Multifunctional Hierarchical Nanoplatform with Anisotropic Bimodal Mesopores for Effective Neural Circuit Reconstruction after Spinal Cord Injury.

A persistent inflammatory response, intrinsic limitations in axonal regenerative capacity, and widespread presence of extrinsic axonal inhibitors impede the restoration of motor function after a spinal cord injury (SCI). A versatile treatment platform is urgently needed to address diverse clinical manifestations of SCI. Herein, we present a multifunctional nanoplatform with anisotropic bimodal mesopores for effective neural circuit reconstruction after SCI. The hierarchical nanoplatform features of a Janus structure consist of dual compartments of hydrophilic mesoporous silica (mSiO2) and hydrophobic periodic mesoporous organosilica (PMO), each possessing distinct pore sizes of 12 and 3 nm, respectively. Unlike traditional hierarchical mesoporous nanomaterials with dual-mesopores interlaced with each other, the two sets of mesopores in this Janus nanoplatform are spatially independent and possess completely distinct chemical properties. The Janus mesopores facilitate controllable codelivery of dual drugs with distinct properties: the hydrophilic macromolecular enoxaparin (ENO) and the hydrophobic small molecular paclitaxel (PTX). Anchoring with CeO2, the resulting mSiO2&PMO-CeO2-PTX&ENO nanoformulation not only effectively alleviates ROS-induced neuronal apoptosis but also enhances microtubule stability to promote intrinsic axonal regeneration and facilitates axonal extension by diminishing the inhibitory effect of extracellular chondroitin sulfate proteoglycans. We believe that this functional dual-mesoporous nanoplatform holds significant potential for combination therapy in treating severe multifaceted diseases.

Improvement of Performance of CZTSSe Solar Cells by the Synergistic Effect of Back Contact Modification and Ag Doping.

To improve the performance of Cu2ZnSn(S,Se)4 solar cells, a strategy is proposed to improve the quality of absorber and back interface simultaneously by substituting V-doped Mo (Mo:V) for a conventional Mo back electrode and incorporating Ag into the Cu2ZnSn(S,Se)4 (ACZTSSe) absorber in this work. Since p+-type V-doped MoSe2 (MoSe2:V) is formed in the site between the absorber and Mo:V during selenization, the conventional Mo/n-MoSe2 back contact is modified to Mo:V/p+-MoSe2:V, a back surface passivation field (BSPF) is established at the back interface, the band bending of MoSe2:V is downward and that of bottom of the absorber is upward. Further investigation reveals that the back contact modification and Ag doping have a synergistic effect on inhibiting carrier recombination, decreasing series resistance and increasing shunt resistance, thereby leading to the PCE of device without antireflection coating increased from 8.61 to 10.98%, which is larger than the sum of increase in PCE induced by Ag doping alone (8.61 to 9.66%) and back contact modification alone (8.61 to 9.63%). It is demonstrated that the synergistic effect stems mainly from the strengthened BSPF and the further reduced back contact barrier height. The former is due to the increased difference in work function (WF) between MoSe2:V and absorber induced by the reduced WF of the absorber after Ag doping and the raised WF of MoSe2:V after V doping. The latter is due to the downshifted valence band maximum of absorber after Ag doping. This work highlights the synergistic effect of back contact modification and Ag doping on improving the performance of CZTSSe solar cells and also provides an effective way to suppress carrier recombination.

A sensing label or gel loaded with an NIR emission fluorescence probe for ultra-fast detection of volatile amine and fish freshness.

A simple benzopyran-based fluorescence probe DCA-Apa detection of volatile amine has been synthesized. DCA-Apa can recognize volatile amines by dual channel mode (changing from blue to light yellow in sunlight, and from weak pink to orange under 365 nm) in pure water system. DCA-Apa has the advantages of ultra-fast response (∼6 s), NIR emission (655 nm), and a good fluorescence response for many amines. The sensing label or gel loaded with DCA-Apa was prepared by the dipping or mixing method using filter paper or gelatin as solid carriers, which can identify volatile amine vapor and monitor the freshness of salmon by colorimetric and fluorescent dual channels. When the color of the label changes to light yellow-green or the fluorescence of the label becomes orange fluorescence (365 nm UV lamp), it indicates that the fish has rotted. The two-channel method makes up for the deficiency of the single colorimetric method, and establishes a theoretical foundation for more precise assessment of fish freshness.

Stratified Treatment in Pediatric Anaplastic Large Cell Lymphoma: Result of a Prospective Open-Label Multiple-Institution Study.

Purpose: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored. Materials and Methods: On the basis of the non-Hodgkin's lymphoma Berlin-Frankfurt-Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL). Results: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% [95% Confidence Interval (CI), 69.0%-83.9%] and 92.3% (95% CI,86.1%-95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5%-95.5%, and 67.9% (95% CI, 55.4%-77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6%-19.0%), 65.7% (95% CI, 47.6%-78.9%), 55.7% (95% CI, 26.2%-77.5%), and 70.7% (95% CI, 48.6%-84.6%), respectively. At the end of follow-up, one of the 5 patients who received maintenance therapy with VBL relapsed, and seven patients receiving ALK inhibitor maintenance therapy did not experience relapse. Conclusion: This study has confirmed the poor prognostic of MDD (+) ，high risk site and SC/LH ,but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305).

Diagnostic implications of ubiquitination-related gene signatures in Alzheimer's disease.

The purpose of this study was to explore the diagnostic implications of ubiquitination-related gene signatures in Alzheimer's disease. In this study, we first collected 161 samples from the GEO database (including 87 in the AD group and 74 in the normal group). Subsequently, through differential expression analysis and the iUUCD 2.0 database, we obtained 3450 Differentially Expressed Genes (DEGs) and 806 Ubiquitin-related genes (UbRGs). After taking the intersection, we obtained 128 UbR-DEGs. Secondly, by conducting GO and KEGG enrichment analysis on these 128 UbR-DEGs, we identified the main molecular functions and biological pathways related to AD. Furthermore, through the utilization of GSEA analysis, we have gained insight into the enrichment of functions and pathways within both the AD and normal groups. Further, using lasso regression analysis and cross-validation techniques, we identified 22 characteristic genes associated with AD. Subsequently, we constructed a logistic regression model and optimized it, resulting in the identification of 6 RUbR-DEGs: KLHL21, WDR82, DTX3L, UBTD2, CISH, and ATXN3L. In addition, the ROC result showed that the diagnostic model we built has excellent accuracy and reliability in identifying AD patients. Finally, we constructed a lncRNA-miRNA-mRNA (competing endogenous RNA, ceRNA) regulatory network for AD based on six RUbR-DEGs, further elucidating the interaction between UbRGs and lncRNA, miRNA. In conclusion, our findings will contribute to further understanding of the molecular pathogenesis of AD and provide a new perspective for AD risk prediction, early diagnosis and targeted therapy in the population.

Visualizing the crucial roles of plasma membrane and peroxynitrite during abdominal aortic aneurysm using two-photon fluorescence imaging.

Peroxynitrite (ONOO-) and cell plasma membrane (CPM) are two key factors in cell pyroptosis during the progression of abdominal aortic aneurysm (AAA). However, their combined temporal and spatial roles in initiating AAA pathogenesis remain unclear. Herein, we developed a two-photon fluorescence probe, BH-Vis, enabling real-time dynamic detection of CPM and ONOO- changes, and revealing their interplay in AAA. BH-Vis precisely targets CPM with reduced red fluorescence intensity correlating with diminished CPM tension. Concurrently, a blue shift of the fluorescence signal of BH-Vis occurs in response to ONOO- offering a reliable ratiometric detection mode with enhanced accuracy by minimizing external testing variables. More importantly, two photon confocal imaging with palmitic acid (PA) and ganglioside (GM1) manipulation, which modulating cell pyroptosis, showcases reliable fluorescence fluctuations. This groundbreaking application of BH-Vis in a mouse AAA model demonstrates its significant potential for accurately identifying cell pyroptosis levels during AAA development.

A novel fluorescence probe for ultrafast detection of SO2 derivatives/biogenic amines and its multi-application: Detecting food and fish freshness, fluorescent dye and bioimaging.

In this study, we have effectively prepared a novel fluorescent probe named HDXM based on benzopyran derivatives for the ultrafast detection (within 3 s) of SO2 derivatives or biogenic amines. HDXM showed a noticeable color change after the addition of SO2 derivatives (from purple to colorless) or biogenic amines (from purple to blue), indicating that HDXM can identify two analytes with the naked eye. It is worth noting that HDXM can be used to detect SO2 derivatives in actual sugar samples, and to image HSO3-/SO32- in living cells. More importantly, sensing labels (HDXM-loaded filter paper or agarose hydrogel) enable real-time visual monitoring of salmon freshness through colorimetric and fluorescence dual channels. Compared with the Chinese national standard method, the sensing label is an effective tool for evaluating the freshness of fish. Benefiting from its excellent solubility and fluorescence performance, HDXM can be used as a versatile fluorescent material in various applications, including flexible films, glass coatings, impregnating dyes, printing, and fingerprint ink. HDXM is expected to be a promising and valuable multifunctional tool for food safety and fluorescent materials.

Impacts of mining on vegetation phenology and sensitivity assessment of spectral vegetation indices to mining activities in arid/semi-arid areas.

Measuring the impact of mining activities on vegetation phenology and assessing the sensitivity of vegetation indices (VIs) to it are crucial for understanding land degradation in mining areas and enhancing the carbon sink capacity following the ecological restoration of mines. To this end, we have developed a novel technical framework to quantify the impact of mining activities on vegetation, and applied it to the Bainaimiao copper mining area in Inner Mongolia. Phenological indices are extracted based on the VI time series data of Sentinel-2, and changes in phenological differences in various directions are used to quantify the impact of mining activities on vegetation. Finally, indicators such as mean difference, standard deviation, index value distribution interval, and concentration of index value distribution were selected to assess the sensitivity of the Enhanced Vegetation Index (EVI), Green Chlorophyll Index (GCI), Global Environmental Monitoring Index (GEMI), Green Normalized Difference Vegetation Index (GNDVI), Normalized Difference Vegetation Index (NDVI), Renormalized Difference Vegetation Index (RDVI), Red-Edge Chlorophyll Index (RECI), and Soil-Adjusted Vegetation Index (SAVI) to mining activities. The results of the study show that the impact of mining activities on surrounding vegetation extends to an area three times larger than the actual mining activity area. When compared with the reference and unaffected areas, the affected area experienced a delay of approximately 10 days in seasonal vegetation development. Environmental pollution caused by the tailings pond was identified as the primary factor influencing this delay. Significant variations in the sensitivity of each VI to assess mining activities in arid/semi-arid areas were observed. Notably, GCI, GNDVI and RDVI displayed relatively high sensitivity to discrepancies in the spectral attributes of vegetation within the affected area, while SAVI reflected the overall spectral stability of the vegetation in the affected area. The research findings have the potential to provide valuable technical guidance for holistic environmental management in mining areas and hold great significance in preventing further land degradation and supporting ecological restoration in mining areas.

Successful treatment by a chlorin e6 derivative mediated photodynamic therapy combined holmium laser for cervical and vaginal giant condyloma acuminata and low-grade intraepithelial neoplasia:A case report.

Photodynamic therapy (PDT) is proved effective for treating low-grade squamous intraepithelial lesions (LSIL) and condylomata acuminata (CA). 5-Aminolevulinicacid (5-ALA) is the most common applied photosensitizer, but high rate of unbearable pain and relative long incubation time were reported. Here, we report a 27-year-old woman suffering from cervical and vaginal giant CA with LSIL involving the whole right vaginal fornix, cervical surface, and vaginal wall. Holmium yttrium aluminum garnet (Ho: YAG) laser was first applied to remove the giant CA lesions. STBF, a derivative of chlorin e6 (Ce6) was then applied on suspicious lesions as a new photosensitizer for 1 h. Lesions were exposed to LED illumination with a wavelength of 630 nm and light dose of 200-284 J/cm2 for cervical canal and the vaginal surfaces, 100-150 J/cm2 for cervix surface. Vaginal giant CA and LSIL lesions got complete remission at 6-month follow-up. Mild tolerable adverse reactions were observed after STBF-PDT and relieved in 24 h. Thus, the combination of Ho: YAG laser and STBF-PDT may be a novel option for cervical and vaginal giant CA and LSIL, especially for special vaginal fornix areas.

Non-pharmacological therapies for the management of the cognitive dysfunctions in post-stroke patients: a systematic review and network meta-analysis.

OBJECTIVE: To investigate the comparative effects of non-pharmacological therapies for managing global, attention, memory and execution cognitive functions in stroke patients. DESIGN: We searched PubMed, EMBASE, CINAHL, Cochrane Library, Web of Science, PEDro and Google Scholar for randomized controlled trials (RCTs) that evaluated the effects of non-pharmacological therapies for treating stroke cognitive dysfunctions. We performed a network meta-analysis (NMA) to estimate the mean treatment effect of 95% credible interval (CrI). RESULTS: 73 RCTs were included in the NMA for evidence syntheses. All therapies had significant effects than control on global cognition in stroke patients. Combined therapy was superior to other therapies for global cognition of all patients (vs cognitive task therapy: 0.71, 95%CrI 0.14 to 1.29; vs exercise: 0.88, 95%CrI 0.31 to 1.45, vs physical modality therapy: 0.77, 95%CrI 0.16 to 1.40). Different therapies have effects on specific cognitive domains in stroke patients. CONCLUSIONS: Our findings suggest that non-pharmacological therapies are effective in improving global cognitive function in stroke patients, with cognitive task therapy, exercise therapy, physical modality therapy, and combined therapy being viable options (most optimal approach: combined therapy). Precise selection of therapies based on the time since stroke onset and specific cognitive domains can further enhance treatment outcomes.

Aliphatic Hyperbranched Polycarbonates Solid Polymer Electrolytes with High Li-Ion Transference Number for Lithium Metal Batteries.

In this work, hyperbranched polycarbonate-poly(ethylene oxide) (PEO)-based solid polymer electrolytes (HBPC-SEs) are successfully synthesized via a straightforward organo-catalyzed "A1"+"B2"-ring-opening polymerization approach. The temperature-dependent ionic conductivity of HBPC-SEs, composed of different polycarbonate linkages and various LiTFSI concentrations, is investigated. The results demonstrate that HBPC-SE with an ether-carbonate alternating structure exhibits superior ionic conductivity, attributed to the solubility of Li salts in the polymer matrix and the mobility of the polymer segments. The HBPC1-SE with 30 wt% LiTFSI presents the highest ionic conductivities of 2.15  × 10-5, 1.78 × 10-4, and 6.07 × 10-4 Scm-1 at 30, 60, and 80 °C, respectively. Compared to traditional PEO-based electrolytes, the incorporation of polycarbonate segments significantly enhances the electrochemical stability window (5 V) and Li+ transference number (0.53) of HBPC-SEs. Furthermore, the LiFePO4/HBPC1-SE-3/Li cell exhibits exceptional rate capability and long-cycling performance, maintaining a discharge capacity of 130 mAh g-1 at 0.5C with a capacity retention of 95% after 300 cycles.

Bi- and tridentate coordination behaviour of a novel bis(phosphinimino)methanide ligand.

Herein, we report the synthesis of a novel ferrocenyl-functionalized bis(phosphinimino)methane ligand (CH2 (PPh2 NFc)2 ). Deprotonation of CH2 (PPh2 NFc)2 with KN(SiMe3 )2 gave the dimeric species [K{CH(PPh2 NFc)2 }]2 , which was further reacted with ECl2 (E=Ge, Sn) to yield the tetrylene compounds [{CH(PPh2 NFc)2 }ECl]. The ligand and the resulting tetrylenes were examined for their electrochemical properties with the aid of cyclic voltammetry. Furthermore, the reaction of the tetrylenes [{CH(PPh2 NFc)2 }ECl] with [AuC6 F5 (tht)] resulted in the bimetallic complexes [{(AuC6 F5 )CH(PPh2 NFc)2 }ECl] with an unusual Au coordination on the ligand backbone.

GREM1 knockdown regulates the proliferation, apoptosis and EMT of benign prostatic hyperplasia by suppressing the STAT3/c-Myc signaling.

BACKGROUND: Gremlin 1 (GREM1) has been reported to be highly expressed in prostate hyperplasia tissues. However, the role and molecular mechanism of GREM1 in benign prostatic hyperplasia (BPH) is still unclear. METHODS: In this study, expression of GREM1 in BPH-1 cells was detected by western blot assay. Cell counting kit-8 assay was performed to assess cell proliferation. Flow cytometry and western blot were used to assess cell apoptosis and cell cycle. The EMT process was detected by western blot assay and immunofluorescence staining. In addition, colivelin was used as a STAT3 activator and the expressions of STAT3/c-Myc signaling were assessed by western blot assay. RESULTS: The data showed that GREM1 silencing inhibited BPH-1 cell proliferation and promoted cell apoptosis. Moreover, GREM1 silencing repressed the cell cycle progression and the development of EMT. In addition, knockdown of GREM1 suppressed the expression of the STAT3/c-Myc signaling in BPH-1 cells and colivelin treatment rehabilitated this signaling. Moreover, c-Myc overexpression or colivelin reversed the effects of GREM1 silencing on BPH-1 cell proliferation, cell apoptosis, cell cycle, as well as EMT. CONCLUSION: To sum up, GREM1 silencing may alleviate the BPH progress by inhibiting the STAT3/c-Myc signaling.

Liver-Derived Ketogenesis via Overexpressing HMGCS2 Promotes the Recovery of Spinal Cord Injury.

The liver is the major ketogenic organ of the body, and ketones are reported to possess favorable neuroprotective effects. This study aims to elucidate whether ketone bodies generated from the liver play a critical role in bridging the liver and spinal cord. Mice model with a contusive spinal cord injury (SCI) surgery is established, and SCI induces significant histological changes in mice liver. mRNA-seq of liver tissue shows the temporal changes of ketone bodies-related genes, ß-hydroxybutyrate dehydrogenase (BDH1) and solute carrier family 16 (monocarboxylic acid transporters), member 6 (SLC16A6). Then, an activated ketogenesis model is created with adult C57BL/6 mice receiving the tail intravenous injection of GPAAV8-TBG-Mouse-Hmgcs2-CMV- mCherry -WPRE (HMGCS2liver ) and mice receiving equal AAV8-Null being the control group (Vectorliver ). Then, the mice undergo either a contusive SCI or sham surgery. The results show that overexpression of HMG-CoA synthase (Hmgcs2) in mice liver dramatically alleviates SCI-mediated pathological changes and promotes ketogenesis in the liver. Amazingly, liver-derived ketogenesis evidently alleviates neuron apoptosis and inflammatory microglia activation and improves the recovery of motor function of SCI mice. In conclusion, a liver-spinal cord axis can be bridged via ketone bodies, and enhancing the production of the ketone body within the liver has neuroprotective effects on traumatic SCI.

A colorimetric and NIR fluorescent probe for ultrafast detecting bisulfite and organic amines and its applications in food, imaging, and monitoring fish freshness.

Herein, for the first time, we have successfully constructed a novel near-infrared (NIR) emission fluorescent probe Dpyt for ultrafast detecting (within 5 s) bisulfate and organic amines based on a 1,2-dihydrocyclopenta[b]chromene-barbiturate conjugation system. Upon addition of bisulfate or organic amines, Dpyt displayed a distinct color change from blue to colorless or from purple to blue, respectively, suggesting that the Dpyt can be used to detect two analytes by the naked eye. Based on quantum chemistry calculations, the fluorescence quenching of Dpyt after the addition of HSO3- is caused by the photoinduced electron transfer (PET) process of the adduct Dpyt-HSO3-. The fluorescence enhancement of Dpyt caused by most organic amines is due to the enhanced intramolecular charge transfer (ICT) process of deprotonated Dpyt. Notably, Dpyt can be applied for detecting HSO3- in actual food samples such as red wine and sugar, as well as for imaging of HSO3- and representative propylamine in living cells. And more importantly, indicator labels constructed by filter paper loaded with Dpyt can visually monitor the freshness of salmon in real-time by daylight and fluorescence dual-mode. The comparison with national standard method of China manifests that indicator labels are a valid tool to assess the freshness of seafood.

A Clinical Classification of Cervical Ossification of the Posterior Longitudinal Ligament to Guide Surgical Strategy.

STUDY DESIGN: A clinical classification of cervical ossification of the posterior longitudinal ligament (COPLL) was developed based on imaging findings. OBJECTIVE: This study aimed to establish a clinical classification for COPLL and provide corresponding surgery strategies for each subtype. SUMMARY OF BACKGROUND DATA: A practical and reliable classification is needed to guide the treatment of COPLL. MATERIALS AND METHODS: This study retrospectively reviewed plain radiographs, computed tomography scans, and magnetic resonance images of patients diagnosed with COPLL between 2018 and 2022 at Shanghai Changzheng Hospital. The types of COPLL were classified according to the location, morphology, and canal-occupying ratio (OR) of the ossification mass. Interobserver and intraobserver reliability were evaluated using Cohen's kappa. RESULTS: A total of 1000 cases were included, which were classified into five types: focal type (F type), short-sequential type (S type), long-sequential type (L type), high type (H type), and mixed type (M type). In addition, each type could be classified into subtype 1 or subtype 2 according to the canal-OR. Then each type could be further classified into other subtypes according to location and morphology. The interobserver reliabilities in the first and second rounds were 0.853 and 0.887, respectively. The intraobserver reliability was 0.888. CONCLUSION: The authors classified COPLL into a system comprised of five types and several subtypes according to canal-OR, location, and morphology. Surgical strategies for each subtype are also suggested. This provides a theoretical guide for the description and surgical management of COPLL.

Lupenone improves motor dysfunction in spinal cord injury mice through inhibiting the inflammasome activation and pyroptosis in microglia via the nuclear factor kappa B pathway.

JOURNAL/nrgr/04.03/01300535-202408000-00034/figure1/v/2023-12-16T180322Z/r/image-tiff Spinal cord injury-induced motor dysfunction is associated with neuroinflammation. Studies have shown that the triterpenoid lupenone, a natural product found in various plants, has a remarkable anti-inflammatory effect in the context of chronic inflammation. However, the effects of lupenone on acute inflammation induced by spinal cord injury remain unknown. In this study, we established an impact-induced mouse model of spinal cord injury, and then treated the injured mice with lupenone (8 mg/kg, twice a day) by intraperitoneal injection. We also treated BV2 cells with lipopolysaccharide and adenosine 5'-triphosphate to simulate the inflammatory response after spinal cord injury. Our results showed that lupenone reduced IκBα activation and p65 nuclear translocation, inhibited NLRP3 inflammasome function by modulating nuclear factor kappa B, and enhanced the conversion of proinflammatory M1 microglial cells into anti-inflammatory M2 microglial cells. Furthermore, lupenone decreased NLRP3 inflammasome activation, NLRP3-induced microglial cell polarization, and microglia pyroptosis by inhibiting the nuclear factor kappa B pathway. These findings suggest that lupenone protects against spinal cord injury by inhibiting inflammasomes.

The combination of holmium laser and ALA-PDT for Bowenoid Papulosis with diffuse large B-cell lymphoma.

Bowenoid Papulosis (BP) is an anogenital pre-malignancy. BP with immunosuppression may recur, worsen, or possibly evolve into squamous cell carcinoma or Bowen's disease (BD), and it may also become resistant to conventional treatment. Here, we describe a complex case of BP together with BD and Diffuse Large B-Cell Lymphoma that was effectively treated with a holmium laser in conjunction with 5-Aminolevulinic Acid Photodynamic Therapy (ALA-PDT). The lesion totally vanished and the affected area remained intact with no recurrence at five years.

Valproic acid ameliorates cauda equina injury by suppressing HDAC2-mediated ferroptosis.

INTRODUCTION: Persistent neuroinflammatory response after cauda equina injury (CEI) lowers nociceptor firing thresholds, accompanied by pathological pain and decreasing extremity dysfunction. Histone deacetylation has been considered a key regulator of immunity, inflammation, and neurological dysfunction. Our previous study suggested that valproic acid (VPA), a histone deacetylase inhibitor, exhibited neuroprotective effects in rat models of CEI, although the underlying mechanism remains elusive. METHODS: The cauda equina compression surgery was performed to establish the CEI model. The Basso, Beattie, Bresnahan score, and the von Frey filament test were carried out to measure the animal behavior. Immunofluorescence staining of myelin basic protein and GPX4 was carried out. In addition, transmission electron microscope analysis was used to assess the effect of VPA on the morphological changes of mitochondria. RNA-sequencing was conducted to clarify the underlying mechanism of VPA on CEI protection. RESULTS: In this current study, we revealed that the expression level of HDAC1 and HDAC2 was elevated after cauda equina compression model but was reversed by VPA treatment. Meanwhile, HDAC2 knockdown resulted in the improvement of motor functions and pathologic pain, similar to treatment with VPA. Histology analysis also showed that knockdown of histone deacetylase (HDAC)-2, but not HDAC1, remarkably alleviated cauda equina injury and demyelinating lesions. The potential mechanism may be related to lowering oxidative stress and inflammatory response in the injured region. Notably, the transcriptome sequencing indicated that the therapeutic effect of VPA may depend on HDAC2-mediated ferroptosis. Ferroptosis-related genes were analyzed in vivo and DRG cells further validated the reliability of RNA-sequencing results, suggesting HDAC2-H4K12ac axis participated in epigenetic modulation of ferroptosis-related genes. CONCLUSION: HDAC2 is critically involved in the ferroptosis and neuroinflammation in cauda equina injury, and VPA ameliorated cauda equina injury by suppressing HDAC2-mediated ferroptosis.