The regulation of inflammation is critical for effective tissue regeneration and repair. Since excessive reactive oxygen species (ROS) and pro-inflammatory factors are key pathological hallmarks of inflammation, their suppression is essential for mitigating inflammatory responses. Herein, we developed a ROS-responsive hydrogel incorporating catalpol-engineered Rehmannia glutinosa extracellular vesicles (C-REVs) to scavenge ROS, precisely inhibit inflammatory mediators, and thereby promote the repair of damaged skin and intervertebral disc tissues. The fabricated hydrogel exhibited excellent ROS-scavenging capacity, injectability, and biocompatibility, indicating its suitability for minimally invasive administration. In vitro experiments demonstrated that the ROS-responsive hydrogel effectively eliminated excess intracellular ROS and significantly suppressed cellular inflammatory responses under oxidative stress conditions. Moreover, in vivo results revealed that C-REVs released from the hydrogel promoted macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, further alleviating local inflammation and creating a favorable microenvironment for tissue regeneration. The synergistic action between the ROS-responsive hydrogel and engineered C-REVs enabled sustained attenuation of inflammation and regulated immune responses, and facilitated the repair and regeneration of injured tissues. This composite system represents a promising and efficacious therapeutic strategy for treating intervertebral disc degeneration and skin injuries.

Intervertebral disc degeneration (IVDD) is a predominant contributor to low back pain, characterized by nucleus pulposus cell (NPC) senescence, extracellular matrix (ECM) metabolic dysfunction, and chronic inflammation. Excessive mitochondrial fission contributes to IVDD, yet the underlying regulatory mechanisms remain unclear. Herein, we identified ETS proto-oncogene 1 (ETS1) as a critical regulator of mitochondrial fission in human NPCs. ETS1 was upregulated in severe human IVDD and correlated with disc degeneration severity and NPC senescence. Mechanistically, inflammatory cytokines induced ETS1 upregulation, which directly bound to the dynamin 1-like (DNM1L, encoding DRP1) promoter and activated its transcription. Increased DRP1 triggered excessive mitochondrial fission, leading to reactive oxygen species accumulation, NPC senescence, and ECM catabolism. Inhibition of ETS1 via AAV5-mediated RNA interference or targeting DRP1 with CRISPR/dCas9-KRAB system or Mdivi-1 alleviated mitochondrial dysfunction, cellular senescence, ECM degradation, and attenuated IVDD progression. Collectively, our findings revealed the ETS1/DRP1 axis as a novel pathogenic mechanism and a potential therapeutic target in IVDD.

Background Intervertebral disc degeneration (IVDD), a leading contributor to low back pain, is closely linked to redox imbalance. Pterostilbene (PTE) is a natural polyphenol with potent antioxidant properties. Purpose This study aimed to investigate whether PTE protects nucleus pulposus cells (NPCs) from ferroptosis under conditions of excessive oxidative stress and to evaluate the therapeutic efficacy of nanoliposomal PTE (PTE-LIP) in vivo. Methods NPCs were pretreated with PTE prior to tert-butyl hydroperoxide (TBHP) stimulation. RNA sequencing and biochemical assays were performed to explore the underlying mechanisms. Lentiviral overexpression and siRNA-mediated knockdown were employed to further delineate the molecular pathway. PTE was encapsulated within nanoliposomes to improve its bioavailability and therapeutic efficacy. In vivo therapeutic efficacy was evaluated in the puncture-induced rat IVDD models using radiographic imaging (X-ray and MRI), histological analyses (H&E and SO/FG staining), and immunohistochemistry. Results Treatment with 20 μM PTE for 24 hours was identified as the optimal protective condition based on dose- and time-dependent analyses. PTE effectively reversed TBHP-induced alterations in ferroptosis-related markers and extracellular matrix degradation. Mechanistically, PTE suppressed excessive ferritinophagy by downregulating NCOA4 and disrupting the NCOA4-FTH1 interaction. Furthermore, NRF2 functioned as an upstream regulator mediating the inhibitory effect of PTE on ferritinophagy. In vivo, intradiscal administration of PTE-LIP preserved disc structure, restored matrix homeostasis, and suppressed ferroptosis. Conclusion PTE protects NPCs from ferritinophagy-mediated ferroptosis via modulation of the NRF2/NCOA4/FTH1 axis. PTE-LIP exerted robust protective effects in vivo, underscoring its potential as a targeted nanotherapeutic strategy for IVDD.

Objectives:. To analyze the correlation among subcutaneous lumbar spine index (SLSI), paraspinal muscle parameters, and lumbar bone mineral density (BMD), and to evaluate their predictive value on lumbar BMD for patients with lumbar spondylolisthesis. Materials and methods:. A total of 216 patients with lumbar spondylolisthesis were included. All of them were divided into groups of normal bone mass, osteopenia, and osteoporosis (OP) according to BMD of L1–4 measured by dual-energy X-ray absorptiometry (DXA). SLSI was obtained by computed tomography, and paraspinal muscle parameters were calculated by the Image J software. The differences between SLSI and paraspinal muscle parameters were compared in 3 groups. Correlation analysis and multiple linear regression were used to analyze the relationship between parameters and lumbar BMD. Results:. SLSI and paraspinal muscle parameters were analyzed among 3 groups. There was a significant difference in cross-sectional areas (CSAs) of psoas major (PS) and quadratus lumborum (QL), PS index, relative cross-sectional areas (rCSAs) of PS and QL, fatty infiltration (FI) of multifidus (MF) and erector spinae (ES) between normal bone mass group and osteopenia group, normal bone mass group and OP group (p < 0.05). Correlation analysis among body mass index (BMI), SLSI, paraspinal muscle parameters, and BMD was adopted for all included patients. There were positive correlations among BMI, CSAs of PS and QL, PS index, rCSAs of PS and QL, and lumbar BMD (p < 0.05). There were negative correlations among MF index, FI of PS, MF and ES, and lumbar BMD (p < 0.05). The regression equation of lumbar BMD: BMD = −3.461 + 0.063 × BMI + 0.943 × rCSA of PS − 3.871 × FI of ES (R2 = 0.111). Conclusions:. For patients with lumbar spondylolisthesis, smaller CSAs of flexor muscle group and more FI of paraspinal muscles are related to less bone mass and lower lumbar BMD. Combined with BMI, rCSA of PS and FI of ES have predictive value on lumbar BMD. For patients with both lumbar spondylolisthesis and OP, those who have higher SLSI are estimated to have less bone mass.

Programmed cell death, particularly pyroptosis mediated by inflammatory signaling pathways, plays a critical role in the pathogenesis of intervertebral disc degeneration (IVDD). However, the regulatory mechanisms underlying pyroptosis and inflammation in IVDD remain poorly understood. Voltage-dependent anion channel 1 (VDAC1), a pivotal mitochondrial protein, forms oligomeric structures under inflammatory stimulation, leading to mitochondrial DNA (mtDNA) release into the cytoplasm and extracellular space. This triggers inflammatory cascades and activates pyroptosis signaling pathways, yet its physiological role and regulatory mechanisms in IVDD are still unclear. In this study, we demonstrated that the expression of VDAC1 was increased in degenerated NP tissues, and oxidative stress induced the expression and oligomerization of VDAC1 in NPC. Inhibiting VDAC1 by specific inhibitor NSC15364 or downregulating the expression of VDAC1 by specific siRNAs attenuated the mitochondrial dysfunction and pyroptosis of NPC. Mechanistically, we proved that inhibiting VDAC1 alleviated the cytosolic leakage of mtDNA, which subsequently blocked the TLR9 signaling pathway, ultimately alleviating the pyroptosis of NPC in vitro and in vivo. Our results proved for the first time that VDAC1-mtDNA-TLR9 signaling pathway might be a novel target for the treatment of IVDD.

Developing therapeutic biomaterials capable of adapting their activation mechanisms according to tissue accessibility remains a major challenge for treating heterogeneous pathological microenvironments. Herein, we report a microenvironment-adaptive hydrogel microneedle platform (CD/MN) by integrating L-arginine-derived carbon dots into a ROS-responsive hydrogel matrix, enabling tissue-depth-dependent nitric oxide (NO) therapy through complementary activation pathways. Under external light irradiation, photo-generated singlet oxygen facilitates NO generation for rapid antibacterial therapy in superficial infected wounds. In contrast, in deep tissues where light penetration is inaccessible, endogenous pathological ROS activates hydrogel degradation, enabling sustained release of L-arg CDs and prolonged NO-mediated immunoregulatory bioactivity. The microneedle architecture further provides localized delivery and prolonged tissue retention, thereby enhancing therapeutic efficiency. Importantly, the same material platform operates through light-triggered activation in superficial infected burns and ROS-driven autonomous activation in intervertebral disc degeneration, demonstrating adaptive therapeutic behavior across tissues with distinct activation accessibility. In vitro studies reveal a ROS-initiated, NO-dominated antibacterial mechanism, while in vivo studies demonstrate effective bacterial clearance, inflammation resolution, angiogenesis, extracellular matrix remodeling, and attenuation of intervertebral disc degeneration. Collectively, this work establishes a tissue-adaptive microneedle platform capable of switching activation modes according to tissue accessibility, providing a generalizable design strategy for intelligent biomaterials targeting heterogeneous ROS-associated diseases.

Responsive hydrogels hold significant promises for precision biomaterial-based therapies and controlled drug delivery. However, persistent inflammatory mediators, the degenerative inflammatory microenvironment, and intrinsic immune responses to implanted scaffolds continue to impede their clinical translation. Here, we developed a reactive oxygen species (ROS)-responsive hydrogel (PVA-CS@HA) that functions as a smart delivery platform for quercetin-loaded kiwifruit extracellular vesicles (KEVs-Q). The hydrogel is cross-linked through a ROS-cleavable linker and selectively degrades within inflammatory microenvironments, simultaneously scavenging excessive ROS and enabling spatiotemporal release of KEVs-Q to regulate gene expression and restore immune homeostasis. This dual functionality couples the intrinsic immunomodulatory activity of plant-derived vesicles with the antioxidant and anti-inflammatory properties of quercetin, yielding synergistic therapeutic outcomes. Furthermore, the composite hydrogel exhibits excellent injectability, strong tissue adhesion, and tunable degradation kinetics, ensuring responsive delivery at pathological sites. Transcriptomic analysis identifies antioxidant gene activation, inflammatory suppression, NF-κB, TNF, and PI3K-Akt pathway modulation underlying its bioactivity. The hydrogel mitigated inflammation-driven fibroblast activation and enhanced tissue repair across multiple models. Through ROS-responsive scaffolding and loaded vesicle integration, it establishes an adaptive platform for dynamic immunomodulation. The PVA-CS@HKEVs-Q platform highlights a broadly applicable and clinically translatable strategy for inflammation-associated tissue repair, advancing next-generation regenerative therapies.

Spinal cord injury (SCI) is often accompanied by significantly enhanced neuroinflammation. The regulation of neuroinflammation may be a potential direction for SCI repair. Cellular communication and interaction between neurons and microglia can affect the level of neuroinflammation and thereby influence SCI repair and function recovery. Increasing evidence highlights that the C-X3-C motif chemokine ligand 1/C-X3-C motif chemokine receptor 1 (CX3CL1/CX3CR1) axis plays a central role in this process. Here, we review the relevant studies on CX3CL1 and CX3CR1 in the field of SCI and summarize the structural characteristics of CX3CL1 and CX3CR1 and their spatiotemporal expression features after SCI. In addition, the bidirectional role of CX3CL1/CX3CR1 axis in neuroinflammation and possible treatment methods focused on CX3CL1/CX3CR1 axis are also discussed. CX3CL1/CX3CR1 axis acts as a dynamic regulator of neuroinflammation and a potential therapeutic target for SCI repair. Further studies are needed to elucidate the spatiotemporal mechanisms of this axis and guide its clinical translation.

Objective This study combined static and dynamic amplitude of low-frequency fluctuation (sALFF and dALFF) to investigate the abnormalities of local spontaneous brain activity in patients with chronic tinnitus and their relationships with the spatial distributions of multiple neurotransmitters, thereby providing a theoretical basis for understanding the neural mechanisms underlying chronic tinnitus. Methods This study included 80 patients with chronic tinnitus and 68 healthy controls. Resting-state functional magnetic resonance imaging (rs-fMRI) data were used to calculate sALFF and dALFF metrics in both groups, and between-group differences were subsequently compared. Furthermore, the relationships between ALFF alterations and neurotransmitter distributions in patients with chronic tinnitus were analyzed. Results Compared with the healthy control group, the sALFF value in the left superior temporal gyrus of patients with chronic tinnitus was significantly increased, and the dALFF value in the right precuneus was significantly decreased (GRF correction, voxel level P<0.001, cluster level P<0.05). Moreover, the alterations of sALFF correlated with the spatial distribution of serotonin transporter, dopamine, glutamate systems, and GABAergic, and the alterations of dALFF correlated with the spatial distribution of serotonin transporter, dopaminergic, and the vesicular acetylcholine transporter (VAChT). Conclusions Chronic tinnitus exhibits not only abnormalities in sALFF, but also aberrant dynamic temporal fluctuations, which spatially correlate with the distribution patterns of different neurotransmitter systems, thereby deepening the understanding of the neural mechanisms underlying chronic tinnitus.

AimsT-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3), an immune checkpoint molecule, is highly expressed in microglia and its expression dynamically increases during central nervous system (CNS) development. Although its immunomodulatory functions are well-established, its role in inflammation following spinal cord injury (SCI) remains unclear. This study aimed to elucidate the regulatory role of microglial Tim-3 in the sterile inflammatory response after SCI and to explore its potential as a therapeutic target.Materials and methodsA SCI model was established using C57BL/6 mice. Microglial Tim-3 function was investigated through adeno-associated virus-mediated Tim-3 overexpression and intervention with the Nrf2 agonist Oltipraz. Luxol fast blue (LFB) and Nissl staining were used to assess lesional area and tissue structure. Basso Mouse Scale (BMS) scoring and the sucrose preference test (SPT) were employed to evaluate motor function recovery and depressive-like behavior. Immunofluorescence was performed to analyze glial activation and neurodegeneration. Expression levels of inflammatory factors were measured by enzyme-linked immunosorbent assay (ELISA) and western blot (WB).Key findingsMicroglia-specific Tim-3 overexpression promoted microglial proliferation and activation, inducing upregulation of iNOS and robust production of pro-inflammatory cytokines. This exacerbated neural tissue damage and motor dysfunction, whereas depressive-like behaviors were not significantly affected. These effects were partially reversed by the Nrf2 agonist.SignificanceAAV-mediated microglial Tim-3 overexpression exacerbates neuroinflammation and functional impairment after SCI, potentially through an association with the Nrf2/HMGB1 signaling axis. Targeting microglial Tim-3 may represent a promising therapeutic strategy for SCI.

BACKGROUND:Tinnitus is a common symptom in otolaryngology with a complex and multifactorial etiology. Ginkgo biloba extract (EGB 761) is widely used in clinical practice, but the reported results vary across studies, partly due to differences in dosage and outcome assessment. OBJECTIVE:To compare tinnitus outcomes between two commonly used EGB 761 dosages (120 mg/day vs. 240 mg/day) in patients with SSNHL-associated newly onset tinnitus, and to identify clinical factors associated with tinnitus prognosis. METHODS:Participants from mainland China were randomly assigned (1:1) to receive either 120 mg/day or 240 mg/day of EGB 761 tablets for one month. Follow-up assessments were conducted at 1, 2, 3, 4, 6, 9, 12, and 18 months after treatment initiation. RESULTS:A total of 195 valid data sets were analyzed. The mean baseline Tinnitus Handicap Inventory (THI) score of 48.99 significantly decreased to 28.33 at 1 month, 16.97 at 6 months, and 10.54 at 18 months. A slightly higher proportion of patients met the improvement criterion in the high-dose group (95.9%) than in the low-dose group (91.9%), but the between-group differences were not statistically significant for THI reduction or other outcomes. In multivariable analyses, higher anxiety (GAD-7 ≥ 10), higher reflux symptom burden (RSI ≥13), and a history of vestibular disorders were associated with less favorable tinnitus outcomes at follow-up. CONCLUSION:Both 120 mg/day and 240 mg/day dosages of EGB 761 demonstrated similar tinnitus outcomes over follow-up. Anxiety, LPR, and a history of vestibular disorders may be prognostic factors for tinnitus.

The insidious onset of osteoporosis and the high cost of DXA examination make it urgent to develop suitable prediction or screening tools. The NHANES cohort contains standardized DXA-BMD results and comprehensive nutrition-related information. Therefore, this study aimed to develop and validate a nomogram clinical prediction model dedicated to predicting the exact probability of osteoporosis occurrence in the elderly population. Data of elderly participants were extracted from the NHANES database and categorized into the training (n = 3181) and validation (n = 1622) groups. Clinical characteristics and BMD results were obtained and analyzed. Univariate and multivariate logistic regression analyses were performed. General and dynamic nomogram clinical prediction models were constructed. The models were validated using ROC curves, calibration curves, DCA curves, and clinical impact curves. Based on 11 variables, including age, gender, race, poverty income ratio (PIR), waist circumference, DBP, physical exercise, protein intake, carbohydrate intake, caffeine intake, and fracture history, a nomogram clinical prediction model was constructed. This model exhibited moderate predictive value (AUC = 0.795), alongside good calibration, clinical benefit, and clinical impact. The constructed online dynamic nomogram (https://jialinwang.shinyapps.io/OP-Prediction-Model/) is interactive, accessible, and user-friendly. This nomogram prediction model and the web-based dynamic nomogram exhibit good practical application value within the U.S. elderly population. However, external validation in non-U.S. cohorts is necessary before widespread global promotion. Ultimately, this tool could facilitate the early prediction, diagnosis, and treatment of osteoporosis, thus contributing to the bone health of the elderly population and promoting the development of public health. This study constructed and validated a nomogram clinical prediction model to predict the probability of developing osteoporosis based on the NHANES cohort. By elucidating the patterns of osteoporosis incidence and its independent risk factors, this interactive tool assists primary care physicians in implementing rapid early screening, ensuring that appropriate interventions can be administered in a timely manner.

Here’s a report on bone cement leakage. Our review of the literature revealed that cases of bone cement leakage are commonly reported, but intradural leakage of bone cement is rare. Here, we present a delayed case of L2 and L3 radiculopathy secondary to bone cement leakage from percutaneous vertebroplasty (PVP). This case exhibited extensive intravertebral and intradural cement leakage, with only a slight decrease in lower extremity strength and lateral thigh pain in the immediate postoperative period. In this case, we describe a rare occurrence of substantial postoperative PVP with intradural leakage. In terms of treatment, early surgical decompression and cement removal should be performed in patients with significant symptomatic cement leakage.

Among adolescents worldwide, osteosarcoma (OS) is one of the most frequently occurring cancers. DSCAM-AS1, a recognized lncRNA, has been noted for its abnormal expression in the development of certain cancers, but its role in OS is still unclear. Quantification of DSCAM-AS1, miR-211-5p, and PDCD6 expression was carried out via qRT-PCR or western blotting in human osteosarcoma cell lines (HOS, MG63, U2OS, SaOS-2) and a normal osteoblastic cell line (hFOB 1.19) using quantitative real-time polymerase chain reaction (qRT-PCR) for RNA detection and western blotting for protein detection, respectively. Cellular proliferation, apoptosis, migration, and invasion in OS cell models were comprehensively evaluated through a combination of experimental approaches, including EdU incorporation assay, CFSE labeling coupled with flow cytometric analysis, as well as transwell invasion and migration assays. To shed light on the molecular mechanisms of interactions among pertinent RNA molecules, researchers conducted luciferase reporter assays, RNA pull-down experiments, and RIP assays. Expression of DSCAM-AS1, miR-211-5p, and PDCD6 was analyzed based on the GEO database, and their correlations were evaluated. The levels of DSCAM-AS1and PDCD6 were predominantly overexpressed, while miR-211-5p was apparently lowly expressed in OS cells. Functional loss-of-function experiments demonstrated that silencing (knockdown) of DSCAM-AS1 expression substantially diminished OS cell proliferation, migration, and invasion, while simultaneously promoting cellular apoptosis in vitro. Mechanistically. DSCAM-AS1 acted as an upstream factor for miR-211-5p and could increase the expression of miR-211-5p-targeted PDCD6. DSCAM-AS1 facilitated the advancement of OS by increasing PDCD6 levels through miR-211-5p sponging. This observation could shed light on a novel therapeutic target option for OS.

ObjectiveTo investigate the correlation between CT values of cochlear bone labyrinth (HU, as a radiological alternative indicator of bone mineral density) and auditory function and disease progression in patients with chronic suppurative otitis media.MethodsA retrospective collection of clinical data was conducted on 128 patients diagnosed with chronic suppurative otitis media who visited the Otolaryngology Department of our hospital from May 2023 to May 2025. All patients underwent high-resolution CT scans of the temporal bone. Parallel pure tone audiometry (including 0.5, 1, 2, and 4 kHz air and bone conduction thresholds) and speech recognition rate testing were performed. Pearson analysis was used to investigate the correlation. A multiple linear regression model was carried out to analyze independent factors.ResultsThe CT values of the affected ear in the basal transition area of the cochlear bone labyrinth were significantly lower than the healthy ear (P < 0.001). Patients with cholesteatoma type CSOM had lower ear basal to CT values compared to patients with simple CSOM (P < 0.001). There was a negative correlation between the basal to CT values of the affected ear and the bone conduction hearing thresholds at various frequencies, and the correlation was increased with increasing frequency (P < 0.001, 0.5 kHz: r = −0.355; 4 kHz: r = −0.521). The CT value was positively correlated with speech recognition rate (r = 0.427, P < 0.001), and significantly negatively correlated with disease duration (r = −0.430, P < 0.001). After adjusting for other influencing factors, disease duration (β = −11.284, P < 0.001), age (β = −7.693, P = 0.001), age of initial treatment (β = 5.827, P = 0.010), and type of otitis media (β = −48.326, P = 0.003) were independent factors associated with basal to CT values. In addition, basal to CT value (β = −0.018, P < 0.001), disease duration (β = 0.517, P < 0.001), age (β = 0.284, P = 0.004), and type of otitis media (β = 6.194, P = 0.002) were independent factors correlated with bone conduction hearing threshold (4 kHz).ConclusionThe course of illness, age, and presence of cholesteatoma are independent factors associated with CT values and hearing loss. Changes in the bony structure of the inner ear and early intervention may help protect auditory function.

BACKGROUND:Intervertebral disc degeneration (IVDD) is a leading cause of low back pain and involves multiple pathological processes, including cell apoptosis, senescence, oxidative stress-inflammation imbalance, and extracellular matrix (ECM) metabolic disorders. Current treatments such as pharmacotherapy, physical therapy, and surgery primarily relieve symptoms but fail to reverse the degenerative process and often carry the risk of complications. METHODS:This review systematically summarizes recent advances in the functional design and therapeutic applications of hydrogels for IVDD, with a focus on delivery systems, microenvironment modulation, and stimulus-responsive mechanisms. In vivo studies and preliminary clinical findings are also reviewed. RESULTS:Hydrogels have emerged as a promising strategy for IVDD regenerative therapy due to their excellent biocompatibility, injectability, and dynamic responsiveness. Acting as multifunctional platforms, hydrogels can precisely deliver stem cells, exosomes, and nucleic acid drugs, regulate apoptotic pathways (e.g. Bax/Bcl-2, Caspase-3), suppress pro-inflammatory cytokines (e.g. TNF-α, IL-1β), and promote ECM synthesis (e.g. collagen II and proteoglycans). Additionally, the incorporation of antioxidant nanoparticles and stimuli-responsive systems allows for effective remodeling of the degenerative microenvironment and interruption of the oxidative stress-inflammation feedback loop. Hydrogels fabricated using 3D bioprinting techniques with biomimetic architectures further improve mechanical stability, preserve disc height, and delay progression of degeneration. Preliminary clinical studies have confirmed the safety and therapeutic potential of hydrogels in IVDD treatment. CONCLUSIONS:Hydrogels demonstrate a multidimensional therapeutic potential ranging from molecular regulation to tissue repair. They hold great promise as a regenerative medicine strategy for precise and effective treatment of IVDD.

Low back pain, largely attributed to intervertebral disc (IVD) degeneration, is correlated with increased sympathetic nerve activity. Toll-like receptor 4 (TLR4)-mediated inflammation in the paraventricular nucleus (PVN) triggers sympathetic nerve activation, which remains uncharted in IVD degeneration. We hypothesized that lumbar spine instability (LSI) surgery in mice elevated sympathetic outflow by activating TLR4/NF-κB axis in PVN, and exacerbated endplate porosities and spinal hyperalgesia following 4 or 8 weeks LSI surgery. Treatment of melatonin for 8 weeks notably alleviated the inflammation and sympathetic outflow in the PVN, and attenuated sympathetic nerve activity, oxidative stress, endplate porosities and spinal hyperalgesia in the peripheral. These effects were abolished by melatonin receptor antagonist luzindole. Immunofluorescent staining of melatonin receptor 1A (MT1) and 1B (MT2) confirmed that MT2 expression exceeded that of MT1 in PVN. Knockdown of MT2 in PVN blocked the inhibitory effect of melatonin on inflammation and sympathetic activation both in PVN and endplate, as well as spinal hyperalgesia, oxidative stress, and porosities of endplate. Additionally, norepinephrine induces inflammation and oxidative stress, disrupts metabolic homeostasis of endplate cells via α2-adrenergic receptor in vitro. This study suggests that melatonin, via activation of MT2, inhibits inflammation and sympathetic activities both in PVN and endplate, therefore, efficiently repairing endplate porosities and alleviating spinal hyperalgesia induced by LSI.

OBJECTIVE:Previous studies have reported that symptoms of tinnitus are associated with changes in brain functional connectivity (FC). Most prior work has focused on static functional connectivity (SFC), while only a few investigations have examined dynamic functional connectivity (DFC). The goal of the present study was therefore to further explore whether DFC is altered in patients with tinnitus by applying sliding-window and clustering analysis techniques. METHODS:Investigations were performed for 60 patients with tinnitus and 53 healthy controls (HC) using the sliding-window and k-means clustering methods. A two-sample t-test was used to determine whether there were significant differences between groups and Spearman correlation analysis was used to investigate the potential relationship between group differences in DFC and scores on clinical assessment scales. RESULTS:The DFC standard deviation (DFC-SD) between left precuneus and right inferior temporal gyrus (ITG) was significantly reduced in the patients with tinnitus compared to the HC (T = 4.52, p < 0.001, FDR), and the reduction showed a significant negative correlation with scores on the Tinnitus Questionnaire (TQ) scale (r = - 0.287, p = 0.026). Additionally, the clustering analysis revealed that the tinnitus group exhibited a longer mean dwell time (MDT) in the hyper-connected state (p = 0.003), and which was significantly negatively correlated with the reduction in DFC-SD between and ITG and precuneus (r = -0.344. p = 0.007) and positively correlated with TQ score (r = 0.309, p = 0.016). CONCLUSIONS:The variability in DFC between precuneus and ITG shows significant relationships with symptom severity and state configurations, and may be a potential new imaging biomarker for diagnosing tinnitus and predicting the severity of symptoms.