Osteoblast-specific down-regulation of NLRP3 inflammasome by aptamer-functionalized liposome nanoparticles improves bone quality in postmenopausal osteoporosis rats.

Rationale: NLRP3 inflammasome is critical in the development and progression of many metabolic diseases driven by chronic inflammation, but its effect on the pathology of postmenopausal osteoporosis (PMOP) remains poorly understood. Methods: We here firstly examined the levels of NLRP3 inflammasome in PMOP patients by ELISA. Then we investigated the possible mechanisms underlying the effect of NLRP3 inflammasome on PMOP by RNA sequencing of osteoblasts treated with NLRP3 siRNA and qPCR. Lastly, we accessed the effect of decreased NLRP3 levels on ovariectomized (OVX) rats. To specifically deliver NLRP3 siRNA to osteoblasts, we constructed NLRP3 siRNA wrapping osteoblast-specific aptamer (CH6)-functionalized lipid nanoparticles (termed as CH6-LNPs-siNLRP3). Results: We found that the levels of NLRP3 inflammasome were significantly increased in patients with PMOP, and were negatively correlated with estradiol levels. NLRP3 knock-down influenced signal pathways including immune system process, interferon signal pathway. Notably, of the top ten up-regulated genes in NLRP3-reduced osteoblasts, nine genes (except Mx2) were enriched in immune system process, and five genes were related to interferon signal pathway. The in vitro results showed that CH6-LNPs-siNLRP3 was relatively uniform with a dimeter of 96.64 ± 16.83 nm and zeta potential of 38.37 ± 1.86 mV. CH6-LNPs-siNLRP3 did not show obvious cytotoxicity and selectively delivered siRNA to bone tissue. Moreover, CH6-LNPs-siNLRP3 stimulated osteoblast differentiation by activating ALP and enhancing osteoblast matrix mineralization. When administrated to OVX rats, CH6-LNPs-siNLRP3 promoted bone formation and bone mass, improved bone microarchitecture and mechanical properties by decreasing the levels of NLRP3, IL-1ß and IL-18 and increasing the levels of OCN and Runx2. Conclusion: NLRP3 inflammasome may be a new biomarker for PMOP diagnosis and plays a key role in the pathology of PMOP. CH6-LNPs-siNLRP3 has potential application for the treatment of PMOP.

Macrocyclization of carbon dioxide with 3-triflyloxybenzynes and tetrahydrofuran: straightforward access to 14-membered macrolactones.

A novel [2+2+5+5] macrocyclization of carbon dioxide with 3-triflyloxybenzynes and tetrahydrofuran has been disclosed for the first time under transition metal-free conditions. The reaction provides a facile method for the synthesis of a rare type of 14-membered macrocyclic lactone, which is potentially useful but difficult to access by existing methods.

Inflammatory response in traumatic brain and spinal cord injury: The role of XCL1-XCR1 axis and T cells.

BACKGROUND: Traumatic brain injury (TBI) and spinal cord injury (SCI) are acquired injuries to the central nervous system (CNS) caused by external forces that cause temporary or permanent sensory and motor impairments and the potential for long-term disability or even death. These conditions currently lack effective treatments and impose substantial physical, social, and economic burdens on millions of people and families worldwide. TBI and SCI involve intricate pathological mechanisms, and the inflammatory response contributes significantly to secondary injury in TBI and SCI. It plays a crucial role in prolonging the post-CNS trauma period and becomes a focal point for a potential therapeutic intervention. Previous research on the inflammatory response has traditionally concentrated on glial cells, such as astrocytes and microglia. However, increasing evidence highlights the crucial involvement of lymphocytes in the inflammatory response to CNS injury, particularly CD8+ T cells and NK cells, along with their downstream XCL1-XCR1 axis. OBJECTIVE: This review aims to provide an overview of the role of the XCL1-XCR1 axis and the T-cell response in inflammation caused by TBI and SCI and identify potential targets for therapy. METHODS: We conducted a comprehensive search of PubMed and Web of Science using relevant keywords related to the XCL1-XCR1 axis, T-cell response, TBI, and SCI. RESULTS: This study examines the upstream and downstream pathways involved in inflammation caused by TBI and SCI, including interleukin-15 (IL-15), interleukin-12 (IL-12), CD8+ T cells, CD4+ T cells, NK cells, XCL1, XCR1+ dendritic cells, interferon-gamma (IFN-γ), helper T0 cells (Th0 cells), helper T1 cells (Th1 cells), and helper T17 cells (Th17 cells). We describe their proinflammatory effect in TBI and SCI. CONCLUSIONS: The findings suggest that the XCL1-XCR1 axis and the T-cell response have great potential for preclinical investigations and treatments for TBI and SCI.

Interplay between mesenchymal stem cells and macrophages: Promoting bone tissue repair.

The repair of bone tissue damage is a complex process that is well-orchestrated in time and space, a focus and difficulty in orthopedic treatment. In recent years, the success of mesenchymal stem cells (MSCs)-mediated bone repair in clinical trials of large-area bone defects and bone necrosis has made it a candidate in bone tissue repair engineering and regenerative medicine. MSCs are closely related to macrophages. On one hand, MSCs regulate the immune regulatory function by influencing macrophages proliferation, infiltration, and phenotype polarization, while also affecting the osteoclasts differentiation of macrophages. On the other hand, macrophages activate MSCs and mediate the multilineage differentiation of MSCs by regulating the immune microenvironment. The cross-talk between MSCs and macrophages plays a crucial role in regulating the immune system and in promoting tissue regeneration. Making full use of the relationship between MSCs and macrophages will enhance the efficacy of MSCs therapy in bone tissue repair, and will also provide a reference for further application of MSCs in other diseases.

Set-Membership State Estimation for Multirate Nonlinear Complex Networks Under FlexRay Protocols: A Neural-Network-Based Approach.

In this article, the set-membership state estimation problem is investigated for a class of nonlinear complex networks under the FlexRay protocols (FRPs). In order to address practical engineering requirements, the multirate sampling is taken into account which allows for different sampling periods of the system state and the measurement. On the other hand, the FRP is deployed in the communication network from sensors to estimators in order to alleviate the communication burden. The underlying nonlinearity studied in this article is of a general nature, and an approach based on neural networks is employed to handle the nonlinearity. By utilizing the convex optimization technique, sufficient conditions are established in order to restrain the estimation errors within certain ellipsoidal constraints. Then, the estimator gains and the tuning scalars of the neural network are derived by solving several optimization problems. Finally, a practical simulation is conducted to verify the validity of the developed set-membership estimation scheme.

Effects of Testosterone in Mediating the Relationship Between Daytime Napping and Osteoporosis in European Populations: A Mendelian Randomization Study.

We aimed to explore the causal effect of daytime napping on the risk of osteoporosis and the mediation role of testosterone in explaining this relationship. Summary data for Mendelian randomization (MR) analysis were obtained from the IEU OpenGWAS database. Univariable MR(UVMR) analysis and multiple sensitivity analyses were applied to explore the casual relationship between daytime napping and bone mineral density (BMD)/osteoporosis. We also conducted multivariable Mendelian randomization (MVMR) analysis to evaluate the correlation between testosterone-associated single-nucleotide variations and BMD/osteoporosis. Then, mediation analysis was performed to explore whether the association between daytime napping and BMD/osteoporosis was mediated via testosterone. Genetically predicted daytime napping was significantly associated with femoral neck BMD (ß [95% CI]: 0.2573 [0.0487, 0.4660]; P = 0.0156), lumbar spine BMD (ß [95% CI]: 0.2526 [0.0211, 0.4840]; P = 0.0324), and osteoporosis (OR [95% CI]: 0.5063 [0.2578, 0.9942]; P = 0.0481). ß and 95%CIs indicate the standard deviation (SD) unit of BMD increase per category increase in daytime napping. OR and 95%CIs represent the change in the odds ratio of osteoporosis per category increase in daytime napping. We observed a potentially causal effect of more frequent daytime napping on higher BMD and a lower risk of osteoporosis. Daytime napping was causally associated with a higher level of bioavailable testosterone (ß [95% CI]: 0.1397 [0.0619, 0.2175]; P = 0.0004). ß and 95%CIs represent the change in the SD of testosterone per category increase in daytime napping. Furthermore, the causal effects of daytime napping on BMD/osteoporosis were partly mediated by bioavailable testosterone. Daytime napping can efficiently increase BMD and reduce the risk of osteoporosis, and testosterone plays a key mediating role in this process.

Expert consensus on Prospective Precision Diagnosis and Treatment Strategies for Osteoporotic Fractures.

Osteoporotic fractures are the most severe complications of osteoporosis, characterized by poor bone quality, difficult realignment and fixation, slow fracture healing, and a high risk of recurrence. Clinically managing these fractures is relatively challenging, and in the context of rapid aging, they pose significant social hazards. The rapid advancement of disciplines such as biophysics and biochemistry brings new opportunities for future medical diagnosis and treatment. However, there has been limited attention to precision diagnosis and treatment strategies for osteoporotic fractures both domestically and internationally. In response to this, the Chinese Medical Association Orthopaedic Branch Youth Osteoporosis Group, Chinese Geriatrics Society Geriatric Orthopaedics Committee, Chinese Medical Doctor Association Orthopaedic Physicians Branch Youth Committee Osteoporosis Group, and Shanghai Association of Integrated Traditional Chinese and Western Medicine Osteoporosis Professional Committee have collaborated to develop this consensus. It aims to elucidate emerging technologies that may play a pivotal role in both diagnosis and treatment, advocating for clinicians to embrace interdisciplinary approaches and incorporate these new technologies into their practice. Ultimately, the goal is to improve the prognosis and quality of life for elderly patients with osteoporotic fractures.

Role of dendritic cells in spinal cord injury.

BACKGROUND: Inflammation can worsen spinal cord injury (SCI), with dendritic cells (DCs) playing a crucial role in the inflammatory response. They mediate T lymphocyte differentiation, activate microglia, and release cytokines like NT-3. Moreover, DCs can promote neural stem cell survival and guide them toward neuron differentiation, positively impacting SCI outcomes. OBJECTIVE: This review aims to summarize the role of DCs in SCI-related inflammation and identify potential therapeutic targets for treating SCI. METHODS: Literature in PubMed and Web of Science was reviewed using critical terms related to DCs and SCI. RESULTS: The study indicates that DCs can activate microglia and astrocytes, promote T-cell differentiation, increase neurotrophin release at the injury site, and subsequently reduce secondary brain injury and enhance functional recovery in the spinal cord. CONCLUSIONS: This review highlights the repair mechanisms of DCs and their potential therapeutic potential for SCI.

New Analogues of Amides and Quinolinones Produced by Streptomyces sp. YIM S01983.

Streptomide (1), a new amide analogue, streptomynone (2), a new quinolinone, and ten known compounds including three aliphatic acids (3-5), two amides (6-7), four cyclic dipeptides (8-11), and an adenosine (12) were isolated from the fermentation broth of Streptomyces sp. YIM S01983 isolated from a sediment sample collected in Bendong Village, Huadong Town, Chuxiong, China. Their structures were determined by analysis of the 1D/2D-NMR and HR-ESI-MS spectra. Compound 12 presented weak antimicrobial activities against Candida albicans and Aligenes faecalis (MIC=64 µg/mL). Compounds 7 and 12 showed weak cytotoxic activity against MHCC97H.

Oridonin-induced ferroptosis and apoptosis: a dual approach to suppress the growth of osteosarcoma cells.

BACKGROUND: Osteosarcoma (OS) is one of the most common aggressive bone malignancy tumors in adolescents. With the application of new chemotherapy regimens, finding new and effective anti-OS drugs to coordinate program implementation is urgent for the patients of OS. Oridonin had been proved to mediate anti-tumor effect on OS cells, but its mechanism has not been fully elucidated. METHODS: The effects of oridonin on the viability, clonal formation and migration of 143B and U2OS cells were detected by CCK-8, colony formation assays and wound-healing test. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was used to explore the mechanism of oridonin on OS. Western blot (WB), real-time quantitative PCR (qRT-PCR) were used to detect the expression levels of apoptosis and ferroptosis-relative proteins and genes. Annexin V-FITC apoptosis detection kit and flow cytometry examination were used to detect the level of apoptosis. Iron assay kit was used to evaluate the relative Fe2+ content. The levels of mitochondrial membrane potential and lipid peroxidation production was determined by mitochondrial membrane potential detection kit and ROS assay kit. RESULTS: Oridonin could effectively inhibit the survival, clonal formation and metastasis of OS cells. The KEGG results indicated that oridonin is associated with the malignant phenotypic signaling pathways of proliferation, migration, and drug resistance in OS. Oridonin was capable of inhibiting expressions of BAX, cl-caspase3, SLC7A11, GPX4 and FTH1 proteins and mRNA, while promoting the expressions of Bcl-2 and ACSL4 in 143B and U2OS cells. Additionally, we found that oridonin could promote the accumulation of reactive oxygen species (ROS) and Fe2+ in OS cells, as well as reduce mitochondrial membrane potential, and these effects could be significantly reversed by the ferroptosis inhibitor ferrostatin-1 (Fer-1). CONCLUSION: Oridonin can trigger apoptosis and ferroptosis collaboratively in OS cells, making it a promising and effective agent for OS therapy.

Recent advances in senescence-associated secretory phenotype and osteoporosis.

The worldwide elderly population is on the rise, and aging is a major osteoporosis risk factor. Senescent cells accumulation can have a detrimental effect the body as we age. The senescence-associated secretory phenotype (SASP), an essential cellular senescence hallmark, is an important mechanism connecting cellular senescence to osteoporosis. This review describes in detail the characteristics of SASPs and their regulatory agencies, and shed fresh light on how SASPs from different senescent cells contribute to osteoporosis development. Furthermore, we summarized various innovative therapy techniques that target SASPs to lower the burden of osteoporosis in the elderly and discussed the potential challenges of SASPs-based therapy for osteoporosis as a new clinical trial.

Cell Reprogramming Strategies for Treating Osteoarthritis and Intervertebral Disc Degeneration.

Osteoarthritis (OA) and intervertebral disc degeneration (IVDD) are the most common degenerative bone and joint diseases, posing a major threat to patients' physical and mental health due to the occurrence of chronic pain and disability. Within this context, the absence of efficacious therapies has led to a growing interest in regenerative medicine. In particular, as a method that can erase the memory of differentiation and re-endow cells with pluripotency, cell reprogramming technologies have ushered in a new era of personalized therapy, which not only show great potential for the treatment of degenerative osteoarthropathies but also promise to achieve tissue regenerative and repair. However, compared to other areas of research, reprogramming technologies to treat OA and IVDD are still in the preliminary stages and require further investigation. This paper briefly introduces the characteristics of cell reprogramming; summarizes the pathological mechanisms of reprogramming to improves energy metabolism, aging, inflammation, oxidative stress, and immune imbalance in OA and IVDD under the background of microenvironment and immunity; highlights the significant advantages of reprogramming-derived cells compared to embryonic stem cells and mesenchymal stem cells, based on these advances, providing important strategies for its development and clinical application in OA and IVDD.

The application of the strip-shaped cymba conchae orthosis in the nonsurgical correction of complex auricular deformity.

Objective: This study aims to evaluate the efficacy and safety of using a strip-shaped cymba conchae orthosis for the nonsurgical correction of complex auricular deformities. Methods: Clinical data were collected from 2020 to 2021 for 6 patients who underwent correction using a strip-shaped cymba conchae orthosis. The indications, corrective effects, and complications associated with use of the orthosis were analyzed. Results: There were four indications for treatment: cryptotia with helix adhesion; cryptotia with grade I microtia; cryptotia with excessive helix thickness; and auricular deformity beyond the treatment time window (≥6 months). Excellent corrective effects were observed in all 6 patients. Complications occurred in one patient, who recovered after symptomatic treatment. Conclusion: The use of a strip-shaped cymba conchae orthosis alone or combined with a U-shaped helix orthosis presents a feasible approach for correcting complex auricular deformities or deformities beyond the treatment time window in pediatric patients.

Nanoadjuvant-triggered STING activation evokes systemic immunotherapy for repetitive implant-related infections.

Repetitive implant-related infections (IRIs) are devastating complications in orthopedic surgery, threatening implant survival and even the life of the host. Biofilms conceal bacterial-associated antigens (BAAs) and result in a "cold tumor"-like immune silent microenvironment, allowing the persistence of IRIs. To address this challenge, an iron-based covalent organic framed nanoadjuvant doped with curcumin and platinum (CFCP) was designed in the present study to achieve efficient treatment of IRIs by inducing a systemic immune response. Specifically, enhanced sonodynamic therapy (SDT) from CFCP combined with iron ion metabolic interference increased the release of bacterial-associated double-stranded DNA (dsDNA). Immunogenic dsDNA promoted dendritic cell (DC) maturation through activation of the stimulator of interferon gene (STING) and amplified the immune stimulation of neutrophils via interferon-ß (IFN-ß). At the same time, enhanced BAA presentation aroused humoral immunity in B and T cells, creating long-term resistance to repetitive infections. Encouragingly, CFCP served as neoadjuvant immunotherapy for sustained antibacterial protection on implants and was expected to guide clinical IRI treatment and relapse prevention.

Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature.

The senescence-associated secretory phenotype (SASP) is a generic term for the secretion of cytokines, such as pro-inflammatory factors and proteases. It is a crucial feature of senescent cells. SASP factors induce tissue remodeling and immune cell recruitment. Previous studies have focused on the beneficial role of SASP during embryonic development, wound healing, tissue healing in general, immunoregulation properties, and cancer. However, some recent studies have identified several negative effects of SASP on fracture healing. Senolytics is a drug that selectively eliminates senescent cells. Senolytics can inhibit the function of senescent cells and SASP, which has been found to have positive effects on a variety of aging-related diseases. At the same time, recent data suggest that removing senescent cells may promote fracture healing. Here, we reviewed the latest research progress about SASP and illustrated the inflammatory response and the influence of SASP on fracture healing. This review aims to understand the role of SASP in fracture healing, aiming to provide an important clinical prevention and treatment strategy for fracture. Clinical trials of some senolytics agents are underway and are expected to clarify the effectiveness of their targeted therapy in the clinic in the future. Meanwhile, the adverse effects of this treatment method still need further study.

Joint State and Unknown Input Estimation for a Class of Artificial Neural Networks With Sensor Resolution: An Encoding-Decoding Mechanism.

This article is concerned with the joint state and unknown input (SUI) estimation for a class of artificial neural networks (ANNs) with sensor resolution (SR) under the encoding-decoding mechanisms. The consideration of SR, which is an important specification of sensors in the real world, caters to engineering practice. Furthermore, the implementation of the encoding-decoding mechanism in the communication network aims to accommodate the limited bandwidth. The objective of this study is to propose a set-membership estimation algorithm that accurately estimates the state of the ANN without being influenced by the unknown input while accounting for the SR and the encoding-decoding mechanism. First, a sufficient condition is derived to ensure an ellipsoidal constraint on the estimation error. Then, by addressing an optimization problem, the design of the estimator gains is accomplished, and the minimal ellipsoidal constraint on the state estimation error is obtained. Finally, an example is provided to confirm the validity of the proposed joint SUI estimation scheme.

The effects of living arrangements and leisure activities on depressive symptoms of Chinese older adults: Evidence from panel data analysis.

BACKGROUND: Livable environment and ways, as the necessary conditions for the elderly to enjoy their old age, have a significant impact on their mental health and happiness. It's crucial to understand how living arrangements affect depressive symptoms in China. Studies on how various leisure activities modify this association are yet limited. METHODS: This study relies on panel data derived from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), collected during waves spanning 2008/2009, 2011/2012, 2014, and 2018. The primary objective is to examine the relationship between living arrangements, leisure activities, and depressive symptoms of elderly individuals. Linear mixed-effects models were used to analyze the data. RESULTS: A total of 26,342 observations aged 65 and over were included in this paper. Older adults living alone (ß = 0.66, 95 % CI: 0.55, 0.76) or living in institutions (ß = 0.69, 95 % CI: 0.40, 0.98) had more depressive symptoms than those living with family. Leisure activities were negatively associated with depressive symptoms (ß = -0.16, 95 % CI: -0.18, -0.15). Moreover, there was significant interactions between living arrangements and leisure activities. No matter which kind of living arrangements, participating in physical, productive or social activity was associated with a lower risk of depressive symptoms. LIMITATIONS: Study design might introduce bias, and it cannot establish causality between the tested variables. CONCLUSIONS: Older adults living alone or in institutions have more possibility to develop depressive symptoms than those living with family, and such a relationship among Chinese older adults can be moderated by participating in leisure activities.

Risk Factors for New Adjacent and Remote Vertebral Fracture After Percutaneous Vertebroplasty.

OBJECTIVE: To analyze the risk factors of new adjacent vertebral fractures (AVF) and remote vertebral fractures (RVF) after percutaneous vertebroplasty (PVP) for osteoporotic vertebral compression fractures (OVCFs). METHODS: Patients who underwent additional PVP for new OVCFs were enrolled. In addition, we set a 1:1 age-, sex-, surgical segment-, and surgical date-matched control group, in which patients underwent PVP without new OVCFs. Data on body mass index, occurrence time of second PVP, vertebral computed tomography (CT) Hounsfield Unit (HU) at the fracture adjacent segment, and RVF segment were collected. RESULTS: A total of 44 patients who underwent additional PVP for new OVCFs at our hospital were included. AVF occurred significantly earlier than RVF (13.5 ± 14.1 vs. 30.4 ± 20.1 months, P = 0.007). Compared to the control group, the AVF segment CT HU was significantly lower in patients with AVF (28.7 ± 16.7 vs. 61.3 ± 14.7, P = 0.000), while there was no significant difference between patients with RVF and control group including both adjacent and RVF segment CT HU. Receiver operating characteristic curves identified a cutoff value of 43 for using adjacent segment CT HU to differentiate patients with AVF from controls, with a sensitivity of 80% and a specificity of 88.9%. CONCLUSIONS: Our study showed that the risk factors for AVF and RVF after PVP surgery were different. The occurrence of AVF was earlier and associated with low adjacent segment CT HU values, whereas the preoperative CT HU in both adjacent and RVF segments was not found to be associated with RVF.

Blood-labyrinth barrier breakdown in Meniere's disease.

OBJECTIVE: We compared the signal intensity ratio (SIR) of the cochlear basal turn between Meniere's disease and healthy controls to investigate potential damage of the blood-labyrinth barrier in Meniere's disease. METHODS: Thirty patients diagnosed with unilateral definite Meniere's disease and 24 healthy controls were enrolled. 3D-FLAIR scan was conducted to assess the grades of endolymphatic hydrops in Meniere's patients while measuring the SIR of cochlear basal turns in both groups. The differences of bilateral SIR between Meniere's disease and healthy control were compared, and the correlation between the SIR on affected ear in Meniere's disease and the grades of cochlear and vestibular hydrops were analyzed. RESULTS: SIR of affected ear in Meniere's disease exhibited significant increase compared to that of unaffected ear. No significant difference was observed in SIR between the two ears in the healthy control. Furthermore, the SIR of unaffected side in Meniere's disease was higher than that of both ears in healthy controls. The SIR in affected ear of Meniere's disease exhibited positive correlation with hydrops in both cochlea and vestibula. CONCLUSION: The permeability of blood-labyrinth barrier is increased in Meniere's disease, in combination with the typical criteria of Meniere's disease it may be a good biological marker. Destruction of blood-labyrinth barrier may be one of the causes of endolymphatic hydrops in Meniere's disease.

Melatonin exerts neuroprotective effects in mice with spinal cord injury by activating the Nrf2/Keap1 signaling pathway via the MT2 receptor.

Spinal cord injury (SCI) is a devastating event that often leads to severe disability, and effective treatments for SCI are currently limited. The present study investigated the potential effects and specific mechanisms of melatonin treatment in SCI. Mice were divided into Sham (Sham), Vehicle (Veh), Melatonin (Mel), and Melatonin + 4-phenyl-2-propionamidotetralin (4P-PDOT) (Mel + 4PP) groups based on randomized allocation. The expression of MT2 and the nuclear factor-erythroid 2-related factor 2 (Nrf2)/Keap1 signaling pathways were examined, along with oxidative stress indicators, inflammatory factors and GFAP-positive cells near the injury site. The polarization of microglial cells in different inflammatory microenvironments was also observed. Cell survival, motor function recovery and spinal cord tissue morphology were assessed using staining and Basso Mouse Scale scores. On day 7 after SCI, the results revealed that melatonin treatment increased MT2 protein expression and activated the Nrf2/Keap1 signaling pathway. It also reduced GFAP-positive cells, mitigated oxidative stress, and suppressed inflammatory responses around the injury site. Furthermore, melatonin treatment promoted the polarization of microglia toward the M2 type, increased the number of neutrophil-positive cells, and modulated the transcription of Bax and Bcl2 in the injured spinal cord. Melatonin treatment alleviated the severity of spinal injuries and facilitated functional recovery in mice with SCI. Notably, blocking MT2 with 4P-PDOT partially reversed the neuroprotective effects of melatonin in SCI, indicating that the activation of the MT2/Nrf2/Keap1 signaling pathway contributes to the neuroprotective properties of melatonin in SCI. The therapeutic and translational potentials of melatonin in SCI warrant further investigation.