX administration. Y3 also reduced the production of calcitonin gene-related peptide (CGRP) in DRGs and at the spinal dorsal horn. Additionally, Y3 suppressed the PTX-enhanced infiltration of Iba1-positive macrophage-like cells in DRGs and overactivation of spinal astrocytes and microglia. Therefore, our results indicate that Y3 attenuates PIP via inhibiting P2X7 function, CGRP production, DRG neuron sensitization, and abnormal spinal glial activation. Our study implies that Y3 could be a promising drug candidate against CIPN-associated pain and neurotoxicity.