Phytoconstituent-derived zingerone nanoparticles disrupt the cell adhesion mechanism and suppress cell motility in melanoma B16F10 cells.

Combining phytochemicals and nanotechnology to improve the unfavorable innate properties of phytochemicals and develop them into potent nanomedicines to enhance antitumor efficacy has become a novel strategy for cancer chemoprevention. Melanoma is the most aggressive, metastatic, and deadly disease of the primary cutaneous neoplasms. In this study, we fabricated phytoconstituent-derived zingerone nanoparticles (NPs) and validated their effects on cell adhesion and motility in melanoma B16F10 cells. Our data indicated that zingerone NPs significantly induced cytotoxicity and anti-colony formation and inhibited cell migration and invasion. Moreover, zingerone NPs dramatically interfered with the cytoskeletal reorganization and markedly delayed the period of cell adhesion. Our results also revealed that zingerone NPs-mediated downregulation of MMPs (matrix metalloproteinases) activity is associated with inhibiting cell adhesion and motility. We further evaluated the effects of zingerone NPs on Src/FAK /Paxillin signaling, our data showed that zingerone NPs significantly inhibited the protein activities of Src, FAK, and Paxillin, indicating that they play important roles in zingerone NP-mediated anti-motility and anti-invasion in melanoma cells. Accordingly, the phytoconstituent-zingerone NPs can strengthen the inhibition of tumor growth, invasion, and metastasis in malignant melanoma. Altogether, these multi-pharmacological benefits of zingerone NPs will effectively achieve the purpose of melanoma prevention and invasion inhibition.

Loganin Attenuates High Glucose-Induced Schwann Cells Pyroptosis by Inhibiting ROS Generation and NLRP3 Inflammasome Activation.

Diabetic peripheral neuropathy (DPN) is caused by hyperglycemia, which induces oxidative stress and inflammatory responses that damage nerve tissue. Excessive generation of reactive oxygen species (ROS) and NOD-like receptor protein 3 (NLRP3) inflammasome activation trigger the inflammation and pyroptosis in diabetes. Schwann cell dysfunction further promotes DPN progression. Loganin has been shown to have antioxidant and anti-inflammatory neuroprotective activities. This study evaluated the neuroprotective effect of loganin on high-glucose (25 mM)-induced rat Schwann cell line RSC96 injury, a recognized in vitro cell model of DPN. RSC96 cells were pretreated with loganin (0.1, 1, 10, 25, 50 µM) before exposure to high glucose. Loganin's effects were examined by CCK-8 assay, ROS assay, cell death assay, immunofluorescence staining, quantitative RT-PCR and western blot. High-glucose-treated RSC96 cells sustained cell viability loss, ROS generation, NF-κB nuclear translocation, P2 × 7 purinergic receptor and TXNIP (thioredoxin-interacting protein) expression, NLRP3 inflammasome (NLRP3, ASC, caspase-1) activation, IL-1ß and IL-18 maturation and gasdermin D cleavage. Those effects were reduced by loganin pretreatment. In conclusion, we found that loganin's antioxidant effects prevent RSC96 Schwann cell pyroptosis by inhibiting ROS generation and suppressing NLRP3 inflammasome activation.

Loganin prevents chronic constriction injury-provoked neuropathic pain by reducing TNF-α/IL-1ß-mediated NF-κB activation and Schwann cell demyelination.

BACKGROUND: Peripheral nerve injury can produce chronic and ultimately neuropathic pain. The chronic constriction injury (CCI) model has provided a deeper understanding of nociception and chronic pain. Loganin is a well-known herbal medicine with glucose-lowering action and neuroprotective activity. PURPOSE: This study investigated the molecular mechanisms by which loganin reduced CCI-induced neuropathic pain. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham, sham+loganin, CCI and CCI+loganin. Loganin (1 or 5 mg/kg/day) was injected intraperitoneally once daily for 14 days, starting the day after CCI. For behavioral testing, mechanical and thermal responses were assessed before surgery and on d1, d3, d7 and d14 after surgery. Sciatic nerves (SNs) were collected to measure proinflammatory cytokines. Proximal and distal SNs were collected separately for Western blotting and immunofluorescence studies. RESULTS: Thermal hyperalgesia and mechanical allodynia were reduced in the loganin-treated group as compared to the CCI group. Loganin (5 mg/kg/day) prevented CCI from inducing proinflammatory cytokines (TNF-α, IL-1ß), inflammatory proteins (TNF-α, IL-1ß, pNFκB, pIκB/IκB, iNOS) and receptor (TNFR1, IL-1R), adaptor protein (TRAF2) of TNF-α, and Schwann cell demyelination and axonal damage. Loganin also blocked IκB phosphorylation (p-IκB). Double immunofluorescent staining further demonstrated that pNFκB/pIκB protein was reduced by loganin in Schwann cells on d7 after CCI. In the distal stumps of injured SN, Schwann cell demyelination was correlated with pain behaviors in CCI rats. CONCLUSION: Our findings indicate that loganin improves CCI-induced neuroinflammation and pain behavior by downregulating TNF-α/IL-1ß-dependent NF-κB activation.

Valproate reduces neuroinflammation and neuronal death in a rat chronic constriction injury model.

Valproate (VPA) is a well-known drug for treating epilepsy and mania, but its action in neuropathic pain is unclear. We used a chronic constriction injury (CCI) model to explore whether VPA prevents neuropathic pain-mediated inflammation and neuronal death. Rats were treated with or without VPA. CCI + VPA rats were intraperitoneally injected with VPA (300 mg/kg/day) from postoperative day (POD) 1 to 14. We measured paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) 1 day before surgery and 1, 3, 7, 14 days after CCI and harvested the sciatic nerves (SN), spinal cord (SC) and dorsal root ganglia (DRG) on POD 3, 7, and 14. PWL and PWT were reduced in CCI rats, but increased in CCI + VPA rats on POD 7 and POD 14. VPA lowered CCI-induced inflammatory proteins (pNFκB, iNOS and COX-2), pro-apoptotic proteins (pAKT/AKT and pGSK-3ß/GSK-3ß), proinflammatory cytokines (TNF-α and IL-1ß) and nuclear pNFκB activation in the SN, DRG and SC in CCI rats. COX-2 and pGSK-3 proteins were decreased by VPA on immunofluorescence analysis. VPA attenuated CCI-induced thermal and mechanical pain behaviors in rats in correlation with anti-neuroinflammation action involving reduction of pNFκB/iNOS/COX-2 activation and inhibition of pAKT/pGSK-3ß-mediated neuronal death from injury to peripheral nerves.

Atorvastatin prevents neuroinflammation in chronic constriction injury rats through nuclear NFκB downregulation in the dorsal root ganglion and spinal cord.

Atorvastatin, traditionally used to treat hyperlipidemia, belongs to a class of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors. This study investigated the antineuroinflammatory and antihyperalgesic effects of atorvastatin in dorsal root ganglia (DRG) and spinal cord for chronic constriction injury (CCI) neuropathic pain in rats. Fifty-four Sprague-Dawley rats were divided into three groups including sham, CCI, and CCI+atorvastatin. Rats were orally administered atorvastatin (10 mg/kg/day) once daily for 2 weeks after surgery and sacrificed at days 3, 7, and 14. All animals were assessed for mechanical allodynia and thermal hyperalgesia in both hindpaws. Western blotting, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were used to detect inflammatory proteins and proinflammatory cytokines at day 7 after surgery. Pain behaviors were significantly reduced in the CCI+atorvastatin group compared to the CCI group. Atorvastatin attenuated CCI-induced inflammatory mediators (pAkt/Akt, COX-2, iNOS, EP1, and EP4) and reduced proinflammatory cytokines TNF-α and IL-1ß levels in DRG and spinal cord. Atorvastatin also inhibited nuclear pNFκB activation. Double immunofluorescent staining further demonstrated that pNFκB proteins were decreased by atorvastatin in DRG satellite cells and spinal microglia. Atorvastatin may primarily inhibit the nuclear translocation of pNFκB to prevent CCI-induced peripheral neuropathic pain. Atorvastatin exhibits antineuroinflammatory and antinociceptive properties in the central and peripheral nerve systems.

Intraspinal tumors: analysis of 184 patients treated surgically.

BACKGROUND: Intraspinal tumors are rare central nervous system neoplasms. The reported clinical features of intraspinal tumors have varied in previous studies. We present here the cases of 184 patients with intraspinal tumors treated surgically in our hospital and a review of the literature. METHODS: We conducted a retrospective review of 184 patients with intraspinal tumors who underwent surgical treatment in our institution between 2002 and 2013. Their age, sex, initial presentation, tumor location, level of affected vertebral column, histological diagnosis, and primary origin of the metastatic tumor were reviewed and analyzed. RESULTS: Of these 184 patients, 97 (52.7%) were men and 87 (47.3%) were women. The mean age was 56.3 years (range 7-83 years). A total of 102 (55.4%) had primary tumors, while 82 (44.6%) patients had developed metastatic tumors. The histological diagnosis of the primary tumors included 55 (53.9%) schwannomas, 16 (15.7%) meningiomas, six (5.9%) ependymomas, five (4.9%) neurofibromas, three (2.9%) hemangiomas, two (2.0%) hemagioblastomas, and 15 (14.7%) other tumor types. The most common primary sites of the metastatic tumors were the lung and breast. CONCLUSION: Primary tumors were more numerous than metastastic tumors in our series of patients. For the primary tumors, our study showed a higher proportion of nerve sheath cell tumors (schwannomas and neurofibromas) and fewer meningiomas and neuroepithelial tumors compared with reports from non-Asian countries. In addition, the lung was the most common origin of the metastatic tumors and more than half of these tumors were located at the thoracic spine. Back pain and radicular pain were the most common presentations in patients with intraspinal tumors.

Dyspnea and choking as presenting symptoms in primary medulla oblongata germinoma.

BACKGROUND: The medulla oblongata is the lower half of the brainstem. It contains the cardiac, respiratory, vomiting, and vasomotor centers and deals with autonomic functions such as breathing, heartbeat, and blood pressure. Primary medulla oblongata germinoma is very rare and less than 20 cases have been reported in the English literature. CASE DESCRIPTION: A 22-year-old female without any particular past medical history presented to us in October 2012 with the chief complaint of dyspnea and frequent choking for 1 month. Neurological examination revealed lower cranial nerve palsies and nystagmus. Her brain computed tomography (CT) and brain magnetic resonance imaging (MRI) demonstrated a mass lesion at the dorsal surface of medulla oblongata with extension into the inferior fourth ventricle and foramen magnum. She underwent bilateral suboccipital craniotomy and C1 laminoplasty with the grossly total resection of the tumor. The histological examination of the tumor proved germinoma. Postoperative adjuvant radiotherapy was arranged. The latest brain MRI and whole spine MRI done 1 year after surgery showed neither residual nor recurrent tumor in the whole axis. She is regularly followed-up at our outpatient department and is doing well except having left vocal cord palsy, which occurred before surgery. CONCLUSION: Medulloblastoma, ependymoma, glioma, hemangioblastoma, and cavernous angioma are common intraaxial tumors in the medulla oblongata and fourth ventricle. Intracranial germ cell tumors originate from extragonadal seminal cells and have been found in 0.4-3.4% of patients with primary central nervous system (CNS) tumors in Western countries, while the incidence is reported to be 5-8 times greater in Japan and the Far East. Although germinoma of medulla oblongata is rare and difficult to diagnose preoperatively, it should be included in the differential diagnosis of medulla masses with fourth ventricle extension, especially in Asian population.

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.

Orbital apex syndrome due to aspergillosis with subsequent fatal subarachnoid hemorrhage.

BACKGROUND: Orbital apex syndrome has been described previously as a syndrome involving damage to the oculomotor nerve (III), trochlear nerve (IV), abducens nerve (VI), and ophthalmic branch of the trigeminal nerve (V1), in association with optic nerve dysfunction. It may be caused by inflammatory, infectious, neoplastic, iatrogenic, or vascular processes. CASE DESCRIPTION: A 73-year-old female having hypertension and rheumatoid arthritis stage 4 under long-term corticosteroid therapy presented to us with the right side orbital apex syndrome. Her magnetic resonance imaging (MRI) of orbit showed progression of a lesion at the right orbital apex and adjacent right superior orbital fissure with mild extension to the right posterior ethmoid sinus. She underwent endoscopic endonasal transethmoid approach with the removal of the lesion. The pathology showed a picture of fungal infection and the culture of the specimen proved Aspergillus fumigatus. Her postoperative course was smooth until 5 days after surgery, when she suffered a massive spontaneous subarachnoid hemorrhage resulting from a ruptured aneurysm, which was proven by computed tomography angiography (CTA) of brain. Unfortunately, she expired due to central failure. CONCLUSION: In cases of immunocompromised patients having orbital apex syndrome, fungal infection should be kept in mind. One of the most lethal but rare sequels of CNS fungal infection is intracranial aneurysms. Early diagnosis and radical resection, combined with antifungal medications is the key to save this particular group of patients.

Spontaneous spinal epidural hematoma: a case report and review of the literatures.

PURPOSE: To emphasize the importance of early recognition and emergent surgery for spontaneous spinal epidural hematoma (SSEH). CASE REPORT: A 61-year-old female presented with sudden onset of severe neck and back pain after finishing worshiping Buddha followed by quadriparesis, sensory deficits below C4 level and sphincter dysfunction. MR imaging demonstrated acute extensive epidural hematoma of cervico-thoracic spinal segments (C2-T7). Idiopathic SSEH was diagnosed and emergent decompressive laminectomy with hematoma evacuation was performed within 12 hours of symptoms onset. Good functional and neurological outcomes were obtained. CONCLUSION: SSEH is a rare but disabling or even fatal entity. Early diagnosis and prompt surgery improve the neurological and functional outcome but still remain a clinical challenge. Relevant physicians should pay attention to the typical symptoms of the rare entity and SSEH should be one of differential diagnoses.

Potassium-channel openers KMUP-1 and pinacidil prevent subarachnoid hemorrhage-induced vasospasm by restoring the BKCa-channel activity.

Alterations in the activity of vascular K channels are commonly associated with abnormalities in cerebral vascular function after subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage-induced vasospasm remains incompletely understood; nevertheless, activation of K channels may be of benefit in relieving spastic constriction. This study was to examine whether the vasodilators KMUP-1 and pinacidil, a KATP-channel opener, have the ability to prevent SAH-induced vasospasm via the large-conductance Ca-activated K (BKCa) channels in cerebral arteries. Rats were divided into four groups including sham-operated, SAH, KMUP-1 treated, and pinacidil treated. Subarachnoid hemorrhage rats were induced by injecting autologous blood into cisterna magna, and then KMUP-1 or pinacidil (1 mg/kg) was injected intraperitoneally 1 and 24 h after SAH. Behavioral tests were assessed on day 2 after SAH before the rats were killed. Cerebral myocytes were enzymatically isolated from rat basilar arteries and used to monitor BKCa-channel activities. In isolated basilar arteries, KMUP-1-treated and pinacidil-treated rats showed normalized vascular reactivity. In whole-cell recordings, BKCa currents were attenuated in SAH rats compared with sham-operated rats. In inside-out patches, the conductance and voltage sensitivity of single BKCa-channels were unchanged among the four groups. In contrast, SAH rats showed markedly decreased BKCa-channel activity and ß1-subunit expression associated Ca sensitivity that was further confirmed by immunofluorescence staining and Western blotting. Subarachnoid hemorrhage-induced deficits in motor function and BKCa-channel inhibition were improved by KMUP-1-treated and pinacidil-treated rats. In addition, SAH appears to modify BKCa-channel calcium sensitivity. KMUP-1 and pinacidil prevent SAH-induced vasospasm at least in part by the restoration of BKCa-channel activities.

KMUP-1 inhibits L-type Ca²âº channels involved the protein kinase C in rat basilar artery myocytes.

This study investigated whether KMUP-1, a xanthine-based derivative, inhibits L-type Ca(2+) currents (I(Ca,L)) in rat basilar artery smooth muscle cells (RBASMCs). We used whole cell patch-clamp recording to monitor Ba(2+) currents (I(Ba)) through L-type Ca(2+) channels (LTCCs). Under voltage-clamp conditions, holding at -40 mV, KMUP-1 (1, 3, 10 µM) inhibited I(Ba) in a concentration-dependent manner and its IC(50) value was 2.27 ± 0.45 µM. A high concentration of KMUP-1 (10 µM) showed without modifying the I(Ba) current-voltage relationship. On the other hand, the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA, 1 µM) increase I(Ba) was inhibited by KMUP-1. Pretreatment with the PKC inhibitor chelerythrine (5 µM) intensified KMUP-1-inhibited I(Ba). However, the Rho kinase inhibitor Y-27632 (30 µM) failed to affect the I(Ba) inhibition by KMUP-1. In light of these results, we suggest that KMUP-1 inhibition of LTCCs in concentration- and voltage-dependent manners in RBASMCs may be due, at least in part, to its modulation of the PKC pathway.

Primary vaginal extraosseous Ewing sarcoma/primitive neuroectodermal tumor with cranial metastasis.

Extraosseous Ewing sarcoma is now regarded as a member of the Ewing sarcoma/primitive neuroectodermal tumor (PNET) family. It typically involves the soft tissues of the chest wall, pelvis, paravertebral region, abdominal wall, retroperitoneal region and extremities of children, adolescents and young adults, but it seldom occurs in the female genital tract. We report an extremely rare case of retrospective diagnosis of vaginal extraosseous Ewing sarcoma/PNET which metastasized to the right frontoparietal scalp, skull, and dura. Surgical resection, followed by adjuvant radiotherapy and chemotherapy resulted in a favourable clinical outcome. Both the vaginal and head tumors had similar light microscopic features supporting the diagnosis.

Skull metastasis from uterine leiomyosarcoma: a case report.

Uterine leiomyosarcoma is a rare malignancy whose presenting symptoms usually are not specific for the disease. The clinical presentations include vaginal bleeding, pelvic pain or pressure, and awareness of an abdominal-pelvic mass. The diagnosis should be considered if rapid uterine enlargement occurs, especially in a post-menopausal woman. Local spreading of the tumor could involve the myometrium, pelvic blood vessels and lymphatics, contiguous pelvic structures, and then the abdominal organs, whereas distant metastasis most often involve the lungs. A 63-year-old female presented a rare uterine leiomyosarcoma metastasis to the skull with the manifestions of a bulging mass over her left occipito-parietal region. On admission, neurological examination revealed right hemiplegia. She underwent total resection of the tumor with the reconstruction of the dura, the skull plate and the scalp. Her post-operative course was smooth and the muscle power of her right limbs was improved from grade 1 to grade 3 after the procedure. The histological diagnosis is leiomyosarcoma. Aggressive management of the metastatic skull tumor is recommended in selected patients at least for a betterquality of life.

Extraskeletal intracranial mesenchymal chondrosarcoma: case report and literature review.

We present the case of a 13-year-old girl with a huge intracranial mesenchymal chondrosarcoma. She had suffered from severe headache, diplopia, intermittent nausea and vomiting for 1 month. Neurologic examination revealed bilateral blurred optic disc margins and abducens paresis. Magnetic resonance imaging demonstrated a giant, heterogeneous, intensely enhancing mass of 7 x 8 x 6 cm, occupying the bilateral frontal and left high parietal regions and based on the anterior cerebral falx. A presumptive diagnosis of aggressive meningioma was made. The patient underwent bicoronal craniotomy and gross total resection of the tumor. Pathologic examination revealed an extraskeletal mesenchymal chondrosarcoma. She was under regular follow-up and remained free of recurrence after surgery. In addition to the current case, we review previously reported cases of extraskeletal intracranial mesenchymal chondrosarcoma and discuss treatment strategies and outcomes.