Moyamoya syndrome after proton beam therapy in a pediatric patient with a pineal germ cell tumor and a germline polymorphism in RNF213.

The effects of RNF213, which leads to moyamoya disease susceptibility, on radiation-induced moyamoya syndrome (MMS) remain unknown. We report a case of MMS after proton beam therapy (PBT) was deployed to treat a brain tumor in a patient with an RNF213 polymorphism. An 8-year-old boy underwent whole ventricular and local PBT for a pineal germ cell tumor and was diagnosed with radiation-induced MMS 9 months later. He underwent right and left revascularization surgeries for cerebral hemodynamic compromise at 17- and 18-years of age, respectively. Genetic analysis revealed a heterozygous germline polymorphism RNF213 p.R4810K. This is the first report to suggest an association between RNF213 polymorphism and radiation-induced MMS.

High-fat diet during early life reshapes the gut microbiome and is associated with the disrupted mammary microenvironment in later life in mice.

The influence of gut microbiota on gut health is well-documented, but it remains obscure for extraintestinal diseases such as breast cancer. Moreover, it is entirely unknown how gut dysbiosis during early life contributes to breast tumorigenesis later in life. In this study, we hypothesized that a high-fat diet during early life leads to alterations in the gut microbiome and is associated with disruptions in the mammary microenvironment. Female C57BL/6 mice were fed a low-fat diet (10% kcal fat) or a high-fat diet (HF, 60% kcal fat) for 8 weeks from the age of 4 to 12 weeks, which is equivalent to human childhood and adolescence. Twelve mice were sacrificed immediately after the 8-week feeding, the remainder were euthanized after switching to a normal lifecycle-supporting diet for an additional 12 weeks; the gut microbiome was then sequenced. The 8-week HF diet feeding altered the beta-diversity (Bray & Jaccard P < .01), and the difference remained significant after switching the diet (Bray & Jaccard P < .05). Immediately after HF feeding, a greater number of microbial taxa (>50) were altered, and about half of the taxa (25) remained significantly changed after switching the diet. The abundance of Alistipes, Bilophila, and Rikenellaceae stood out as significantly associated with multiple metabolic and inflammatory biomarkers in mammary tissue, including aromatase, Ccl2, and Cox2. In conclusion, an 8-week early-life HF feeding reshaped the gut microbiome, which connected with disrupted mammary microenvironments.

Turicibacter fermentation enhances the inhibitory effects of Antrodia camphorata supplementation on tumorigenic serotonin and Wnt pathways and promotes ROS-mediated apoptosis of Caco-2 cells.

Introduction: Diet-induced obesity has been shown to decrease the abundance of Turicibacter, a genus known to play a role in the serotonin signaling system, which is associated with colorectal tumorigenesis, making the presence of Turicibacter potentially influential in the protection of intestinal tumorigenesis. Recently, Antrodia camphorata (AC), a medicinal fungus native to Taiwan, has emerged as a promising candidate for complementary and alternative cancer therapy. Small molecules and polysaccharides derived from AC have been reported to possess health-promoting effects, including anti-cancer properties. Methods: Bacterial culture followed with cell culture were used in this study to determine the role of Turicibacter in colorectal tumorigenesis and to explore the anti-cancer mechanism of AC with Turicibacter fermentation. Results: Turicibacter fermentation and the addition of AC polysaccharide led to a significant increase in the production of nutrients and metabolites, including α-ketoglutaric acid and lactic acid (p < 0.05). Treatment of Turicibacter fermented AC polysaccharide was more effective in inhibiting serotonin signaling-related genes, including Tph1, Htr1d, Htr2a, Htr2b, and Htr2c (p < 0.05), and Wnt-signaling related protein and downstream gene expressions, such as phospho-GSK-3ß, active ß-catenin, c-Myc, Ccnd1, and Axin2 (p < 0.05). Additionally, it triggered the highest generation of reactive oxygen species (ROS), which activated PI3K/Akt and MAPK/Erk signaling and resulted in cleaved caspase-3 expression. In comparison, the treatment of AC polysaccharide without Turicibacter fermentation displayed a lesser effect. Discussion: Our findings suggest that AC polysaccharide effectively suppresses the tumorigenic serotonin and Wnt-signaling pathways, and promotes ROS-mediated apoptosis in Caco-2 cells. These processes are further enhanced by Turicibacter fermentation.

High-Fat Diet Exposure in Early Life Alters Mammary Metabolic and Inflammatory Microenvironment in Favor of Breast Tumorigenesis Later in Life in Mice.

Emerging evidence highlights the important impact of early-life exposures on cancer development later in life. The present study aimed to investigate the impacts of a high-fat diet in early life on the mammary microenvironment in relation to breast tumorigenesis. Forty-four female C57BL/6 mice were fed a low-fat diet (LF, 10 kcal% fat) or a high-fat diet (HF, 60 kcal% fat) for 8 weeks starting at ~4 weeks of age. Twenty-two mice were sacrificed immediately after an 8 week feeding, and the rest of mice were switched to a normal diet for maintenance (Lab Diet, #5P76) for additional 12 weeks. A panel of metabolic parameters, inflammatory cytokines, as well as tumorigenic Wnt-signaling target genes were analyzed. The HF diet increased body weight and exacerbated mammary metabolic and inflammatory status. The disrupted microenvironment remains significant to the later life equivalent to young adulthood (p < 0.05). Mammary Wnt-signaling was elevated right after the HF diet as indicated by the upregulated expression of its downstream genes, whereas it was surprisingly suppressed after switching diets (p < 0.05). In summary, HF-induced overweight/obesity in early life altered the mammary metabolic and inflammatory microenvironments in favor of breast tumorigenesis, although its overall impact to breast cancer later in life warrants further investigation.

Tumor necrosis factor-α knockout mitigates intestinal inflammation and tumorigenesis in obese Apc1638N mice.

Strong evidence from observational studies shows that having body fatness is associated with an individual's risk of developing colorectal cancer (CRC), but the causality between obesity and CRC remains inadequately elucidated. Our previous studies have shown diet-induced obesity is associated with elevated TNF-α and enhanced activation of Wnt-signaling, yet the causal role of TNF-α on intestinal tumorigenesis has not been precisely studied. The present study aims to examine the functionality of TNF-α in the development of CRC associated with obesity. We first examined the extent to which diet-induced obesity elevates intestinal tumorigenesis by comparing Apc1638N mice fed a low fat diet (LFD, 10 kcal% fat) with those fed a high fat diet (HFD, 60 kcal% fat), and then investigated the degree that the genetic ablation of TNF-α attenuates the effect by crossing the TNF-α-/- mice with Apc1638N mice and feeding them with the same HFD (TNF-α KO HFD). After 16-weeks of feeding, the HFD significantly increased intestinal tumorigenesis, whereas the deletion of TNF-α attenuated the effect (P < .05). Accompanying the changes in macroscopic tumorigenesis, HFD significantly elevated intestinal inflammation and procarcinogenic Wnt-signaling, whereas abolishment of TNF-α mitigated the magnitude of these elevations (P < .05). In summary, our findings demonstrate that the knockout of TNF-α attenuates obesity-associated intestinal tumorigenesis by decreasing intestinal inflammation and thereby the Wnt-signaling, indicating that TNF-α signaling is a potential target that can be utilized to reduce the risk of CRC associated with obesity.

Tumor Volume Reduction Rate to Induction Chemotherapy is a Prognostic Factor for Locally Advanced Head and Neck Squamous Cell Carcinoma: A Retrospective Cohort Study.

Introduction: Aim of this retrospective cohort study is to evaluate the prognostic value of tumor volume reduction rate status post-induction chemotherapy in locally advanced head and neck squamous cell carcinoma. Methods: Patients newly diagnosed from year 2007 to 2016 at a single center were included in this retrospective study. All patients had received induction Taxotere, Platinum, Fluorouracil followed by daily definitive intensity-modulated radiotherapy for 70 Gy in 35 fractions concurrent with or without cisplatin-based chemotherapy. Tumor volume reduction rate was measured and calculated by contrast-enhanced computed tomography images at diagnosis, and after at least 1 cycle of induction chemotherapy, and analyzed though a univariate and multivariate Cox regression model. Results: Ninety patients of the primary cancer sites at hypopharynx (31/90, 34.4%), oropharynx (29/90, 32.2%), oral cavity (19/90, 21.1%), and larynx (11/90, 12.2%) were included in this study, with a median follow-up time interval of 3.9 years. In multivariate Cox regression analysis, the tumor volume reduction rate of the primary tumor (TVRR-T) was also an independently significant prognostic factor for disease-free survival (DFS) (hazard ratio 0.77, 95% confidence interval 0.62-0.97; P-value = .02). Other factors including patient's age at diagnosis, the primary cancer site, and RECIST (Response Evaluation Criteria in Solid Tumors), were not significantly related. At a cutoff value using 50% in Kaplan-Meier survival analysis, the DFS was higher with TVRR-T ≥ 50% group (log-rank test, P = .024), and a trend of improved overall survival. (log-rank test, P = .069). Conclusion: TVRR-T is a probable prognostic factor for DFS. With a cut-off point of 50%, TVRR-T may indicate better DFS.

Microstructural Evidence of Neuroinflammation for Psychological Symptoms and Pain in Patients With Fibromyalgia.

OBJECTIVE: In patients with fibromyalgia (FM), the brain shows altered structure and functional connectivity, but the mechanisms underlying these changes remain unclear. This study investigated the associated changes in brain microstructures and neuroinflammation of patients with FM. METHODS: We recruited 14 patients with FM and 14 healthy controls (HCs). Visual analog scale (VAS), Beck Anxiety Inventory (BAI), and Beck Depression Inventory-II (BDI-II) were used for assessing their pain, anxiety, and depression levels, respectively. Diffusion kurtosis imaging (DKI) was used to visualize microstructural alterations associated with neuroinflammation in specific brain regions. The biomarkers for neuron damage, including serum tau and amyloid ß protein fragment 1-42 (Aß1-42) levels, were assessed. Spearman correlation of DKI parameters with VAS, BAI, and BDI-II scores as well as tau and Aß1-42 levels were assessed. RESULTS: The patients with FM had significantly higher levels of Aß1-42 levels than HCs. Compared with HCs, the patients with FM showed significantly lower DKI parameters in the bilateral dorsolateral prefrontal cortex and orbitofrontal cortex. Patients with FM showed a significant correlation between the axial kurtosis values of the amygdala and VAS scores (left: ρ = -0.60, P = 0.02; right: ρ = -7.04, P = 0.005). CONCLUSION: To the best of our knowledge, this is the first study to use DKI to examine the brains of patients with FM. We noted significant DKI changes associated with neuroinflammation at specific areas in patients with FM. Our results provide valuable information on brain neuroinflammation and pathophysiological changes in patients with FM.

Systematic Review and Meta-Analysis of Inguinal Versus Classic Obturator Nerve Block.

Obturator nerve block (ONB) has been widely applied in transurethral resection of bladder tumor and knee surgery to prevent serious complications such as bladder perforation or to improve the quality of anesthesia during knee surgery. The classic/pubic and inguinal ONB methods are the two primary approaches used. The classic and inguinal ONB methods are two techniques for anesthetizing the obturator nerve, and each method may result in different respective outcomes. We aimed to compare the efficacy of the classic and inguinal methods. We presumed the inguinal approach to be an overall superior technique because it was recently invented and has been reported to provide numerous benefits. This study included randomized controlled trials comparing classic and inguinal approaches to ONB. Two independent investigators extracted study-level data for a random-effects meta-analysis of the comparison between the classic approach and inguinal approaches. We identified five studies comprising 312 patients. The pooled results revealed a higher success rate (risk ratio, 1.15; 95% confidence interval [CI], 1.04-1.27), fewer puncture attempts (mean difference, -0.84; 95% CI, -1.55 to -0.12), and shorter procedure time (mean difference, -28.87; 95% CI, -47.19 to -10.54) for patients given inguinal ONB. The inguinal approach is, overall, the superior method for performing the ONB procedure. The inguinal method resulted in a higher success rate, fewer puncture attempts, and shorter procedure time.

Detection of endophenotypes associated with neuropsychiatric deficiencies in a mouse model of tuberous sclerosis complex using diffusion tensor imaging.

Tuberous sclerosis complex (TSC) is a rare hereditary disease, which results from the mutation of either TSC1 or TSC2, and its clinical features include benign tumors and dysfunctions in numerous organs, including the brain. Many individuals with TSC manifest neuropsychiatric symptoms, such as learning impairments, cognitive deficits and anxiety. Current pharmacological treatment for TSC is the use of mTOR inhibitors. However, they are not effective in treating neuropsychiatric symptoms. We previously used curcumin, a diet-derived mTOR inhibitor, which possesses both anti-inflammatory and antiproliferative properties, to improve learning and memory deficits in Tsc2+/- mice. Diffusion tensor imaging (DTI) provides microstructural information in brain tissue and has been used to study the neuropathological changes in TSC. In this study, we confirmed that the impaired recognition memory and increased anxiety-like behavior in Tsc2+/- mice can be reversed by curcumin treatment. Second, we found altered fractional anisotropy and mean diffusivity in the anterior cingulate cortex and the hippocampus of the Tsc2+/- mice, which may indicate altered circuitry. Finally, the mTOR complex 1 hyperactivity was found in the cortex and hippocampus, coinciding with abnormal cortical myelination and increased glial fibrillary acidic protein expression in the hippocampal CA1 of Tsc2+/- mice, both of which can be rescued with curcumin treatment. Overall, DTI is sensitive to the subtle alterations that cannot be detected by conventional imaging, suggesting that noninvasive DTI may be suitable for longitudinally monitoring the in vivo neuropathology associated with the neuropsychiatric symptoms in TSC, thereby facilitating future clinical trials of pharmacological treatments.

The NF-[Formula: see text]B Signaling and Wnt/[Formula: see text]-catenin Signaling in MCF-7 Breast Cancer Cells in Response to Bioactive Components from Mushroom Antrodia Camphorata.

Breast cancer is the leading cancer, accounting for approximately 15% cancer deaths in women worldwide. This study investigated the anti-inflammation and anticancer properties of two bioactive components from Antrodia camphorata(AC), a rare medicinal mushroom natively grown in Taiwan and commonly used in Chinese traditional medicine. The anti-inflammatory and antitumorigenic functions of Antroquinonol (AQ) and 4-Acetylantroquinonol B (4-AAQB) from AC were examined on breast cancer cell line MCF-7 with/without TNF-[Formula: see text] stimulation. Among nine inflammatory mediators (IL6, IL10, IL1[Formula: see text], IFN[Formula: see text], PTGS2, TGF[Formula: see text]1, TNF-[Formula: see text], CCL2 andCSF1) examined, AQ inhibited two of them (IL-10 and PTGS2), while 4-AAQB inhibited three of them (IL-10, PTGS2 andTNF-[Formula: see text] ([Formula: see text]¡ 0.05). TNF-[Formula: see text] stimulated expressions of five mediators (IL6, IL10, IFN[Formula: see text], PTGS2, and CCL2), and AQ and 4-AAQB inhibited IL6 elevation ([Formula: see text]¡ 0.05). Both components inhibited aromatase expression with/without TNF-[Formula: see text] stimulation, with 4-AAQB to be more effective ([Formula: see text]¡ 0.05). For immune checkpoint CD47, both components inhibited CD47 expression ([Formula: see text]¡ 0.05), but it did not respond to TNF-[Formula: see text] stimulation. For Wnt/[Formula: see text]- catenin signaling downstream genes (CCND1, C-MYC and AXIN2), both components have significant or marginal inhibitory effect on C-MYC in the condition with/without TNF-[Formula: see text] stimulation. The luciferase assay demonstrated that both components exhibited inhibitory effect on NF-[Formula: see text]B signaling and Wnt/[Formula: see text]-catenin signaling in the condition without TNF-[Formula: see text] stimulation. In conclusion, our results displayed an overall pattern that AQ and 4-AAQB possess potential anti-inflammatory and antitumorigenic functions in MCF-7 breast cancer cells and warranted further in vivo pre-clinical and clinical studies to explore their anticancer properties.

Automated Hypofractionated IMRT treatment planning for early-stage breast Cancer.

BACKGROUND: Hypofractionated whole-breast irradiation is a standard adjuvant therapy for early-stage breast cancer. This study evaluates the plan quality and efficacy of an in-house-developed automated radiotherapy treatment planning algorithm for hypofractionated whole-breast radiotherapy. METHODS: A cohort of 99 node-negative left-sided breast cancer patients completed hypofractionated whole-breast irradiation with six-field IMRT for 42.56 Gy in 16 daily fractions from year 2016 to 2018 at a tertiary center were re-planned with an in-house-developed algorithm. The automated plan-generating C#-based program is developed in a Varian ESAPI research mode. The dose-volume histogram (DVH) and other dosimetric parameters of the automated and manual plans were directly compared. RESULTS: The average time for generating an autoplan was 5 to 6 min, while the manual planning time ranged from 1 to 1.5 h. There was only a small difference in both the gantry angles and the collimator angles between the autoplans and the manual plans (ranging from 2.2 to 5.3 degrees). Autoplans and manual plans performed similarly well in hotspot volume and PTV coverage, with the autoplans performing slightly better in the ipsilateral-lung-sparing dose parameters but were inferior in contralateral-breast-sparing. The autoplan dosimetric quality did not vary with different breast sizes, but for manual plans, there was worse ipsilateral-lung-sparing (V4Gy) in larger or medium-sized breasts than in smaller breasts. Autoplans were generally superior than manual plans in CI (1.24 ± 0.06 vs. 1.30 ± 0.09, p < 0.01) and MU (1010 ± 46 vs. 1205 ± 187, p < 0.01). CONCLUSIONS: Our study presents a well-designed standardized fully automated planning algorithm for optimized whole-breast radiotherapy treatment plan generation. A large cohort of 99 patients were re-planned and retrospectively analyzed. The automated plans demonstrated similar or even better dosimetric quality and efficacy in comparison with the manual plans. Our result suggested that the autoplanning algorithm has great clinical applicability potential.

The role of 5-methoxytryptophan in pediatric-onset lupus nephritis: A retrospective cohort study.

BACKGROUND: This clinical study investigates the role of 5-methoxytryptophan (5-MTP) in pediatric systemic lupus erythematosus (SLE), with a particular interest in lupus nephritis (LN). PATIENTS AND METHODS: One hundred ten children with SLE were enrolled in the cohort study. Among the patients, seventy-seven (70%) had active LN and thirty-three (30%) were not present with LN during their first visit to the clinic. The diagnoses of LN were biopsy-proven. Serum samples were collected before and after administration of immunosuppressive medications to evaluate 5-MTP levels and regular laboratory data. Data were analyzed longitudinally. RESULTS: Before any treatment started, patients with active LN had significantly higher 5-MTP levels as compared to patients with no LN (1.021 ± 0.709 vs. 0.719 ± 0.606, P = 0.0456). Also, in patient with active LN, 5-MTP level was significant decreased after treatment, compared with the levels before treatment (1.021 ± 0.709 vs. 0.802 ± 0.597, P = 0.0484). Patients who reached complete remission also had significantly higher initial serum 5-MTP levels than that in patients with no remission (1.244 ± 0.784 vs. 0.846 ± 0.556, P = 0.0488). There was an overall reduction in 5-MTP levels after six months of immunosuppressive treatment, regardless of the disease outcome. Subgroup analysis further revealed a significantly higher 5-MTP level during the active stage of LN (1.127 ± 0.149 vs. 0.742 ± 0.092, P = 0.0384). CONCLUSION: We demonstrated that serum 5-MTP level is positively correlated to the disease activity, prognosis, and remission status of pediatric LN in vivo.

Timing of Symptomatic Infarct Swelling Following Intravenous Thrombolysis in Acute Middle Cerebral Artery Infarction: A Case-Control Study.

BACKGROUND: The risk of symptomatic infarct swelling has been reported to be higher in patients treated with recombinant tissue plasminogen activator (rt-PA). The aim of this study was to evaluate the timing of symptomatic infarct swelling after rt-PA treatment. METHODS: We retrospectively analyzed 14 868 patients with acute ischemic stroke from a stroke registry databank. We recruited patients with massive middle cerebral artery (MCA) infarction and symptomatic infarct swelling and excluded those with parenchymal or symptomatic hemorrhage. Multiple linear regression and multivariate logistic regression analyses were used to estimate the impact of rt-PA on the timing of symptomatic infarct swelling. RESULTS: A total of 23 patients with rt-PA treatment and 117 patients without rt-PA treatment were included. The rt-PA treatment group had a lower rate of coronary artery disease (8.7% vs 32.5%; P = .023), lower severity of baseline National Institutes of Health Stroke Scale score (19 vs 23; P = .014), shorter duration of infarct swelling (27.6 vs 45.4 hours; P < .001), and higher rate of hemicraniectomy surgery (65.2% vs 28.2%; P =.001) than those without rt-PA treatment. After adjusting for variables in multiple linear regression analysis, rt-PA treatment and an elevated C-reactive protein level were associated with early symptomatic infarct swelling ( P = .014 and P = .041, respectively). The rt-PA treatment was an independent factor related to early symptomatic infarct swelling within 36 hours ( P = .005; odds ratio [OR]: 5.3; confidence interval [CI]: 1.65-17.0) or 48 hours ( P = .009; OR: 16.4; CI: 2.00-134). CONCLUSION: Intravenous rt-PA treatment may hasten the onset of cerebral edema and subsequent cerebral herniation in large MCA territory infarction.

The modulation of Th2 immune pathway in the immunosuppressive effect of human umbilical cord mesenchymal stem cells in a murine asthmatic model.

BACKGROUND: Asthma is a chronic airway inflammatory disease that has a high prevalence nowadays, and seeking the means of relieving asthmatic symptoms is now an issue with increased importance. While mesenchymal stem cells have been demonstrated to display immunomodulatory effects, the effect of fetus-type mesenchymal stem cells (MSCs) on asthmatic symptoms in vivo have not been reported to date. METHODS: Female BALB/c mice at 8 weeks of age were sensitized by ovalbumin, and MSCs derived from Wharton's jelly of human umbilical cord mesenchymal stem cells (hUCMSCs) were injected into the asthmatic mice. Airway hyper-responsiveness, lung eosinophil infiltration, cytokine level in splenocyte cultures and serum immunoglobulin level were measured. Enzyme-linked immunosorbent assay was used to determine cytokine and immunoglobulin levels. RESULTS: This current study demonstrated that hUCMSCs attenuated both lung lymphocyte and eosinophil infiltration, and significantly decreased the concentration of Th2 cytokines interleukin-5 in splenocyte cultures. CONCLUSIONS: Human umbilical cord mesenchymal stem cells have the advantage of being easily harvested non-invasively and are capable of rapid proliferation, therefore an ideal material for stem cell-based immune therapies. The current study showed that fetal-type MSCs were able to suppress asthmatic symptoms efficiently, and its immunomodulatory effect resulted primarily from suppressing the Th2 pathway in the animal model. This study suggested that hUCMSCs could be an ideal candidate for cell-based therapies of asthma.

Xanthine derivative KMUP-1 reduces inflammation and hyperalgesia in a bilateral chronic constriction injury model by suppressing MAPK and NFκB activation.

Neuropathic pain is characterized by spontaneous pain, hyperalgesia, and allodynia. The aim of this study was to investigate whether KMUP-1 (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) could improve pain hypersensitivity and reduce inflammatory mediators, and also explore possible mechanisms in the rat sciatic nerve using bilateral chronic constriction injury (CCI) to induce neuropathic pain. Sprague-Dawley rats were randomly divided into four groups: Sham, Sham+KMUP-1, CCI, and CCI+KMUP-1. KMUP-1 (5 mg/kg/day) was injected intraperitoneally starting at day 1 after surgery. Mechanical and thermal responses were assessed before surgery and at days 3, 7, and 14 after CCI. Sciatic nerves around the injury site were isolated for Western blots and enzyme-linked immunosorbent assay to analyze protein and cytokine levels. The results show that thermal hyperalgesia and mechanical allodynia were reduced in the KMUP-1 treated group as compared to that in the CCI group. Inflammatory proteins (COX2, iNOS, and nNOS) and proinflammatory cytokines (TNF-α and IL-1ß) induced by CCI were decreased in the KMUP-1 treated group at day 7 after surgery. KMUP-1 also inhibited neuropathic pain-related mechanisms, including p38 and ERK activation, but not JNK. Furthermore, KMUP-1 blocked IκB phosphorylation (p-IκB) and phospho-nuclear factor κB (p-NF-κB) translocation to nuclei. Double immunofluorescent staining further demonstrated that p-IκB (an indicator of activated NFκB) and p-NFκB proteins were almost abolished by KMUP-1 in peripheral macrophages and spinal microglia cells at day 7 after surgery. On the basis of these findings, we concluded that KMUP-1 has antiinflammatory and antihyperalgesia properties in CCI-induced neuropathic pain via decreases in MAPKs and NF-κB activation.