Effects of low-intensity ultrasound opening the blood-brain barrier on Alzheimer's disease-a mini review.

Due to the complex pathological mechanisms of Alzheimer's disease (AD), its treatment remains a challenge. One of the major difficulties in treating AD is the difficulty for drugs to cross the blood-brain barrier (BBB). Low-intensity ultrasound (LIUS) is a novel type of ultrasound with neuromodulation function. It has been widely reported that LIUS combined with intravenous injection of microbubbles (MB) can effectively, safely, and reversibly open the BBB to achieve non-invasive targeted drug delivery. However, many studies have reported that LIUS combined with MB-mediated BBB opening (LIUS + MB-BBBO) can improve pathological deposition and cognitive impairment in AD patients and mice without delivering additional drugs. This article reviews the relevant research studies on LIUS + MB-BBBO in the treatment of AD, analyzes its potential mechanisms, and summarizes relevant ultrasound parameters.

Resveratrol improves the prognosis of rats after spinal cord injury by inhibiting mitogen-activated protein kinases signaling pathway.

Spinal cord injury (SCI) is a serious condition that results in irreparable nerve damage and severe loss of motor or sensory function. Resveratrol (3,4',5-trihy- droxystilbene) is a naturally occurring plant-based polyphenol that has demonstrated powerful antioxidative, anti-inflammatory, and anti-carcinogenic pharmaceutical properties in previous studies. In the central nervous system, it promotes neuronal recovery and protects residual function. However, the role of resveratrol in SCI recovery remains elusive. In this study, the potential mechanisms by which resveratrol affect SCI in rats were assessed by constructing a contusion model of SCI. Resveratrol was intraperitoneally administered to rats. Behavioral scores and electrophysiological examinations were performed to assess functional recovery. After magnetic resonance imaging and staining with hematoxylin and eosin (HE) and Luxor Fast Blue (LFB), tissue recovery was analyzed. Immunofluorescence with NeuN and glial fibrillary acidic protein (GFAP) was employed to evaluate neuronal survival and glial changes. TdT-mediated dUTP nick end labeling (TUNEL) assay was performed to examine apoptotic rates. Moreover, network pharmacology was performed to identify relevant pathways of resveratrol for the treatment of SCI. Lastly, ELISA was performed to detect the expression levels of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and IL-6. Our findings revealed that resveratrol dramatically improved the hindlimb locomotor function and their electrophysiological outcomes. Notably, lesion size was significantly reduced on magnetic resonance imaging. HE and LFB staining exposed increased sparseness of tissue and myelin. GFAP and NeuN immunofluorescence assays at the lesion site determined that resveratrol boosted neuronal survival and attenuated glial cell overgrowth. In addition, resveratrol reduced the density and number of TUNEL-positive cells in rats after injury. Additionally, gene ontology analysis revealed that the enriched differentially expressed protein was associated with the JNK/p38MAPK (c-jun N-terminal kinase/p38 mitogen-activated protein kinase) signaling pathway. Following resveratrol treatment, the expression levels of IL-1ß, TNF-α, and IL-6 were decreased. In summary, the administration of resveratrol protects motor function and neuronal survival in rats after SCI. Furthermore, resveratrol exerts an anti-inflammatory effect by blocking the JNK/p38MAPK signaling pathway.

Characteristics of paraspinal muscle degeneration in patients with adult degenerative scoliosis.

INTRODUCTION: Adult degenerative scoliosis (ADS) is a 3D deformity that greatly affects the quality of life of patients and is closely related to the quality of paraspinal muscles (PSMs), but the specific degenerative characteristics have not been described. METHODS: This study included ADS patients who were first diagnosed in our hospital from 2018 to 2022. Muscle volume (MV) and fat infiltration (FI) of PSM were measured by 3D reconstruction, and spinal parameters were assessed by X-ray. The values of convex side (CV) and concave side (CC) were compared. RESULTS: Fifty patients were enrolled with a mean age of 64.1 ± 5.8 years old. There were significant differences in MV, FI, and Cobb angle between male and female groups. The MV of MF and PS on the CC was significantly larger than that on the CV. In the apex and the segments above the apex, the FI of the MF on the CC is greater than the CV, and in the CV of the segment below the apex, the FI of the MF is greater than the CC. Besides, there was a significant positive correlation between the FI and Cobb angle in the MF of the CC-CV. CONCLUSION: There were significant differences in the MV and FI of PSM on both sides of the spine in ADS patients. It was determined that the PSM of ADS showed different degrees of degeneration in different levels of the lumbar spine and were positively correlated with Cobb angle.

Corrigendum: Network pharmacology integrated with experimental validation to explore the therapeutic role and potential mechanism of Epimedium for spinal cord injury.

[This corrects the article DOI: 10.3389/fnmol.2023.1074703.].

Network pharmacology integrated with experimental validation to explore the therapeutic role and potential mechanism of Epimedium for spinal cord injury.

Objective: Epimedium (EPI) is a common Chinese herb with neuroprotective effects against a variety of central nervous system disorders, especially spinal cord injury (SCI). In this study, we performed network pharmacology and molecular docking analyses to reveal the mechanism underlying EPI treatment of SCI, then validated its efficacy using animal models. Methods: The active ingredients and targets of EPI were screened by Traditional Chinese Medicine Systems Pharmacology (TCMSP) and their targets annotated on the UniProt platform. SCI-related targets were searched from OMIM, TTD, and GeneCards databases. We employed the STRING platform to construct a protein-protein interaction (PPI) network then visualized the results using Cytoscape (3.8.2) software. We also subjected key EPI targets to ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, then docked the main active ingredients with the key targets. Finally, we established an SCI rat model to evaluate efficacy of EPI in treating SCI and validate the effects of different biofunctional modules predicted by network pharmacology. Results: A total of 133 EPI targets were associated with SCI. GO terms and KEGG pathway enrichment results showed that EPI's effect in treating SCI was significantly associated with inflammatory response, oxidative stress and the PI3K/AKT signaling pathway. Molecular docking results indicated that EPI's active ingredients have a high affinity for the key targets. Results from animal experiments revealed that EPI not only markedly improved Basso, Beattie, and Bresnahan scores in SCI rats, but also significantly improved p-PI3K/PI3K and p-AKT/AKT ratio. Moreover, EPI treatment not only mediated a significant decrease in malondialdehyde (MDA) but also increased both superoxide dismutase (SOD), and glutathione (GSH). However, this phenomenon was successfully reversed by LY294002, a PI3K inhibitor. Conclusion: EPI improves behavioral performance in SCI rats through anti-oxidative stress, which may be mediated by activation of the PI3K/AKT signaling pathway.

Mitochondrial regulatory mechanisms in spinal cord injury: A narrative review.

Spinal cord injury is a severe central nervous system injury that results in the permanent loss of motor, sensory, and autonomic functions below the level of injury with limited recovery. The pathological process of spinal cord injury includes primary and secondary injuries, characterized by a progressive cascade. Secondary injury impairs the ability of the mitochondria to maintain homeostasis and leads to calcium overload, excitotoxicity, and oxidative stress, further exacerbating the injury. The defective mitochondrial function observed in these pathologies accelerates neuronal cell death and inhibits regeneration. Treatment of spinal cord injury by preserving mitochondrial biological function is a promising, although still underexplored, therapeutic strategy. This review aimed to explore mitochondrial-based therapeutic advances after spinal cord injury. Specifically, it briefly describes the characteristics of spinal cord injury. It then broadly discusses the drugs used to protect the mitochondria (e.g., cyclosporine A, acetyl-L-carnitine, and alpha-tocopherol), phenomena associated with mitochondrial damage processes (e.g., mitophagy, ferroptosis, and cuproptosis), mitochondrial transplantation for nerve cell regeneration, and innovative mitochondrial combined protection therapy.

Identification of key genes involved in recovery from spinal cord injury in adult zebrafish.

Zebrafish are an effective vertebrate model to study the mechanisms underlying recovery after spinal cord injury. The subacute phase after spinal cord injury is critical to the recovery of neurological function, which involves tissue bridging and axon regeneration. In this study, we found that zebrafish spontaneously recovered 44% of their swimming ability within the subacute phase (2 weeks) after spinal cord injury. During this period, we identified 7762 differentially expressed genes in spinal cord tissue: 2950 were up-regulated and 4812 were down-regulated. These differentially expressed genes were primarily concentrated in the biological processes of the respiratory chain, axon regeneration, and cell-component morphogenesis. The genes were also mostly involved in the regulation of metabolic pathways, the cell cycle, and gene-regulation pathways. We verified the gene expression of two differentially expressed genes, clasp2 up-regulation and h1m down-regulation, in zebrafish spinal cord tissue in vitro. Pathway enrichment analysis revealed that up-regulated clasp2 functions similarly to microtubule-associated protein, which is responsible for axon extension regulated by microtubules. Down-regulated h1m controls endogenous stem cell differentiation after spinal cord injury. This study provides new candidate genes, clasp2 and h1m, as potential therapeutic intervention targets for spinal cord injury repair by neuroregeneration. All experimental procedures and protocols were approved by the Animal Ethics Committee of Tianjin Institute of Medical & Pharmaceutical Sciences (approval No. IMPS-EAEP-Q-2019-02) on September 24, 2019.

Secondary tuberculosis of adjacent segments after anterior cervical discectomy and fusion: A case report.

Introduction: Anterior cervical discectomy and fusion (ACDF) is a common operation for spinal surgery to treat a variety of cervical diseases. The postoperative infection rate of this procedure is extremely low, and adjacent segments are rarely involved. Tuberculosis (TB) is a common infectious disease that affects the spine in less than 1% of cases and is more common in the thoracolumbar and rarely cervical spine. Herein, for the first time, we report tuberculosis infection in adjacent segments after ACDF. Case presentation: We report a 50-year-old patient with cervical spondylotic myelopathy (CSM) who was discharged from the hospital after receiving ACDF at the C3/4 level. Two months later, he was admitted to the hospital with neck pain and found to be infected with tuberculosis in C4/5. After 4 months of anti-tuberculosis treatment, the vertebral body was fused. Conclusion: After ACDF, the adjacent cervical vertebrae were infected with TB but the infection was limited. We believe that the special vertebral blood supply and postoperative secondary blood-borne infection may lead to the occurrence of extrapulmonary tuberculosis.

Identification of four genes and biological characteristics associated with acute spinal cord injury in rats integrated bioinformatics analysis.

BACKGROUND: Spinal cord injury (SCI) is a serious condition that can cause physical disability and sensory dysfunction. Cytokines play an extremely important role in the acute phase of SCI. Clarifying the cytokine expression profile is of great importance. METHODS: Cytokine array analysis was used to explore the changes in 67 different proteins at 0 hours, 2 hours, 1 day, 3 days, and 7 days after acute SCI in rats. The differentially expressed cytokines in the various periods were analyzed and compared. The biological processes related to the differentially expressed proteins were examined using Gene Ontology (GO) analysis. RESULTS: Immediately after SCI (0 hours), only ciliary neurotrophic factor (CNTF) was slightly up-regulated, while 23 other proteins were down-regulated. At 2 hours after SCI, there were 3 upregulated and 21 downregulated proteins. At 1 day after SCI, there were 5 upregulated and 6 downregulated proteins. At 3 days after SCI, there were 6 upregulated and 4 downregulated proteins. At 7 days after SCI, there were 4 upregulated and 9 downregulated proteins. Erythropoietin (EPO) and Fms related tyrosine kinase 3 ligand (Flt-3L) were downregulated at all time points. CD48 was decreased at 2 hours to 7 days after SCI. Monocyte chemotactic protein-1 (MCP-1) was the only protein that was upregulated at 2 hours to 7 days. The GO and pathway analyses revealed that the cytokine-related pathways, cell death, and proliferation might play a key role during secondary SCI. CONCLUSIONS: This study identified 3 downregulated proteins during SCI, that being EPO, Flt-3L, and CD48. MCP-1 was the only upregulated protein, and its expression was upregulated till day 7 following SCI. These 4 identified genes may be potential therapeutic targets for the treatment of SCI.

Deferoxamine promotes recovery of traumatic spinal cord injury by inhibiting ferroptosis.

Ferroptosis is an iron-dependent novel cell death pathway. Deferoxamine, a ferroptosis inhibitor, has been reported to promote spinal cord injury repair. It has yet to be clarified whether ferroptosis inhibition represents the mechanism of action of Deferoxamine on spinal cord injury recovery. A rat model of Deferoxamine at thoracic 10 segment was established using a modified Allen's method. Ninety 8-week-old female Wistar rats were used. Rats in the Deferoxamine group were intraperitoneally injected with 100 mg/kg Deferoxamine 30 minutes before injury. Simultaneously, the Sham and Deferoxamine groups served as controls. Drug administration was conducted for 7 consecutive days. The results were as follows: (1) Electron microscopy revealed shrunken mitochondria in the spinal cord injury group. (2) The Basso, Beattie and Bresnahan locomotor rating score showed that recovery of the hindlimb was remarkably better in the Deferoxamine group than in the spinal cord injury group. (3) The iron concentration was lower in the Deferoxamine group than in the spinal cord injury group after injury. (4) Western blot assay revealed that, compared with the spinal cord injury group, GPX4, xCT, and glutathione expression was markedly increased in the Deferoxamine group. (5) Real-time polymerase chain reaction revealed that, compared with the Deferoxamine group, mRNA levels of ferroptosis-related genes Acyl-CoA synthetase family member 2 (ACSF2) and iron-responsive element-binding protein 2 (IREB2) were up-regulated in the Deferoxamine group. (6) Deferoxamine increased survival of neurons and inhibited gliosis. These findings confirm that Deferoxamine can repair spinal cord injury by inhibiting ferroptosis. Targeting ferroptosis is therefore a promising therapeutic approach for spinal cord injury.

Dianhydrogalactitol, a potential multitarget agent, inhibits glioblastoma migration, invasion, and angiogenesis.

The complexity of cancer has led to single-target agents exhibiting lower-than-desired clinical efficacy. Drugs with multiple targets provide a feasible option for the treatment of complex tumors. Multitarget anti-angiogenesis agents are among the new generation of anticancer drugs and have shown favorable clinical efficacy. Dianhydrogalactitol (DAG) is a chemotherapeutic agent for chronic myeloid leukemia and lung cancer. Recently, it has been tested in phase II trials of glioblastoma treatment; however, mechanisms of DAG in glioblastoma have not been elucidated. Here we show that DAG could inhibit the migration and invasion of U251 cell line by inhibiting matrix metalloproteinase-2 (MMP2) expression. Furthermore, DAG could also inhibit tumor angiogenesis in vitro as well as in the zebrafish model. Mechanistic studies reveal that DAG inhibited both VEGFR2 and FGFR1 pathways. Our results suggest that DAG may be a potential multitarget agent that can inhibit tumor migration, invasion, and angiogenesis, and the anti-angiogenic effects may be involved in dual-suppression VEGF/VEGFR2 and FGF2/FGFR1 signal pathways.

Long-term intravenous administration of carboxylated single-walled carbon nanotubes induces persistent accumulation in the lungs and pulmonary fibrosis via the nuclear factor-kappa B pathway.

Numerous studies have demonstrated promising application of single-walled carbon nanotubes (SWNTs) in drug delivery, diagnosis, and targeted therapy. However, the adverse health effects resulting from intravenous injection of SWNTs are not completely understood. Studies have shown that levels of "pristine" or carboxylated carbon nanotubes are very high in mouse lungs after intravenous injection. We hypothesized that long-term and repeated intravenous administration of carboxylated SWNTs (c-SWNTs) can result in persistent accumulation and induce histopathologic changes in rat lungs. Here, c-SWNTs were administered repeatedly to rats via tail-vein injection for 90 days. Long-term intravenous injection of c-SWNTs caused sustained embolization in lung capillaries and granuloma formation. It also induced a persistent inflammatory response that was regulated by the nuclear factor-kappa B signaling pathway, and which resulted in pulmonary fibrogenesis. c-SWNTs trapped within lung capillaries traversed capillary walls and injured alveolar epithelial cells, thereby stimulating production of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta) and pro-fibrotic growth factors (transforming growth factor-beta 1). Protein levels of type-I and type-III collagens, matrix metalloproteinase-2, and the tissue inhibitor of metalloproteinase-2 were upregulated after intravenous exposure to c-SWNTs as determined by immunohistochemical assays and Western blotting, which suggested collagen deposition and remodeling of the extracellular matrix. These data suggest that chronic and cumulative toxicity of nanomaterials to organs with abundant capillaries should be assessed if such nanomaterials are applied via intravenous administration.