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Idiopathic pulmonary fibrosis is a devastating disease with multiple contributing factors. Insulin-like growth factor 1 receptor (IGF1R), with a reciprocal function to aryl hydrocarbon receptor (AhR), is involved in airway inflammation. The exact relationship between IGF1R and AhR in lung fibrogenesis is unclear. This study aimed to investigate the cascade pathway involving IGF1R and AhR in idiopathic pulmonary fibrosis.The AhR and IGF1R expressions were determined in the lungs of idiopathic pulmonary fibrosis patients and in a rodent fibrosis model. Pulmonary fibrosis was evaluated in bleomycin (BLM)-induced lung injury in wild type and AhR knockout (AhrThere were increased IGF1R levels but AhR expression decreased in the lung of idiopathic pulmonary fibrosis patients and BLM-induced mice. Knockout of AhR aggravated lung fibrosis, while the use of IGF1R inhibitor and AhR agonist significantly attenuated such effects and inhibited TGF-β1-induced epithelial-mesenchymal transition in Beas2B cells. Both TGF-β1 and BLM markedly suppressed AhR expression through endoplasmic reticulum stress and consequently, IGF1R activation. The IGF1R inhibitor and specific knockdown of IGF1R reversed the activation of the TGF-β1 signal pathway.In the development of idiopathic pulmonary fibrosis, AhR and IGF1R play opposite roles via the TGF-β/Smad/STAT signalling cascade. The AhR/IGF1R axis is a potential target for the treatment of lung injury and fibrosis.

Purpose The combination of re-irradiation and bevacizumab has emerged as a potential therapeutic strategy for patients experiencing their first glioblastoma multiforme (GBM) recurrence. This study aims to assess the effectiveness of the re-irradiation and bevacizumab combination in treating second-progression GBM patients who are resistant to bevacizumab monotherapy. Methods and materials This retrospective study enrolled 64 patients who developed a second progression after single-agent bevacizumab therapy. The patients were divided into two groups: 35 underwent best supportive care (none-ReRT group), and 29 received bevacizumab and re-irradiation (ReRT group). The study measured the overall survival time after bevacizumab failure (OST-BF) and re-irradiation (OST-RT). Statistical tests were used to compare categorical variables, evaluate the difference in recurrence patterns between the two groups, and identify optimal cutoff points for re-irradiation volume. Results The results of the Kaplan-Meier survival analysis indicated that the re-irradiation (ReRT) group experienced a significantly higher survival rate and longer median survival time than the non-ReRT group. The median OST-BF and OST-RT were 14.5 months and 8.8 months, respectively, for the ReRT group, while the OST-BF for the none-ReRT group was 3.9 months (p < 0.001). The multivariable analysis identified the re-irradiation target volume as a significant factor for OST-RT. Moreover, the re-irradiation target volume exhibited excellent discriminatory ability in the area under the curve (AUC) analysis, with an optimal cutoff point of greater than 27.58 ml. Conclusions These findings suggest that incorporating re-irradiation with bevacizumab therapy may be a promising treatment strategy for patients with recurrent GBM resistant to bevacizumab monotherapy. The re-irradiation target volume may serve as a valuable selection factor in determining which patients with recurrent GBM are likely to benefit from the combined re-irradiation and bevacizumab treatment modality.

Purpose Recurrent glioblastoma (GBM) is challenging, and effective treatment options after bevacizumab failure are limited. Re-irradiation combined with bevacizumab has emerged as a potential therapeutic option for recurrent GBM patients who have failed bevacizumab treatment. This study aims to evaluate the efficacy of re-irradiation in patients with progressive GBM refractory to bevacizumab monotherapy and explore the factors that may impact survival. Methods and materials This retrospective study enrolled 64 patients who developed a second progression after single-agent bevacizumab therapy. The patients were divided into two groups: 35 continued with bevacizumab alone (none-ReRT group), and 29 received bevacizumab and re-irradiation (ReRT group). The study measured overall survival time after bevacizumab failure (OST-BF) and after re-irradiation (OST-RT). Statistical tests were used to compare categorical variables, evaluate the difference in recurrence patterns between the two groups, and identify optimal cutoff points for re-irradiation volume. Results The Kaplan-Meier survival analysis revealed that the ReRT group had a significantly higher survival rate and longer median survival time than the none-ReRT group. The median OST-BF and OST-RT were 14.5 months and 8.8 months, respectively, for the ReRT group, while the OST-BF for the none-ReRT group was 3.9 months (p < 0.001). Cox univariate analysis for overall survival time after bevacizumab failure (OST-BF) identified KPS at bevacizumab failure, ORR, bevacizumab failure pattern, re-irradiation, and re-irradiation target volume as significant predictors of survival time after bevacizumab failure. The multivariable analysis found only the re-irradiation target volume to be significant for OST-RT. Conclusions The study suggests that re-irradiation combined with bevacizumab therapy may be a valuable treatment option for patients with recurrent GBM who have failed bevacizumab therapy. The re-irradiation target volume may be a valuable prognostic factor for these patients, with smaller target volumes associated with better survival outcomes. Further studies with larger sample sizes and prospective designs are necessary to confirm these results and determine the optimal treatment approach for these patients.

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. GBM has a very low 5-year survival rate and reaching merely a median of ~15 months even with aggressive treatments. PPARγ (Peroxisome proliferator- activated receptor gamma) agonists (ciglitazone), while being widely used on patients of type 2 diabetes mellitus, also have approved anticancer effects. Their action mechanisms on malignant glioma are not fully understood. The aim of this study is to investigate the potential therapeutic effect of PPARγ agonists on maligant glioma. Glioma cell line and in-vivo/ex-vivo animal model intervened by ciglitazone were used to assess the associated mechanism and therapeutic effect. Our results from in vivo and ex vivo experiments showed that ciglitazone not only inhibited tumor growth and its associated angiogenesis, but it also reduced colony formation and migration of tumors. Ciglitazone inhibited the phosphorylation of STAT3 (signal transducer and activator of transcription 3) (at the point of tyrosine 705 by increasing both the amount and activity of SHP-2 (Src homology region 2-containing protein tyrosine phosphatase 2) proteins, based on evidence obtained from immunoprecipitation and immunohistochemistry. Furthermore, ciglitazone activated proteasomes and lysosomes to degrade cell-cycle-related proteins like Cyclin D1, Cyclin E, CDK2 (Cyclin-dependent kinase 2), and CDK4 (Cyclin-dependent kinase 4). Ciglitazone triggered expressions of LC3 (Microtubule-associated protein 1A/1B-light chain 3) and formation of acidic vesicular organelles (AVOs), both of which were implicated in the autophagy pathway. In conclusion, ciglitazone showed the multiple actions to regulate the growth of glioma, which appeared to be a potential candidate for treating malignant glioma.

Purpose Gamma knife radiosurgery (GK) is a commonly used approach for the treatment of intracranial lesions. Its radiation response is typically not immediate, but delayed. In this study, we analyzed cases from a prospectively collected database to assess the influence of COVID-19 pandemic on the decision making in patients treated by gamma knife radiosurgery. Methods From January 2019 to August 2021, 540 cases of intracranial lesions were treated by GK with 207 cases before COVID-19 pandemic as a control. During the COVID-19 pandemic, 333 cases were similarly treated on patients with or without the COVID-19 vaccination. All the GK treated parameters as well as time profile in the decision making were analyzed. The parameters included age, sex, characteristic of lesion, targeted volume, peripheral radiation dose, neurological status, Karnofsky Performance Status (KPS), time interval from MRI diagnosis to consultation, time interval from the approval to treatment, frequency of outpatient department (OPD) visit, and frequency of imaging follow-up. Results Longer time intervals from diagnosis to GK consultation and treatment were found in the pandemic group (36.8 ± 25.5/54.5 ± 27.6 days) compared with the pre-COVID control (17.1 ± 22.4/45.0 ± 28.0 days) or vaccination group (12.2 ± 7.1/29.6 ± 10.9 days) (p p p p Conclusions The decision making in patients requiring gamma knife treatment was most likely influenced by the status of the COVID-19 pandemic, while vaccination appeared to attenuate their hesitant behaviors. Patients with pre-treatment neurological deficits and high co-morbidity undergoing the gamma knife treatment were less affected by the COVID-19 pandemic.

Background Peripheral nerve injuries result in muscle denervation and apoptosis of the involved muscle, which subsequently reduces mitochondrial content and causes muscle atrophy. The local injection of mitochondria has been suggested as a useful tool for restoring the function of injured nerves or the brain. Objective To determine outcomes following the administration of isolated mitochondria into denervated muscle after nerve injury that have not been investigated. Methods Muscle denervation was conducted in a sciatic nerve crushed by a vessel clamp and the denervated gastrocnemius muscle was subjected to 195 μg hamster green fluorescent protein (GFP)-mitochondria intramuscular infusion for 10 min. Results The mitochondria were homogeneously distributed throughout the denervated muscle after intramuscular infusion. The increases in caspase 3, 8-oxo-dG, Bad, Bax, and ratio of Bax/Bcl-2 levels in the denervated muscle were attenuated by mitochondrial infusion, and the downregulation of Bcl-2 expression was prevented by mitochondrial infusion. In addition, the decrease in the expression of desmin and the acetylcholine receptor was counteracted by mitochondrial infusion; this effect paralleled the amount of distributed mitochondria. The restoration of the morphology of injured muscles and nerves was augmented by the local infusion of mitochondria. Mitochondrial infusion also led to improvements in sciatic functional indexes, compound muscle action potential amplitudes, and conduction latencies as well as the parameters of CatWalk (Noldus) gait analysis. Conclusion The local infusion of mitochondria can successfully prevent denervated muscle atrophy and augment nerve regeneration by reducing oxidative stress in denervated muscle.

Neuropathic pain is well known to occur after damage to the somatosensory system. Aryl hydrocarbon receptor (AhR) has neuroprotective effects when the central nervous system is subjected to internal and external stimulations. However, the exact mechanism by which AhR regulates neuropathic pain is poorly understood. Nerve explant culture and the chronic constrictive nerve injury (CCI) model in wild or AhR-knockout mice were used in this study. In the nerve explant culture, the ovoid number increased in the AhR−/− condition and was decreased by omeprazole (AhR agonist) in a dose-dependent manner. Increased nerve degeneration and the associated inflammation response appeared in the AhR−/− condition, and these changes were attenuated by omeprazole. High expression of AhR in the injured nerve was noted after CCI. Deletion of AhR aggravated nerve damages and this was restored by omeprazole. Deletion of AhR increased NGF expression and reduced axon number in the paw skin, but this was attenuated by omeprazole. A highly expressed inflammation reaction over the dorsal spinal cord, somatosensory cortex, and hippocampus was noted in the AhR-deleted animals. Administration of omeprazole attenuated not only the inflammatory response, but also the amplitude of somatosensory evoked potential. Deletion of AhR further aggravated the neurobehavior compared with the wild type, but such behavior was attenuated by omeprazole. Chronic constrictive nerve injury augmented AhR expression of the injured nerve, and AhR deletion worsened the damage, while AhR agonist omeprazole counteracted such changes. AhR agonists could be potential candidates for neuropathic pain treatment.

Background: Activated microglia-mediated neuro-inflammation plays a vital aspect in regulating the micromilieu of the central nervous system. Neuro-inflammation involves distinct alterations of microglial phenotypes, containing nocuous pro-inflammatory (M1) phenotype and neuroprotective anti-inflammatory (M2) phenotype. Currently, there is no effective treatment for modulating such alterations. Little evidence shows that melatonin prevents the detrimental cascade of activated microglia-mediated neuro-inflammation. Methods: The expression levels of M1/M2 marker of primary microglia influenced by Melatonin were detected via qPCR. Functional activities were explored by western blotting, luciferase activity, EMSA, and ChIP assay. Structure interaction was assessed by molecular docking and LIGPLOT analysis. ER stress detection was examined by ultrastructure TEM, calapin activity, and ERSE assay. The neurobehavioral evaluations and immunofluorescence staining in animals were used for investigation of Melatonin on the neuroinflammation in vivo. Results: Melatonin had targeted on Peroxisome Proliferator Activated Receptor Delta (PPARd) activity, boosted LPS-stimulated alterations in polarization from the M1 to the M2 phenotype, and thereby inhibited NFkB–IKKb activation in primary microglia. The PPARd agonist L-165041 or over-expression of PPARd plasmid (ov-PPARd) showed similar results. Molecular docking screening, dynamic simulation approaches, and biological studies of melatonin showed that the activated site was located at PPARd (phospho-Thr256-PPARd). Furthermore, we found that activated microglia had lowered PPARd activity as well as the downstream SIRT1 formation via enhancing ER stress. Melatonin, PPARd agonist and ov-PPARd all effectively reversed the above-mentioned effects. Melatonin blocked ER stress by regulating calapin activity and expression in LPS-activated microglia. Additionally, melatonin or L-165041 ameliorated the neurobehavioral deficits in LPS-aggravated neuroinflammatory mice through blocking microglia activities, and also promoted phenotype changes to M2-predominant microglia. Conclusions Melatonin suppressed neuro-inflammation in vitro and in vivo by tuning microglial activation through the ER stress-dependent PPARd/SIRT1 signaling cascade. We proposed that this treatment strategy is an encouraging pharmacological approach for the remedy of neuro-inflammation associated disorders.

BACKGROUND Cervical disc arthroplasty (CDA) is an alternative treatment to traditional interbody fusion that maintains postoperative cervical spine mobility. However, the CDA postoperative period is impacted by osteolysis, subsidence, metallosis, or heterotopic ossification (HO). We report a case of severe HO in a seronegative spondyloarthritis patient after cervical Bryan disc arthroplasty. CASE SUMMARY A 34-year-old man received hybrid surgery for C4-C5 and C5-C6 arthroplasty with Bryan discs and C6-C7 arthrodesis with polyetheretherketone cage due to traumatic herniation of the intervertebral disc (HIVD). After four years, cervical spine radiographs revealed severe HO around the Bryan discs over the C4-C5 and C5-C6 levels. The magnetic resonance image revealed HIVD over the C3-C4 level with spinal cord compression. Seronegative spondyloarthritis was diagnosed after consultation with a rheumatologist. A second CDA for the adjacent segment disease HIVD with Baguera C disc over the C3-C4 level achieved an excellent outcome. CONCLUSION Minimizing intraoperative tissue trauma and achieving postoperative interbody stability avoid soft tissue traction to prevent HO formation after CDA.

Background and purpose: Histone deacetylase (HDAC) inhibitors (HDIs) were shown to modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs have attracted much attention in the field of drug discovery. This study aimed to the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression.Experimental Approach: Clinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signalings were analyzed using binding assays, Differential Scanning Calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting and Wnt/b-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by the PET/CT tomography.Key Results: HDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPb signaling, which was reversed by the over-expression of plasmids of NFκBp65/CEBPb. Honokiol-inhibited NFκBp65/CEBPb activation could be reversed by 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo. Conclusions and Implications: Honokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked.

Background and purpose Histone deacetylase (HDAC) inhibitors (HDIs) can modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs are attracted much attention in the field of drug discovery. This study aimed to discern the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression. Experimental approach Clinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signaling were analyzed using binding assays, differential scanning calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting, and Wnt/β-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by PET/CT tomography. Key results HDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPβ signaling, which could be reversed by the over-expression of plasmids of NFκBp65/CEBPβ. Treatments with 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing inhibited Honokiol-inhibited NFκBp65/CEBPβ activation. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo. Conclusions and implications Honokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked. Graphical abstract Conceptual model showing the working hypothesis on the interaction among Honokiol, HDAC3, and ER stress in the peritoneal dissemination of gastric cancer. Honokiol targeting HDAC3 by ER stress cascade and mitigating the peritoneal spread of gastric cancer. Honokiol-induced ER stress–activated calpain activity targeted HDAC3 and blocked Tyr298 phosphorylation, subsequently blocked cooperating with EMT transcription factors and cancer progression. The present study provides evidence to demonstrate that HDAC3 is a positive regulator of EMT and metastatic growth of gastric cancer cells. The findings here imply that overexpressed HDAC3 is a potential therapeutic target for honokiol to reverse EMT and prevent gastric cancer migration, invasion, and metastatic dissemination. • Honokiol significantly abolished HDAC3 activity on catalytic tyrosine 298 residue site. In addition, Honokiol-induced ER stress markedly inhibited HDAC3 expression via inhibition of NFκBp65/CEBPβ signaling. • HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol. • Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination.

Objective Pediatric lumbar disc herniation (LDH), although uncommon, causes significant pain, discomfort, and sometimes disability. We examined the efficacy of percutaneous endoscopic lumbar discectomy (PELD) for pediatric LDH and the degree of lumbar disc degeneration at 1 year after PELD. Methods We retrospectively reviewed the data of pediatric patients with LDH who underwent PELD from December 2007 to July 2018. The patients’ symptoms, physical examination findings, clinical images, visual analog scale (VAS) scores, Oswestry Disability Index (ODI), and perioperative results (blood loss, length of hospital stay, and complications) were obtained from the medical records. Lumbar disc degeneration was graded using the modified Pfirrmann grading system at the 1-year postoperative magnetic resonance imaging (MRI) examination. Results Six boys and four girls who underwent PELD were evaluated. The patients’ mean age was 15.6 years (range, 13–17 years). The mean VAS score for low back pain, mean VAS score for lower limb pain, and mean ODI preoperatively and 1 year postoperatively were 6.2 and 0.3, 6.9 and 0.5, and 20 and 0.1, respectively. MRI showed significant disc degeneration after PELD. Conclusions Treating pediatric LDH with PELD is safe and effective. It relieves pain and reduces disability. However, lumbar disc degeneration still occurs.

Background High-frequency transcutaneous neuromuscular electrical nerve stimulation (TENS) is currently used for the administration of electrical current in denervated muscle to alleviate muscle atrophy and enhance motor function; however, the time window (i.e. either immediate or delayed) for achieving benefit is still undetermined. In this study, we conducted an intervention of sciatic nerve crush injury using high-frequency TENS at different time points to assess the effect of motor and sensory functional recovery. Results Animals with left sciatic nerve crush injury received TENS treatment starting immediately after injury or 1 week later at a high frequency(100 Hz) or at a low frequency (2 Hz) as a control. In SFI gait analysis, either immediate or late admission of high-frequency electrical stimulation exerted significant improvement compared to either immediate or late administration of low-frequency electrical stimulation. In an assessment of allodynia, immediate high frequency electrical stimulation caused a significantly decreased pain threshold compared to late high-frequency or low-frequency stimulation at immediate or late time points. Immunohistochemistry staining and western blot analysis of S-100 and NF-200 demonstrated that both immediate and late high frequency electrical stimulation showed a similar effect; however the effect was superior to that achieved with low frequency stimulation. Immediate high frequency electrical stimulation resulted in significant expression of TNF-α and synaptophysin in the dorsal root ganglion, somatosensory cortex, and hippocampus compared to late electrical stimulation, and this trend paralleled the observed effect on somatosensory evoked potential. The CatWalk gait analysis also showed that immediate electrical stimulation led to a significantly high regularity index. In primary dorsal root ganglion cells culture, high-frequency electrical stimulation also exerted a significant increase in expression of TNF-α, synaptophysin, and NGF in accordance with the in vivo results. Conclusion Immediate or late transcutaneous high-frequency electrical stimulation exhibited the potential to stimulate the motor nerve regeneration. However, immediate electrical stimulation had a predilection to develop neuropathic pain. A delay in TENS initiation appears to be a reasonable approach for nerve repair and provides the appropriate time profile for its clinical application. Electronic supplementary material The online version of this article (10.1186/s12868-018-0437-9) contains supplementary material, which is available to authorized users.

Background Magnesium supplementation has potential for use in nerve regeneration. The expression of some magnesium transporter genes is reflective of the intracellular magnesium levels. Objective To assess the expression of various magnesium transporter genes as they relate to neurological alterations in a sciatic nerve injury model. Methods Sciatic nerve injury was induced in rats, which were then fed either basal or high magnesium diets. Magnesium concentrations and 5 magnesium transporter genes (SLC41A1, MAGT1, CNNM2, TRPM6, and TRPM7) were measured in the tissue samples. Results The high magnesium diet attenuated cytoskeletal loss in a dose-dependent manner in isolated nerve explants. The high magnesium diet augmented nerve regeneration and led to the restoration of nerve structure, increased S-100, and neurofilaments. This increased regeneration was consistent with the improvement of neurobehavioral and electrophysiological assessment. The denervated muscle morphology was restored with the high magnesium diet, and that was also highly correlated with the increased expression of desmin and acetylcholine receptors in denervated muscle. The plasma magnesium levels were significantly elevated after the animals consumed a high magnesium diet and were reciprocally related to the down-regulation of CNNM2, MagT1, and SCL41A1 in the blood monocytes, nerves, and muscle tissues of the nerve crush injury model. Conclusion The increased plasma magnesium levels after consuming a high magnesium diet were highly correlated with the down-regulation of magnesium transporter genes in monocytes, nerves, and muscle tissues after sciatic nerve crush injury. The study findings suggest that there are beneficial effects of administering magnesium after a nerve injury.

Transferring exogenous mitochondria has therapeutic effects on damaged heart, liver, and lung tissues. Whether this protective effect requires the symbiosis of exogenous mitochondria in host cells remains unknown. Here xenogenic mitochondria derived from a hamster cell line were applied to ischemic rat brains and rat primary cortical neurons. Isolated hamster mitochondria, either through local intracerebral or systemic intra-arterial injection, significantly restored the motor performance of brain-ischemic rats. The brain infarct area and neuronal cell death were both attenuated by the exogenous mitochondria. Although internalized mitochondria could be observed in neurons and astrocytes, the low efficacy of mitochondrial internalization could not completely account for the high rate of rescue of the treated neural cells. We further illustrated that disrupting electron transport or ATPase synthase in mitochondria significantly attenuated the protective effect, suggesting that intact respiratory activity is essential for the mitochondrial potency on neural protection. These results emphasize that nonsymbiotic extracellular mitochondria can provide an effective cell defense against acute injurious ischemic stress in the central nervous system.

BackgroundThe gold standard surgical treatment of nerve injury includes direct repair, nerve graft, and neurolysis. The underlying effects (either beneficial or detrimental) of angiogenesis during nerve regeneration by rotational muscle flap have not yet determined. We assess the neurological outcome and angiogenesis of nerve injury following a rotational muscle flap.MethodsWe retrospectively analyzed the outcome of the patients with severe radial nerve injury by neurolysis and rotational muscle flap; we also mimicked the clinical situation by nerve crush followed by rotational muscle flap in animals to assess associated angiogenesis factor expression.ResultsTwenty-three out of 25 (92%) cases of severe radial nerve injury underwent neurolysis assisted by muscle flap rotation and eventually reached their preinjury neurological outcome. In the animal study, both FITC-dextran and Dil infusion showed a remarkably increased vascular structure in the crushed nerve integrated by the muscle flap and abolished by Avastin injection. The rotational muscle flap significantly increased angiogenesis factor expression, and this was attenuated by Avastin injection. The increased angiogenesis factor expression paralleled the improvement seen in neurobehavioral and electrophysiological studies as well as the significant expression of nerve regeneration markers and the restoration of denervated muscle morphology.ConclusionBased on the clinical and animal data analysis, we conclude that muscle flap rotation provides a platform for angiogenesis in the acceleration of nerve regeneration. It appears that the muscle flap rotation augmented the nerve regeneration process which may be beneficial for nerve repair in clinical application.

Dual leucine zipper kinase (DLK) is a member of mitogen-activated protein kinase kinase kinase (MAP3K) family mainly involved in neuronal degeneration. However, the role of DLK signaling in the neuropathic pain has not yet been fully determined. Chronic constrictive injury (CCI) was conducted by four 3-0 chromic gut ligatures loosely ligated around the sciatic nerve. Escalated DLK expression over the dorsal root ganglion was observed from one to four rings of CCI. Remarkable expression of DLK was observed in primary dorsal root ganglion cells culture subjected to electrical stimulation and attenuated by DLK short hairpin RNA (shRNA) treatment. Intrathecal injection of DLK shRNA attenuates the expression of DLK over the dorsal root ganglion and hippocampus neurons and increased the threshold of mechanical allodynia and decreased thermal hyperalgesia. In CatWalk gait analysis, significant decreases of print area, maximum contact maximum intensity, stand phase, single stance, and regular index by CCI were alleviated by the DLK shRNA administration. In conclusion, the expression of DLK was up-regulated in chronic constrictive injury and attenuated by the administration of DLK shRNA, which paralleled the improvement of neurobehavior of neuropathic pain. The modulation of DLK expression is a potential clinic treatment option for neuropathic pain.

Gamma knife treatment outcome of large pituitary tumors which are only partially irradiated secondary to immediate proximity to critical structures such as the optic apparatus have not been rigorously studied.From July 2003 to December 2013, there were 41 cases of recurrent or residual nonfunctioning pituitary macroadenoma partially treated with gamma knife radiosurgery (GKRS) because the adenoma obscured part of the optic apparatus on planning SRS MR imaging.The follow up period after GKRS was 92.3 ± 5.6 months. The percentage of tumor coverage with the full dose was 88.5 ± 0.7%. Five of 43 (11.6%) patients experienced a transient visional decrease and one patient experienced a permanent visual field defect. During the follow up, two patients underwent transphenoidal surgery and one patient had a craniotomy due to tumor progression. Seven patients (16.2%) developed cortisol and thyroxine deficiencies. In multiple variant analyses, transient visual decline was correlated to the tumor volume ( 3.5 cc), percentage of tumor coverage ( 90%), the distance from the optic apparatus to the pituitary stalk ( 15 mm) and percentage of tumor above the orbital apex (65%).In the limited case of this cohort, we found that partially treated pituitary nonfunctioning macroadenoma yielded a high tumor control rate. However, visual decline as a result of tumor progression or radiation effect can occur in a minority of patients. The radiosurgical technique warrants further study to better define the long-term risk to benefit profile for its use in complex pituitary macroadenoma obscuring part of the optic apparatus.

Peritoneal dissemination of tumor has high mortality and is associated with the loss of epithelial features, acquisition of motile mesenchymal morphology characteristics, and invasive properties by tumor cells. Melatonin is an endogenously produced molecule in all plant species that is known to exert antitumor activity, but to date, its underlying mechanisms and antiperitoneal metastasis efficacy is not well defined. This study determined the antiperitoneal dissemination potential of melatonin in vivo and assessed its association with the inhibition of epithelial-to-mesenchymal transition (EMT) signaling mechanism by endoplasmic reticulum (ER) stress, which may be a major molecular mechanism of melatonin against cancer. The results demonstrate that melatonin inhibited peritoneal metastasis in vivo and activated ER stress in Cignal ERSE Reporter Assay, organelle structure in transmission electron microscopy images, calpain activity, and protein biomarkers like p-elf2α. Moreover, the overexpression of transcription factor C/EBPβ in gastric cancer interacted with NFκB and further regulates COX-2 expression. These were dissociated and downregulated by melatonin, as proven by immunofluorescence imaging, immunoprecipitation, EMSA, and ChIP assay. Melatonin or gene silencing of C/EBPβ decreased the EMT protein markers (E-cadherin, Snail, and Slug) and Wnt/beta-catenin activity by Topflash activity, and increased ER stress markers. In an animal study, the results of melatonin therapy were consistent with those of in vitro findings and attenuated systemic proangiogenesis factor production. In conclusion, C/EBPβ and NFκB inhibition by melatonin may impede both gastric tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT.

Additional file 1. The ARRIVE guidelines checklist.

Peritoneal dissemination is a major clinical obstacle in gastrointestinal cancer therapy, and it accounts for the majority of cancer‐related mortality. Calreticulin (CRT) is over‐expressed in gastric tumors and has been linked to poor prognosis. In this study, immunohistochemistry studies revealed that the up‐regulation of CRT was associated with lymph node and distant metastasis in patients with gastric cancer specimens. CRT was significantly down‐regulated in highly metastatic gastric cancer cell lines and metastatic animal by Honokiol‐treated. Small RNA interference blocking CRT by siRNA‐CRT was translocated to the cells in the early immunogenic response to Honokiol. Honokiol activated endoplasmic reticulum (ER) stress and down‐regulated peroxisome proliferator‐activated receptor‐γ (PPARγ) activity resulting in PPARγ and CRT degradation through calpain‐II activity, which could be reversed by siRNA‐calpain‐II. The Calpain‐II/PPARγ/CRT axis and interaction evoked by Honokiol could be blocked by gene silencing or pharmacological agents. Both transforming growth factor (TGF)‐β1 and N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG) induced cell migration, invasion and reciprocal down‐regulation of epithelial marker E‐cadherin, which could be abrogated by siRNA‐CRT. Moreover, Honokiol significantly suppressed MNNG‐induced gastrointestinal tumor growth and over‐expression of CRT in mice. Knockdown CRT in gastric cancer cells was found to effectively reduce growth ability and metastasis in vivo. The present study provides insight into the specific biological behavior of CRT in epithelial‐to‐mesenchymal transition (EMT) and metastasis. Taken together, our results suggest that the therapeutic inhibition of CRT by Honokiol suppresses both gastric tumor growth and peritoneal dissemination by dictating early translocation of CRT in immunogenic cell death, activating ER stress, and blocking EMT.

Background Gamma Knife radiosurgery (GKRS) is an important part of the neurosurgical armamentarium in the treatment of acoustic neuromas. However, the treatment outcome related to the morphology of the tumor has not been rigorously studied. In this cohort, we evaluated the morphological features of the tumor in the tumor response and neurological outcomes after GKRS. Material and methods From July 2003 to December 2008, there were 93 cases of acoustic neuromas treated upfront with GKRS with 64 cases with serviceable hearing and 29 cases without serviceable hearing to fulfill the margin dose of 12Gy with at least follow up 5 years. Results The duration of symptom before GKRS in serviceable /no serviceable hearing was 7.9 ± 1.2 and 15.3 ± 3.1 months (p

Background Axon degeneration leads to cytoskeletal disassembly, metabolism imbalance, and mitochondrial dysfunction during neurodegeneration or nerve injury. Objective In this study, we assess the possibility of mitigating axon degeneration by local injection of mitochondria in a crushed sciatic nerve. Methods Sciatic nerve explants cocultured with mitochondria were assessed for the optimal dosage in local injection and nerve regeneration potential. The left sciatic nerve was crushed in Sprague-Dawley rats and then local injection of mitochondria into the distal end of the injured nerve was conducted for further assessment. Results Mitochondrial coculture attenuated cytoskeletal loss and oxidative stress in isolated nerve explants. In Vivo analyses also showed that mitochondrial transplantation improved animal neurobehaviors, electrophysiology of nerve conduction, and muscle activities. Mitochondria injection significantly attenuated the oxidative stress and increased the expression of neurotrophic factors both in injured nerves and denervated muscles, as well as restored muscular integrity, and increased the pool of muscular progenitor cells and total muscle weight. Conclusion Mitochondria injection can protect injured nerves from axonal degeneration both in Vitro and in Vivo. This improvement was accompanied with the expression of neurotrophic factors as well as the reduction of oxidative stress, which may account for the functional recovery of both injured nerves and denervated muscles.

Purpose Whole brain irradiation (WBRT) either with or without resection has historically been the treatment for brain metastases from non-small cell lung cancer (NSCLC). The effect of gamma knife (GK) radiosurgery, chemotherapy, or the combination remains incompletely defined. In this study, we assessed the outcome of brain metastases from non-small cell lung cancer treated by WBRT followed by GK, gefitinib, or the combination of GK and gefitinib. Material and methods We retrieved the records of NSCLC patients with brain metastases from the National Health Insurance Research Database (NHIRD) of Taiwan from 2004 to 2010. WBRT either with or without resection was the first line treatment for nearly all patients. The decision to add GK and/or gefitinib treatment was at the discretion of the treating physician and based upon a patient’s medical records and imaging data. These patients were classified into four groups including WBRT, WBRT + gefitinib, WBRT + GK, WBRT + gefitinib + GK. These data was evaluated for difference in survival and factors that portended an extended survival from the time of brain metastasis diagnosis. Results Of the 60194 patients with newly diagnosed NSCLC, 23874 (39.6 %) developed brain metastases. The distribution of patients for the groups was WBRT for 20241, WBRT + gefitinib for 3379, WBRT + GK for 155, and WBRT+ gefitinib + GK for 99 patients. The median survival for the time of brain metastasis diagnosis for WBRT, WBRT+ gefitinib, WBRT+ GK, WBRT+ gefitinib + GK groups was 0.53, 1.01, 1.46, and 2.25 years, respectively (p

Object.This retrospective review was conducted to determine the surgical treatment principle for rheumatoid arthritis (RA) patients with atlantoaxial instability (AAI).Methods.Thirteen patients with AAI, including 5 RA patients, received preoperative computed tomography- (CT-) based image-guided navigation system (IGS) in C1 lateral mass-C2 pedicle screw-rod system fixation (LC1-PC2 fixation). These 13 patients were analyzed for 52 screws inserted into C1 and C2. We defined these patients as non-RA group (8 patients, 32 screws) and RA group (5 patients, 20 screws). The neurological status for RA group was evaluated using the Ranawat classification. The causes of AAI, surgical indications, complications, surgical method revolution, and CT-based navigation application are discussed.Results.None of the 13 patients expressed neurological function deterioration. The non-RA group screw accuracy was 100%. In the RA group, 1 RA patient developed left C2 screw loosening at 1+months after operation due to screw malposition. The screw accuracy for this group was 95%.Conclusions.Higher intraoperative surgical complication rate was described in RA patients. Preoperative CT-based IGS in LC1-PC2 fixation can provide good neurological function and screw accuracy results. However, for higher screw accuracy in RA patients, intraoperative CT-based IGS application may be considered.

Purpose The skeletal muscle develops various degrees of atrophy and metabolic dysfunction following nerve injury. Neurotrophic factors are essential for muscle regeneration. Human amniotic fluid derived stem cells (AFS) have the potential to secrete various neurotrophic factors necessary for nerve regeneration. In the present study, we assess the outcome of neurological function by intramuscular injection of AFS in a muscle denervation and nerve anastomosis model. Materials and Methods Seventy two Sprague-Dawley rats weighing 200–250 gm were enrolled in this study. Muscle denervation model was conducted by transverse resection of a sciatic nerve with the proximal end sutured into the gluteal muscle. The nerve anastomosis model was performed by transverse resection of the sciatic nerve followed by four stitches reconnection. These animals were allocated to three groups: control, electrical muscle stimulation, and AFS groups. Results NT-3 (Neurotrophin 3), BDNF (Brain derived neurotrophic factor), CNTF (Ciliary neurotrophic factor), and GDNF (Glia cell line derived neurotrophic factor) were highly expressed in AFS cells and supernatant of culture medium. Intra-muscular injection of AFS exerted significant expression of several neurotrophic factors over the distal end of nerve and denervated muscle. AFS caused high expression of Bcl-2 in denervated muscle with a reciprocal decrease of Bad and Bax. AFS preserved the muscle morphology with high expression of desmin and acetylcholine receptors. Up to two months, AFS produced significant improvement in electrophysiological study and neurological functions such as SFI (sciatic nerve function index) and Catwalk gait analysis. There was also significant preservation of the number of anterior horn cells and increased nerve myelination as well as muscle morphology. Conclusion Intramuscular injection of AFS can protect muscle apoptosis and likely does so through the secretion of various neurotrophic factors. This protection furthermore improves the nerve regeneration in a long term nerve anastomosis model.

Purpose The neurobehavior of neuropathic pain by chronic constriction injury (CCI) of sciatic nerve is very similar to that in humans, and it is accompanied by a profound local inflammation response. In this study, we assess the potentiality of human amniotic fluid derived mesenchymal stem cells (hAFMSCs) for alleviating the neuropathic pain in a chronic constriction nerve injury model. Methods and Methods This neuropathic pain animal model was conducted by four 3–0 chromic gut ligatures loosely ligated around the left sciatic nerve in Sprague—Dawley rats. The intravenous administration of hAFMSCs with 5x105 cells was conducted for three consecutive days. Results The expression IL-1β, TNF-α and synaptophysin in dorsal root ganglion cell culture was remarkably attenuated when co-cultured with hAFMSCs. The significant decrease of PGP 9.5 in the skin after CCI was restored by administration of hAFMSCs. Remarkably increased expression of CD 68 and TNF-α and decreased S-100 and neurofilament expression in injured nerve were rescued by hAFMSCs administration. Increases in synaptophysin and TNF-α over the dorsal root ganglion were attenuated by hAFMSCs. Significant expression of TNF-α and OX-42 over the dorsal spinal cord was substantially attenuated by hAFMSCs. The increased amplitude of sensory evoked potential as well as expression of synaptophysin and TNF-α expression was alleviated by hAFMSCs. Human AFMSCs significantly improved the threshold of mechanical allodynia and thermal hyperalgesia as well as various parameters of CatWalk XT gait analysis. Conclusion Human AFMSCs administration could alleviate the neuropathic pain demonstrated in histomorphological alteration and neurobehavior possibly through the modulation of the inflammatory response.