Jen-Kun Cheng

Spinal cord injury (SCI) is a devastating neurological condition characterized by irreversible primary damage followed by a complex secondary injury cascade involving oxidative stress, neuroinflammation, iron dysregulation, and regulated cell death. Among these mechanisms, ferroptosis, a distinct, iron-dependent form of regulated cell death driven by lipid peroxidation and redox imbalance, is increasingly recognized as a critical mediator of neurodegeneration after SCI. The miRNAs play essential roles in neural injury responses by modulating inflammation, oxidative stress, and cell-death pathways. Growing evidence indicates that miRNAs closely regulate ferroptosis-related signaling networks following SCI, influencing key molecular targets including iron metabolism, antioxidant defense systems, and lipid peroxidation pathways. Conversely, ferroptotic stress may alter miRNA expression profiles, suggesting a bidirectional regulatory relationship. In addition, ferritinophagy, a selective autophagy pathway degrading ferritin via nuclear receptor coactivator 4 (NCOA4), has emerged as an important yet underexplored regulator of intracellular iron homeostasis and ferroptosis susceptibility in SCI. This review systematically summarizes current evidence on the molecular mechanisms linking miRNAs and ferroptosis in SCI, highlights how miRNA-mediated regulation of ferroptosis contributes to neuronal death, glial responses, and impaired regeneration, and discusses emerging therapeutic strategies targeting this axis to promote neuroprotection and functional recovery. By integrating recent experimental findings, we aim to provide mechanistic insight and identify translational opportunities for miRNA- and ferroptosis-based interventions in SCI.

Spinal cord injury (SCI) is a devastating neurological condition characterized by irreversible primary damage followed by a complex secondary injury cascade involving oxidative stress, neuroinflammation, iron dysregulation, and regulated cell death. Among these mechanisms, ferroptosis a distinct, iron-dependent form of regulated cell death driven by lipid peroxidation and redox imbalance is increasingly recognized as a critical mediator of neurodegeneration after SCI. The miRNAs play essential roles in neural injury responses by modulating inflammation, oxidative stress, and cell death pathways. Growing evidence indicates that miRNAs closely regulate ferroptosis-related signaling networks following SCI, influencing key molecular targets including iron metabolism, antioxidant defense systems, and lipid peroxidation pathways. Conversely, ferroptotic stress may alter miRNA expression profiles, suggesting a bidirectional regulatory relationship. In addition, ferritinophagy a selective autophagy pathway degrading ferritin via nuclear receptor coactivator 4 (NCOA4) has emerged as an important yet underexplored regulator of intracellular iron homeostasis and ferroptosis susceptibility in SCI. This review systematically summarizes current evidence on the molecular mechanisms linking miRNAs and ferroptosis in SCI, highlights how miRNA-mediated regulation of ferroptosis contributes to neuronal death, glial responses, and impaired regeneration, and discusses emerging therapeutic strategies targeting this axis to promote neuroprotection and functional recovery. By integrating recent experimental findings, we aim to provide mechanistic insight and identify translational opportunities for miRNA and ferroptosis-based interventions in SCI.

Background: Neuropathic pain presents a significant clinical challenge, with spinal cord epigenetic mechanisms playing a critical role in its development. This study investigated the impact of nerve injury on the Barrier-to-Autointegration Factor (BAF) in the rat spinal dorsal horn. Methods: Adult Sprague-Dawley rats underwent spinal nerve ligation (SNL) to model neuropathic pain. Pain behaviors were assessed using von Frey and burrow tests. Biochemical analyses measured mRNA and protein expression in the dorsal horn. Results: SNL elevated BAF levels, which interacts with LEM domain–containing protein 2 (LEMD2), activating the histone-modifying enzyme EZH2. This enzyme adds a gene-silencing mark, H3K27me3, to the promoter region of the Oprm1 gene, which encodes the mu-opioid receptor. Consequently, the expression of the mu-opioid receptor is decreased, potentially contributing to neuropathic pain. Using gene knockdown techniques to reduce BAF expression, we reversed the changes in LEMD2, EZH2, and mu-opioid receptor expressions induced by SNL and attenuated mechanical allodynia. Additionally, knocking down LEMD2 disrupted the binding of BAF to the Oprm1 promoter, without affecting BAF levels. Inhibiting EZH2 also reversed the signaling without altering BAF and LEMD2 levels. Glutamate activated BAF pathways via pNR2B receptors, and NR2B receptor blockade reversed this effect. Conclusion: These findings suggest that spinal pNR2B receptors may activate BAF, which interacts with LEMD2 to enhance EZH2-mediated H3K27me3 at the mu-opioid receptor promoter after nerve injury. Targeting this pathway may offer novel strategies to inhibit neuropathic pain.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic strategy for spinal cord injury (SCI). These nanosized vesicles possess unique properties such as low immunogenicity and the ability to cross biological barriers, making them ideal carriers for delivering bioactive molecules to injured tissues. MSC-EVs have been demonstrated to exert multiple beneficial effects in SCI, including reducing inflammation, promoting neuroprotection, and enhancing axonal regeneration. Recent studies have delved into the molecular mechanisms underlying MSC-EV-mediated therapeutic effects. Exosomal microRNAs (miRNAs) have been identified as key regulators of various cellular processes involved in SCI pathogenesis and repair. These miRNAs can influence inflammation, oxidative stress, and apoptosis by modulating gene expression. This review summarized the current state of MSC-EV-based therapies for SCI, highlighting the underlying mechanisms and potential clinical applications. We discussed the challenges and limitations of translating these therapies into clinical practice, such as inconsistent EV production, complex cargo composition, and the need for targeted delivery strategies. Future research should focus on optimizing EV production and characterization, identifying key therapeutic miRNAs, and developing innovative delivery systems to maximize the therapeutic potential of MSC-EVs in SCI.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic strategy for spinal cord injury (SCI). These nanosized vesicles possess unique properties such as low immunogenicity and the ability to cross biological barriers, making them ideal carriers for delivering bioactive molecules to injured tissues. MSC-EVs have been demonstrated to exert multiple beneficial effects in SCI, including reducing inflammation, promoting neuroprotection, and enhancing axonal regeneration. Recent studies have delved into the molecular mechanisms underlying MSC-EV-mediated therapeutic effects. Exosomal microRNAs (miRNAs) have been identified as key regulators of various cellular processes involved in SCI pathogenesis and repair. These miRNAs can influence inflammation, oxidative stress, and apoptosis by modulating gene expression. This review summarizes the current state of MSC-EV-based therapies for SCI, highlighting the underlying mechanisms and potential clinical applications. We discuss the challenges and limitations of translating these therapies into clinical practice, such as inconsistent EV production, complex cargo composition, and the need for targeted delivery strategies. Future research should focus on optimizing EV production and characterization, identifying key therapeutic miRNAs, and developing innovative delivery systems to maximize the therapeutic potential of MSC-EVs in SCI.

Background: Spinal cord injury (SCI) is a debilitating illness in humans that causes permanent loss of movement or sensation. To treat SCI, exosomes, with their unique benefits, can circumvent limitations through direct stem cell transplantation. Therefore, we utilized Gelfoam encapsulated with exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-EX) in a rat SCI model. Methods: SCI model was established through hemisection surgery in T9 spinal cord of female Sprague-Dawley rats. Exosome-loaded Gelfoam was implanted into the lesion site. An in vivo uptake assay using labeled exosomes was conducted on day 3 post-implantation. Locomotor functions and gait analyses were assessed using Basso-Beattie-Bresnahan (BBB) locomotor rating scale and DigiGait Imaging System from weeks 1 to 8. Nociceptive responses were evaluated through von Frey filament and noxious radiant heat tests. The therapeutic effects and potential mechanisms were analyzed using Western blotting and immunofluorescence staining at week 8 post-SCI. Results: For the in vivo exosome uptake assay, we observed the uptake of labeled exosomes by NeuN⁺, Iba1⁺, GFAP⁺, and OLIG2⁺ cells around the injured area. Exosome treatment consistently increased the BBB score from 1 to 8 weeks compared with the Gelfoam-saline and SCI control groups. Additionally, exosome treatment significantly improved gait abnormalities including right-to-left hind paw contact area ratio, stance/stride, stride length, stride frequency, and swing duration, validating motor function recovery. Immunostaining and Western blotting revealed high expression of NF200, MBP, GAP43, synaptophysin, and PSD95 in exosome treatment group, indicating the promotion of nerve regeneration, remyelination, and synapse formation. Interestingly, exosome treatment reduced SCI-induced upregulation of GFAP and CSPG. Furthermore, levels of Bax, p75NTR, Iba1, and iNOS were reduced around the injured area, suggesting anti-inflammatory and anti-apoptotic effects. Moreover, exosome treatment alleviated SCI-induced pain behaviors and reduced pain-associated proteins (BDNF, TRPV1, and Cav3.2). Exosomal miRNA analysis revealed several promising therapeutic miRNAs. The cell culture study also confirmed the neurotrophic effect of HucMSCs-EX. Conclusion: Implantation of HucMSCs-EX-encapsulated Gelfoam improves SCI-induced motor dysfunction and neuropathic pain, possibly through its capabilities in nerve regeneration, remyelination, anti-inflammation, and anti-apoptosis. Overall, exosomes could serve as a promising therapeutic alternative for SCI treatment.

Hydrogels, recognized for their flexibility and diverse characteristics, are extensively used in medical fields such as wearable sensors and soft robotics. However, many hydrogel sensors derived from biomaterials lack mechanical strength and fatigue resistance, emphasizing the necessity for enhanced formulations. In this work, we utilized acrylamide and polyacrylamide as the primary polymer network, incorporated chemically modified poly(ethylene glycol) (DF-PEG) as a physical crosslinker, and introduced varying amounts of methacrylated lysine (LysMA) to prepare a series of hydrogels. This formulation was labeled as poly(acrylamide)-DF-PEG-LysMA, abbreviated as pADLx, with x denoting the weight/volume percentage of LysMA. We observed that when the hydrogel contained 2.5% w/v LysMA (pADL2.5), compared to hydrogels without LysMA (pADL0), its stress increased by 642 ± 76%, strain increased by 1790 ± 95%, and toughness increased by 2037 ± 320%. Our speculation regarding the enhanced mechanical performance of the pADL2.5 hydrogel revolves around the synergistic effects arising from the co-polymerization of LysMA with acrylamide and the formation of multiple intermolecular hydrogen bonds within the network structures. Moreover, the acid, amine, and amide groups present in the LysMA molecules have proven to be instrumental contributors to the self-adhesion capability of the hydrogel. The validation of the pADL2.5 hydrogel’s exceptional mechanical properties through rigorous tensile tests further underscores its suitability for use in strain sensors. The outstanding stretchability, adhesive strength, and fatigue resistance demonstrated by this hydrogel affirm its potential as a key component in the development of robust and reliable strain sensors that fulfill practical requirements.

Chronic pain disorders are often associated with negative emotions, including anxiety and depression. The central nucleus of the amygdala (CeA) has emerged as an integrative hub for nociceptive and affective components during central pain development. Prior adverse injuries are precipitating factors thought to transform nociceptors into a primed state for chronic pain. However, the cellular basis underlying the primed state and the subsequent development of chronic pain remains unknown. Here, we investigated the cellular and synaptic alterations of the CeA in a mouse model of chronic muscle pain. In these mice, local infusion of pregabalin, a clinically approved drug for fibromyalgia and other chronic pain disorders, into the CeA or chemogenetic inactivation of the somatostatin-expressing CeA (CeA-SST) neurons during the priming phase prevented the chronification of pain. Further, electrophysiological recording revealed that the CeA-SST neurons had increased excitatory synaptic drive and enhanced neuronal excitability in the chronic pain states. Finally, either chemogenetic inactivation of the CeA-SST neurons or pharmacological suppression of the nociceptive afferents from the brainstem to the CeA-SST neurons alleviated chronic pain and anxio-depressive symptoms. These data raise the possibility of targeting treatments to CeA-SST neurons to prevent central pain sensitization.

Anesthesia for patients with mucopolysaccharidoses (MPS) is quite challenging due to vital systemic dysfunction following progressive accumulation of lysosomal glycosaminoglycans. Previous studies focused on perioperative difficult airway management under general anesthesia but rarely depicted the concern of choosing the size of the endotracheal tube (ETT) as well as neuraxial anesthesia. This study aimed to analyze the overall anesthetic management and related complications for a thorough anesthetic strategy. Within the study period from 2002 to 2021, each record of the anesthetic and perioperative quality assurance/improvement system for patients with a diagnosis of MPS at MacKay Memorial Hospital was retrospectively reviewed. A total of 51 individuals with 151 anesthesia for 163 interventions were cohort studied, and there were 136 general anesthesia and 15 neuraxial anesthesia. We found that the most common interventions for MPS patients were otolaryngological surgeries (49.6%). Additionally, a secured airway played a marked preference for the most general anesthesia (87.1%). The incidence of difficult intubation was 12.5%. In view of ETT size, a smaller than estimated size was used in MPS type II, III, IV, and VI patients and also in patients who received intubation with multiple attempts. However, a larger than estimated size of ETT was adopted whilst choosing cuffed ones. For neuraxial anesthesia, two failed spinal anesthesia procedures were converted to general anesthesia and 73 percent of the patients received perioperative sedation. In conclusion, through the individualized anesthetic strategy and build-up of an experienced team for airway management, high-quality anesthesia can be ensured in each patient.