Erratum to "Isocudraxanthone K Induces Growth Inhibition and Apoptosis in Oral Cancer Cells via Hypoxia Inducible Factor-1α".

[This corrects the article DOI: 10.1155/2014/934691.].

HIF-2 Inhibition Supresses Inflammatory Responses and Osteoclastic Differentiation in Human Periodontal Ligament Cells.

Recent reports suggest that hypoxia inducible factor-2α (HIF-2α) is a key regulator of osteoarthritis cartilage destruction. However, the precise role of HIF-2α in the inflammatory response and osteoclast differentiation remains unclear. The purpose of this study was to investigate the effect of HIF-2α on inflammatory cytokines, extracellular matrix (ECM) destruction enzymes, and osteoclastic differentiation in nicotine and lipopolysaccharide (LPS)-stimulated human periodontal ligament cells (PDLCs). HIF-2α was upregulated in chronically inflamed PDLCs of periodontitis patients, and in nicotine- and LPS-exposed PDLC in dose- and time-dependent manners. HIF-2α inhibitor and HIF-2α siRNA attenuated the nicotine- and LPS- induced production of NO and PGE2 , upregulation of iNOS, COX-2, pro-inflammatory cytokines (IL-1ß, TNF-α, IL-1ß, IL-6, IL-8, IL-10, IL-11, and IL-17), and matrix metalloproteinases (MMPs; MMP-1, -8, -13, -2 and -9), and reversed the effect on TIMPs (TIMP-1 and -2) in PDLCs. The conditioned medium produced by nicotine and LPS-treated PDLCs increased the number of TRAP-stained osteoclasts, TRAP activity and osteoclast-specific genes, which has been blocked by HIF-2α inhibition and silencing. HIF-2α inhibitor and HIF-2α siRNA inhibited the effects of nicotine and LPS on the activation of Akt, JAK2 and STAT3, ERK and JNK MAPK, nuclear factor-κB, c-Jun, and c-Fos. Taken together, this study is the first to demonstrate that HIF-2α inhibition exhibits anti-inflammatory activity through the inhibition of inflammatory cytokines and impairment of ECM destruction, as well as blocking of osteoclastic differentiation in a nicotine- and periodontopathogen-stimulated PDLCs model. Thus, HIF-2α inhibition may be a novel molecular target for therapeutic approaches in periodontitis.

Pneumocephalus during cervical transforaminal epidural steroid injections: a case report.

A cervical transforaminal epidural injection of anesthetic and corticosteroids (CTFESI) is a frequently used procedure for cervical radiculopathy. Most cases of pneumocephalus after an epidural block occur when using an interlaminar approach with the loss-of-resistance technique. The authors present the first case of pneumocephalus after cervical transforaminal epidural injection of anesthetic and corticosteroids. A 64-yr-old woman with left C7 radiculopathy was undergoing C6-7 transforaminal epidural injection of anesthetic and corticosteroids. The epidural spread of contrast was checked by fluoroscope, and 5 mg of dexamethasone in 4 ml of 0.1875% ropivacaine was injected. She lost consciousness 5 mins after the procedure and regained awareness after manual ventilation. She subsequently complained of nausea and headache, and a computed tomography brain scan revealed pneumocephalus. After carefully assessing the fluoroscopic images, the authors believe that the needle may have punctured the dura mater of the nerve root sleeve, allowing air to enter the subdural space. Thus, fluoroscopic images should be carefully examined to reduce dural puncture when performing cervical transforaminal epidural injection of anesthetic and corticosteroids, and air should be completely removed from the needle, extension tube, and syringe.

Two novel FAH gene mutations in a patient with hereditary tyrosinemia type I.

BACKGROUND: Hereditary tyrosinemia type I (HT I) is a severe inborn metabolic disorder affecting the tyrosine degradation pathway. Most untreated patients die within the first two years of life. HT I results from fumarylacetoacetate hydrolase (FAH) deficiency caused by mutations in the FAH gene. The diagnosis of HT I is confirmed by measuring FAH enzyme activity in cultured fibroblasts or liver tissue and/or detecting disease-causing mutations in the FAH gene. METHODS: A female neonate was referred to our hospital for further evaluation of an abnormal newborn screening test that showed elevated tyrosine levels. We analyzed amino acids and organic acids in the patient's blood and urine. To identify the genetic abnormality, all the coding exons and flanking introns of the FAH gene were analyzed via PCR. RESULTS: A repeat newborn screening test and plasma amino acid analysis revealed increased tyrosine levels in the patient. Urine organic acid analysis showed increased urinary excretion of 4-hydroxyphenyllactate, 4-hydroxyphenylpyruvate, and succinylacetone. Sequence analysis of the FAH gene identified two novel variations (c.536A>G (p.Gln179Arg) and c.913+5G>A) that had not been previously reported and that were not found in 170 healthy controls. CONCLUSIONS: HT I was confirmed in this patient by molecular genetic analysis of the FAH gene, with highly suggestive biochemical findings. The novel sequence variations detected in the present study should be considered disease-causing mutations by in silico analysis. In the Korean population, this is the first described case of HT I caused by a point mutation in the FAH gene.

Isocudraxanthone K induces growth inhibition and apoptosis in oral cancer cells via hypoxia inducible factor-1α.

Isocudraxanthone K (IK) is a novel, natural compound from a methanol extract of the root bark of Cudrania tricuspidata. It has not been shown previously that IK possessed antitumor activity. We investigated the antitumor effects and molecular mechanism of IK and related signal transduction pathway(s) in oral squamous cell carcinoma cells (OSCCCs). The MTT assay revealed that IK had an antiproliferative effect on OSCCCs, in a dose- and time-dependent manner. IK induced apoptosis in OSCCCs, as identified by a cell-cycle analysis, annexin V-FITC and propidium iodide staining, and the nuclear morphology in cell death. IK caused time-dependent phosphorylation of Akt, p38, and ERK (extracellular signal-regulated kinase). In addition, IK increased the cytosolic to nuclear translocation of nuclear factor-κB (NF-κB) p65 and the degradation and phosphorylation of IκB-α in HN4 and HN12 cells. Furthermore, IK treatment downregulated hypoxia-inducible factor 1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF). Cobalt chloride (CoCl2), a HIF-1α activator, attenuated the IK-induced growth-inhibiting and apoptosis-inducing effects, and blocked IK-induced expression of apoptosis regulatory proteins, such as Bax, Bcl-2, caspase-3, caspase-8, and caspase-9, and cytochrome c. Collectively, these data provide the first evidence of antiproliferative and apoptosis-inducing effects of IK as a HIF-1α inhibitor and suggest it may be a drug candidate for chemotherapy against oral cancer.

Evaluation of the neurological safety of epidural milnacipran in rats.

BACKGROUND: Milnacipran is a balanced serotonin norepinephrine reuptake inhibitor with minimal side effects and broad safety margin. It acts primarily on the descending inhibitory pain pathway in brain and spinal cord. In many animal studies, intrathecal administration of milnacipran is effective in neuropathic pain management. However, there is no study for the neurological safety of milnacipran when it is administered neuraxially. This study examined the neurotoxicity of epidural milnacipran by observing behavioral and sensory-motor changes with histopathological examinations of spinal cords in rats. METHODS: Sixty rats were divided into 3 groups, with each group receiving epidural administration of either 0.3 ml (3 mg) of milnacipran (group M, n = 20), 0.3 ml of 40% alcohol (group A, n = 20), or 0.3 ml of normal saline (group S, n = 20). RESULTS: There were no abnormal changes in the behavioral, sensory-motor, or histopathological findings in all rats of groups M and S over a 3-week observation period, whereas all rats in group A had abnormal changes. CONCLUSIONS: Based on these findings, the direct epidural administration of milnacipran in rats did not present any evidence of neurotoxicity in behavioral, sensory-motor and histopathological evaluations.