Mitochondrial damage in dorsal root ganglion (DRG) neurons contributes to the pathogenesis of paclitaxel (PTX)-induced peripheral neuropathic pain (PIPNP). Fibroblast growth factor 13 (FGF13), abundantly expressed in DRG neurons, is crucial for the regulation of somatosensation; however, its role in PIPNP remains unclear. Here, we demonstrated that FGF13 expression is upregulated in DRG neurons of PIPNP model mice. Conditional knockout of Fgf13 in DRG neurons effectively alleviates PTX-induced mitochondrial damage and neuropathic pain. RNA sequencing analysis revealed that mitophagy mediates the regulatory effects of FGF13 in PIPNP. Mechanistically, FGF13 physically interacts with vasohibin 1 (VASH1), regulating the binding of VASH1 to microtubules and promoting microtubule detyrosination. FGF13 ablation disrupts assembly of the FGF13-VASH1-α-tubulin ternary complex, impairing VASH1-mediated microtubule detyrosination and increasing microtubule tyrosination. The resulting accumulation of tyrosinated microtubules facilitates kinesin-3 (KIF1A)-driven lysosomal trafficking, which in turn promotes mitophagy activation and ultimately ameliorates PTX-induced mitochondrial damage and PIPNP. Furthermore, VASH1 overexpression in DRG neurons reversed the alleviating effects of FGF13 deficiency on PTX-induced mitochondrial damage and PIPNP. In summary, our findings demonstrate that FGF13 deficiency alleviates mitochondrial dysfunction and PIPNP by suppressing VASH1-dependent microtubule detyrosination and subsequently activating mitophagy. Targeting FGF13 may be a promising therapeutic strategy for PIPNP.

Postoperative pain impairs patients' quality of life. Mechanisms underlying postoperative pain remain incompletely understood. We investigated postoperative pain in a mouse model of skin plus deep tissue incision (INC). We found Cxcl5 was among the top upregulated genes in incision site, which was produced from both incised skin and muscle. Single-cell RNA-sequencing reveals elevated human CXCL5 gene expression in human skin wounds. Neutralizing CXCL5 abrogated INC pain. Global knockout of CXCL5 receptor CXCR2 improved INC pain, but markedly delayed wound healing. Cxcr2 conditional knockout in nociceptive sensory neurons improved INC pain without affecting wound healing and local inflammation. CXCR2 expression and its coupling with TRPA1 were enhanced in DRG neurons innervating the incised site, resulting in neuron hyperexcitability upon CXCL5 stimulation. CXCL5 further enhances TRPV1 activity via neuronal CXCR2-mediated signaling in DRG neurons innervating the incised site. Neuronal CXCR2-mediated TRPV1/TRPA1 modulation synergistically contributes to heat and mechanical hypersensitivities of INC pain. Targeted Cxcr2 knockdown in incision site-innervating DRG neurons ameliorates INC pain. Our work reveals a critical role of neuronal CXCR2 signaling in nociceptive sensory neurons that mediates INC pain via concurrently activating TRPA1 and sensitizing TRPV1. Targeting sensory neuronal CXCR2 represents a promising strategy for INC pain without affecting wound healing.

Complex regional pain syndrome type I (CRPS-I) develops after an initial injury. It causes prolonged pain that persists beyond the usual expected time for tissue healing. Mechanisms underlying pain chronicity of CRPS-I remain unknown. Here, we identified the presence of long-lasting infiltration of macrophages in local dorsal root ganglia (DRG) of a rat model of CRPS-I. We demonstrate that regenerating islet-derived 3β (Reg3β) is specifically produced by DRG neurons upon model establishment and functions as an important signaling molecule to drive proinflammatory macrophage infiltration in local DRG. Infiltrated macrophages produce TNF-α, which causes hyperexcitability of nociceptive DRG neurons and reciprocally promotes Reg3β overexpression and secretion from DRG neurons to recruit more macrophages. Our work reveals a positive feedback signaling conveyed by neuronal Reg3β/macrophage TNF-α that contributes to neuroinflammation in DRG, resulting in persistent pain in a rat model of CRPS-I. This finding provides insights into the neuroimmune interaction in local DRG that contributes to pain chronicity of CRPS-I.

Diabetes is linked to male infertility, but the mechanisms and therapeutic options remain unclear. This study investigates the effects of semaglutide on testicular function in a diabetes mouse model. Clinical data shows that diabetes affects blood glucose, lipid levels, and sperm quality. Single-cell and transcriptome analyses reveal changes in testicular tissue cell proportions and activation of ferroptosis pathways in diabetic patients/rats. In the diabetes mouse model, sperm quality decreases significantly. Treatment with semaglutide (Sem) and the ferroptosis inhibitor ferrostatin-1 (Fer-1) alleviates testicular damage, as evidenced by improved lipid peroxidation and ferroptosis markers. Moreover, the diabetes-induced decrease in the TM-3 cell line's vitality, increased lipid peroxidation, ROS, ferrous ions, and mitochondrial membrane potential damage are all improved by semaglutide and ferrostatin-1 intervention. Overall, these findings highlight semaglutide's potential as a therapeutic approach for mitigating diabetes-induced testicular damage through modulation of the ferroptosis pathway.

Itching is an aversive somatosensation that triggers the desire to scratch. Transient receptor potential (TRP) channel proteins are key players in acute and chronic itch. However, whether the modulatory effect of fibroblast growth factor 13 (FGF13) on acute and chronic itch is associated with TRP channel proteins is unclear. Here, we demonstrated that conditional knockout of Fgf13 in dorsal root ganglion neurons induced significant impairment in scratching behaviors in response to acute histamine-dependent and chronic dry skin itch models. Furthermore, FGF13 selectively regulated the function of the TRPV1, but not the TRPA1 channel on Ca2+ imaging and electrophysiological recordings, as demonstrated by a significant reduction in neuronal excitability and current density induced by TRPV1 channel activation, whereas TRPA1 channel activation had no effect. Changes in channel currents were also verified in HEK cell lines. Subsequently, we observed that selective modulation of TRPV1 by FGF13 required its microtubule-stabilizing effect. Furthermore, in FGF13 knockout mice, only the overexpression of FGF13 with a tubulin-binding domain could rescue TRP channel function and the impaired itch behavior. Our findings reveal a novel mechanism by which FGF13 is involved in TRPV1-dependent itch transduction and provide valuable clues for alleviating pathological itch syndrome.

Gouty arthritis evokes joint pain and inflammation. Mechanisms driving gout pain and inflammation remain incompletely understood. Here we show that CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to drive gout pain and inflammation. CXCL5 expression was increased in ankle joints of gout arthritis model mice, whereas CXCR2 showed expression in joint-innervating sensory neurons. CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to trigger TRPA1 activation, resulting in hyperexcitability and pain. Neuronal CXCR2 coordinates with neutrophilic CXCR2 to contribute to CXCL5-induced neutrophil chemotaxis via triggering CGRP- and substance P-mediated vasodilation and plasma extravasation. Neuronal Cxcr2 deletion ameliorates joint pain, neutrophil infiltration and gait impairment in model mice. We confirmed CXCR2 expression in human dorsal root ganglion neurons and CXCL5 level upregulation in serum from male patients with gouty arthritis. Our study demonstrates CXCL5-neuronal CXCR2-TRPA1 axis contributes to gouty arthritis pain, neutrophil influx and inflammation that expands our knowledge of immunomodulation capability of nociceptive sensory neurons. Here, the authors demonstrate that CXCL5 expression is increased in ankle joints of gouty arthritis model mice. CXCL5-neuronal CXCR2-TRPA1 axis contributes to gouty arthritis pain, neutrophil influx and joint inflammation.

Background: Gouty arthritis causes severe pain and inflammation. Alginate oligosaccharides (AOSs) are natural products derived from alginate and have anti-inflammatory properties. We explored the potential effects of AOSs with different degrees of polymerization (Dp) on gouty arthritis and associated mechanisms. Methods: We established a mouse model of gouty arthritis by injecting monosodium urate (MSU) into ankle joint. Nocifensive behavior, gait and ankle swelling were used to study AOS's effects. Biochemical assays, in vivo imaging, live cell Ca2+ imaging, electrophysiology, RNA-sequencing, etc. were used for mechanism exploration. Results: AOS2 (Dp=2), AOS3 (Dp=3) and AOS4 (Dp=4) all inhibited ankle swelling, whereas AOS2&3 produced the most obvious analgesia on model mice. AOS3, which was picked for further evaluation, produced dose-dependent ameliorative effects on model mice. AOS3 reversed gait impairments but did not alter locomotor activity. AOS3 inhibited NLRP3 inflammasome activation and inflammatory cytokine up-regulation in ankle joint. AOS3 ameliorated MSU-induced oxidative stress and reactive oxygen species (ROS) production both in vivo and in vitro and reversed the impaired mitochondrial bioenergetics. AOS3 activated the Nrf2 pathway and promoted Nrf2 disassociation from Keap1-bound complex and Nrf2 nuclear translocation, thus facilitating antioxidant gene expression via Nrf2-dependent mechanism. Nrf2 gene deficiency abolished AOS3's ameliorative effects on pain, inflammation and oxidative stress in ankle joints of model mice. AOS3 reduced TRPV1 functional enhancement in DRG neurons and constrained neuroactive peptide release. Conclusions: AOS3 ameliorates gouty arthritis via activating Nrf2-dependent antioxidant signaling, resulting in suppression of ROS-mediated NLRP3 inflammasome activation and TRPV1 enhancement. AOS3 may be novel therapeutics for gouty arthritis.

Introduction:Fibroblast growth factor homologous factors (FHFs), among other fibroblast growth factors, are increasingly found to be important regulators of ion channel functions. Although FHFs have been link to several neuronal diseases and arrhythmia, its role in inflammatory pain still remains unclear.Objectives:This study aimed to investigate the role and mechanism of FGF13 in inflammatory pain.Methods:Fgf13 conditional knockout mice were generated and CFA-induced chronic inflammatory pain model was established to measure the pain threshold. Immunostaining, western blot and quantitative real-time reverse transcription PCR (qRT-PCR) were performed to detect the expression of FGF13 in CFA-induced inflammatory pain. Whole-cell patch clamp recording was used to record the action potential firing properties and sodium currents of DRG neurons.Results:Conditional knockout of Fgf13 in dorsal root ganglion (DRG) neurons (Fgf13-/Y) led to attenuated pain responses induced by complete Freund's adjuvant (CFA). FGF13 was expressed predominantly in small-diameter DRG neurons. CFA treatment resulted in an increased expression of FGF13 proteins as well as an increased excitability in nociceptive DRG neurons which was inhibited when FGF13 was absent. The role of FGF13 in neuronal excitability of DRG was linked to its modulation of voltage-gated Na+ channels mediated by microtubules. Overexpression of FGF13, but not FGF13 mutant which lacks the ability to bind and stabilize microtubules, rescued the decreased neuronal excitability and Na+ current density in DRG neurons of Fgf13-/Y mice.Conclusion:This study revealed that FGF13 could stabilize microtubules to modulate sodium channel function in DRG neurons and modulate inflammatory pain. This study provides a novel mechanism for FGF13 modulation of sodium channel function and suggests that FGF13 might be a novel target for inflammatory pain treatment.

蒽环类药物是经典有效的细胞毒性药物,多药耐药和药物不良反应是该类药物存在的棘手问题.细胞药代动力学研究可以明确蒽环类药物在胞内的动力学过程,针对目前存在的问题探寻解决方案.本文综述了细胞药代动力学在蒽环类药物多药耐药和心脏毒性研究中的应用及常用方法,旨在为之后的蒽环类药物的细胞药代动力学研究提供参考.

Deafness is known to occur in more than 400 syndromes and accounts for almost 30% of hereditary hearing loss. The molecular mechanisms underlying such syndromic deafness remain unclear. Furthermore, deafness has been a common feature in patients with three main syndromes, the BÖrjeson-Forssman-Lehmann syndrome, Wildervanck syndrome, and Congenital Generalized Hirsutism, all of which are characterized by loss-of-function mutations in the Fgf13 gene. Whether the pathogenesis of deafness in these syndromes is associated with the Fgf13 mutation is not known. To elucidate its role in auditory function, we generated a mouse line with conditional knockout of the Fgf13 gene in the inner ear ( Fgf13 cKO). FGF13 is expressed predominantly in the organ of Corti, spiral ganglion neurons (SGNs), stria vascularis, and the supporting cells. Conditional knockout of the gene in the inner ear led to sensorineural deafness with low amplitude and increased latency of wave I in the auditory brainstem response test but had a normal distortion product otoacoustic emission threshold. Fgf13 deficiency resulted in decreased SGN density from the apical to the basal region without significant morphological changes and those in the number of hair cells. TUNEL and caspase-3 immunocytochemistry assays showed that apoptotic cell death mediated the loss of SGNs. Further detection of apoptotic factors through qRT-PCR suggested the activation of the mitochondrial apoptotic pathway in SGNs. Together, this study reveals a novel role for Fgf13 in auditory function, and indicates that the gene could be a potential candidate for understanding deafness. These findings may provide new perspectives on the molecular mechanisms and novel therapeutic targets for treatment deafness.

目的 利用心电植入子比较五种全麻药对SD大鼠心率的影响.方法 利用心电植入子测定五种全麻药对大鼠120 min内的麻醉效果、心率及心电图变化情况;腹腔注射异丙肾上腺素(0.025 mg/mL),比较五种全麻药对异丙肾上腺素提高大鼠心电活动的影响.结果 异氟醚和丙泊酚起效快,麻醉稳定,心率变化较小;依托咪酯和氯胺酮起效较快,但持续时间较短;戊巴比妥钠起效慢,麻醉时间长,苏醒慢,心脏抑制作用明显.2％异氟醚和氯胺酮对心率影响较小,其余三种麻醉药均可明显降低异丙肾上腺素对心率的加快作用.结论 异氟醚和丙泊酚对SD大鼠麻醉效果最好,心率影响较小,其中异氟醚对异丙肾上腺素引起的心率加快影响最小,更适用于麻醉操作以及对一些心血管活性药的心率作用研究.