The Clinical Implication of Conversion Surgery in Patients with Stage IV Gastric Cancer Who Received Systemic Chemotherapy.

With the advances in chemotherapy and immunotherapy, a small subset of patients may be eligible for conversion surgery after achieving tumor regression with chemotherapy. This is a retrospective cohort study of 118 patients with stage IV gastric cancer who received palliative chemotherapy and conversion surgery with a negative resection margin at Samsung Medical Center. Baseline features included comorbidities, body mass index (BMI), carcinoembryonic antigen (CEA) level, primary tumor size, biopsy histology, distant metastatic sites, and molecular markers-HER2, MSI/MMR, PD-L1, and EBV. Post-chemotherapy features included BMI, CEA level, chemotherapy regimen, objective response to chemotherapy, and number of preoperative chemotherapy cycles. Post-operational features included tumor size, histologic differentiation and Lauren's classification, pathologic tumor and nodal stages, invasion of lymphatics/vessels/nerves, peritoneal cytology, and the receipt of postoperative chemotherapy. Of 118 patients, 60 patients received total gastrectomy and 58 patients received subtotal gastrectomy. In all, 21 patients achieved a pathologic complete response, and 97 patients achieved downstaging to yp stage I, II, or III. Before conversion surgery, patients received first-line capecitabine/oxaliplatin (62%), HER2 inhibitors combined with chemotherapy (18%), immune checkpoint inhibitors (15%), and inhibitors of MET or VEGFR2 (5%). In the multivariable analysis, BMI at the time of diagnosis, either HER2 positive, high MSI, or deficient MMR, and the use of targeted agents were significant prognostic factors. Conversion surgery could be considered in patients with stage IV gastric cancer regardless of the initial disease burden. BMI and molecular markers are important prognostic factors that can be used to select candidates.

In Silico Analysis of Pyeongwi-San Involved in Inflammatory Bowel Disease Treatment Using Network Pharmacology, Molecular Docking, and Molecular Dynamics.

BACKGOUND: Pyeongwi-san (PWS) is a widely used formula for treating digestive disorders in Korea and China. Inflammatory bowel disease (IBD) is characterized by progressive inflammation of the gastrointestinal tract. Emerging evidence supports the protective effect of PWS against IBD, but specific mechanisms are still elusive. METHODS: Active compounds of PWS were screened from the medicinal materials and chemical compounds in Northeast Asian traditional medicine (TM-MC) in the consideration of drug-likeness and oral bioavailability. Target candidates of active compounds were predicted using the ChEMBL database. IBD-related targets were obtained from the GeneCards and DisGeNET databases. The network of composition-targets-disease was constructed. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analyzed. Molecular docking was used to simulate the binding affinity of active compounds on target proteins and molecular dynamics was used to validate the molecular docking result. RESULTS: A total of 26 core target proteins of PWS were related to IBD. Enrichment analysis suggested that PWS is highly associated with tumor necrosis factor signaling pathway, apoptosis, and the collapse of tight junctions. Moreover, molecular docking and molecular dynamics simulation proposed ß-eudesmol and (3R,6R,7S)-1,10-bisaboladien-3-ol to ameliorate IBD through the binding to TNF and MMP9, respectively. CONCLUSION: Present in silico analysis revealed potential pathways and insight of PWS to regulate IBD. These results imply that the therapeutic effect of PWS might be achieved via an inhibitory effect.

Rumex japonicus Houtt. Extract Suppresses Colitis-Associated Colorectal Cancer by Regulating Inflammation and Tight-Junction Integrity in Mice.

Irritable bowel disease (IBD), which results in an elevated risk of colitis-associated colorectal cancer (CAC), is characterized by inflammation and barrier disruption of the gut. The genus Rumex has anti-oxidative and anti-inflammatory effects, and the roots of Rumex japonicus Houtt (RJ) have been traditionally used in East Asia to treat digestive problems. We investigated the protective effect of RJ against azoxymethane (AOM)-and dextran sulfate sodium (DSS)-induced CAC in C57BL/6N male mice. The mice were intraperitoneally injected with AOM on the first day and orally treated with 2% DSS for 2 weeks (on the third and sixth weeks). RJ extract (100 mg/kg) was administered to the mice in the RJ group for 4 weeks (from the third to sixth week), and all mice were sacrificed on the final day of the eighth week. Changes in morphology, tight junctions (TJs), inflammation-related factors in the colon and serum inflammatory cytokine levels were measured. The colons of AOM/DSS-treated mice were shorter and heavier than those of normal mice. The number of tumors in the colons of AOM/DSS-treated mice increased; however, RJ suppressed these changes. RJ also reduced the levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß in the colon and serum, and it increased the level of IL-10 in the colon. Moreover, RJ inhibited the barrier disruption and apoptosis in the colons of AOM/DSS-treated mice. RJ effectively suppressed AOM/DSS-induced CAC by inhibiting tumor formation, inflammation, disruption of TJ, and apoptosis in the colon.

Rumex japonicus Houtt. Protects Dopaminergic Neurons by Regulating Mitochondrial Function and Gut-Brain Axis in In Vitro and In Vivo Models of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Rumex japonicus Houtt. (RJ) has been used to treat gastrointestinal and inflammatory diseases in East Asia. However, it is unknown whether RJ can prevent PD. We investigated the neuroprotective effects of RJ in cellular and animal PD models, focused on mitochondrial function and the gut-brain axis. SH-SY5Y cells were treated with RJ (0.01 mg/mL) for 24 h, after which they were treated with the 1-methyl-4-phenylpyridinium ion (MPP+). MPP+-induced apoptosis increased mitochondrial reactive oxygen species and decreased ATP, PINK1, and DJ-1, which were inhibited by RJ. Ten-week-old C57BL/6N male mice were treated with 30 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 5 days and orally administered 50 or 100 mg/kg of RJ for 14 days. RJ alleviated MPTP-induced behavioral impairment, dopaminergic neuronal death, and mitochondrial dysfunction in the substantia nigra (SN) and suppressed the MPTP-induced increase in lipopolysaccharide, interleukin-1ß, tumor necrosis factor-α, α-synuclein, and apoptotic factors in the SN and colon. Moreover, RJ inhibited the MPTP-mediated disruption of the tight junction barrier in the colon and blood-brain barrier of mice. Therefore, RJ alleviates MPTP-induced inflammation and dopaminergic neuronal death by maintaining mitochondrial function and tight junctions in the brain and colon.

Korean red ginseng decreases 1-methyl-4-phenylpyridinium-induced mitophagy in SH-SY5Y cells.

OBJECTIVE: Mitophagy is known to contribute towards progression of Parkinson's disease. Korean red ginseng (KRG) is a widely used medicinal herb in East Asia, and recent studies have reported that KRG prevents 1-methyl-4-phenylpyridinium ion (MPP+)-induced cell death. This study was undertaken to investigate whether KRG suppresses MPP+-induced apoptosis and mitophagy. METHODS: SH-SY5Y cells were incubated with KRG for 24 h, and subsequently exposed to MPP+. The MPP+-induced cell death was confirmed with the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. Changes in the structure and function of mitochondria were confirmed using mitotracker, MitoSOX red mitochondrial superoxide indicator, parkin, and phosphatase and tensin homolog deleted on chromosome ten-induced putative kinase 1 (PINK1) immunofluorescent staining. Western blotting was performed to evaluate the expression of apoptosis-related factors in whole cells, including Bax, Bcl-2 and cleaved caspase-3, and mitophagy-related factors in the mitochondrial fraction, including cytochrome c, parkin, PINK1, translocase of the outer membrane 20 (TOM20), p62 and Beclin 1. RESULTS: MPP+ induced cell death by cytochrome c release and caspase-3 activation; however, this effect was suppressed by KRG's regulation of the expressions of Bcl-2 and Bax. Moreover, MPP+ exposure increased the mitochondrial expressions of parkin, PINK1, Beclin 1 and p62, and decreased TOM20, cytochrome c and Bcl-2 expressions. These MPP+-induced changes in the mitochondrial fraction were attenuated by treatment with KRG. CONCLUSION: KRG effectively prevents MPP+-induced SH-SY5Y cell death by regulating cytochrome c release from mitochondria and PINK1/parkin-mediated mitophagy, through regulation of the Bcl-2 family.

Korean red ginseng suppresses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced inflammation in the substantia nigra and colon.

Parkinson's disease (PD) is a neurodegenerative disease involving dopaminergic neuronal death in the substantia nigra (SN); recent studies have shown that interactions between gut and brain play a critical role in the pathogenesis of PD. In this study, the anti-inflammatory effect of Korean red ginseng (KRG) and the changes in gut microbiota were evaluated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Male nine-week-old C57BL/6 mice were injected intraperitoneally with 30 mg/kg of MPTP at 24-h intervals for 5 days. Two hours after the daily MPTP injection, the mice were orally administered 100 mg/kg of KRG, which continued for 7 days beyond the MPTP injections, for a total of 12 consecutive days. Eight days after the final KRG administration, the pole and rotarod tests were performed and brain and colon samples of the mice were collected. Dopaminergic neuronal death, activation of microglia and astrocytes, α-synuclein and expressions of inflammatory cytokines and disruption of tight junction were evaluated. In addition, 16S ribosomal RNA gene sequencing of mouse fecal samples was performed to investigate microbiome changes. KRG treatment prevented MPTP-induced behavioral impairment, dopaminergic neuronal death, activation of microglia and astrocytes in the nigrostriatal pathway, disruption of tight junction and the increase in α-synuclein, interleukin-1ß and tumor necrosis factor-α expression in the colon. The 16S rRNA sequencing revealed that MPTP altered the number of bacterial species and their relative abundances, which were partially suppressed by KRG treatment. Especially, KRG suppressed the abundance of the inflammation-related phylum Verrucomicrobia and genera Ruminococcus and Akkermansia (especially Akkermansia muciniphila), and elevated the abundance of Eubacterium, which produces the anti-inflammatory substances. These findings suggest that KRG prevents MPTP-induced dopaminergic neuronal death, activation of microglia and astrocytes, and accumulation of α-synuclein in the SN, and the regulation of inflammation-related factors in the colon may influence the effect.

Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors in Korea: Literature Review and Expert Opinion.

Neuroendocrine tumors (NETs) are a group of malignancies arising from neuroendocrine cells and frequently originate in the gastrointestinal tract and pancreas. Although curative resection is the main treatment for localized disease, systemic therapy is needed for relapsed or metastatic/unresectable gastroenteropancreatic NETs (GEP-NETs). Although there are several NET treatment guidelines from various countries, the geographical discrepancies between patient clinical characteristics, the regulatory approval status for therapeutic agents, and medical practices necessitate specific guidelines for Korean patients. We here provide a consensus review of the diagnosis, staging and systemic treatment of Korean GEP-NET patients. Systemic therapy options and the current Korean expert consensus on these treatments, including somatostatin analogs, targeted therapies such as everolimus and sunitinib, peptide receptor radionuclide treatments, and cytotoxic chemotherapies are addressed.

Korean Red Ginseng Regulates Intestinal Tight Junction and Inflammation in the Colon of a Parkinson's Disease Mouse Model.

Recent studies have determined that gastrointestinal function contributes to the control of Parkinson's disease (PD). Gastrointestinal dysfunction results in a leaky intestinal barrier, inducing inflammation in the gut. Korean red ginseng (KRG) is widely used for the treatment of numerous afflictions, including inflammation and neurodegenerative disease. We investigated changes in the intestinal tight junctions and proinflammatory cytokines in the colon, and alpha-synuclein (aSyn) in the colon and the substantia nigra (SN) of a PD mouse model. Eight-week-old male C57BL/6 mice were intraperitoneally administered 30 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) once a day for 5 days, and orally given 100 mg/kg of KRG for 12 consecutive days. Alterations in the levels of occludin, zonula occludens-1 (ZO-1), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) in the colon, and the expressions of aSyn and tyrosine hydroxylase (TH) in the colon and the SN were evaluated. Oral administration of KRG significantly prevents the MPTP-induced motor dysfunction, and suppresses the MPTP-induced disruption of occludin and ZO-1, and suppresses the increase in TNF-α and IL-1ß in the colon of mice. In addition, KRG prevents accumulation of aSyn and TH in the colon and the SN. These results suggest that KRG has the potential to prevent MPTP-induced leaky gut barrier, inflammation, and accumulation of aSyn.

Rumex japonicus Houtt. alleviates dextran sulfate sodium-induced colitis by protecting tight junctions in mice.

BACKGROUND: Rumex japonicus Houtt. (RJ) is widely distributed in Korea, Japan, and China. The root of RJ has traditionally been used to treat constipation, jaundice, hematemesis, dysfunctional uterine bleeding, and gastrointestinal diseases. According to recent studies, plants of the genus Rumex have beneficial functionalities such as anti-microbial, antioxidative, and anti-inflammatory effects. Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, is a chronic inflammatory disease characterized by an abnormal immune response and epithelial barrier dysfunction. This study evaluates the protective effect of RJ against dextran sulfate sodium (DSS)-induced colitis. METHODS: Male 8-week-old C57BL/6 N mice were treated with methanolic extract of RJ for 14 days, and DSS-induced groups were administered 2.5% DSS for last 7 days. After sacrifice, the length and weight of the colon were measured, and colon sections were subjected to H&E staining, immunohistochemistry and Western blotting to investigate the changes of inflammatory cytokines, tight junction and apoptosis-related factors. RESULTS: The colon of DSS-treated mouse was significantly shorter and heavier than the normal mouse. Moreover, DSS exposure induced an increase of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, occludin, zonula occludens-1, p21, p53 and Bcl-2, and decreased the expressions of IL-10, claudin-2 and cleaved caspase-3 in the colon tissue. These DSS-induced changes were inhibited by RJ treatment. CONCLUSION: Our results indicate that RJ effectively suppresses DSS-induced colitis by protecting tight junction connections in the colonic tissue. We therefore infer that RJ has the potential as a medicine or ingredient for treating colitis.

Bridging genomics and phenomics of gastric carcinoma.

Genetic alterations are the starting point leading to numerous changes in clinical and pathologic features (phenotypes) of individual cancers; however, their inter-relationships in gastric cancers (GC) are unclear. We performed massive parallel sequencing of 381 cancer-related genes and compared the results with clinical and pathologic findings in 330 GC. High tumor mutation burden (TMB) accounted for 11% of GC (n = 37) and all 19 MSI-H GCs were high TMB. High TMB was significantly more frequent in intestinal-type by Lauren, tumor with higher host cellular immune response, earlier AJCC stage and favorable prognosis. The most significantly mutated genes were TP53 (54%), ARID1A (23%), CDH1 (22%), PIK3CA (12%), RNF43 (10%) and KRAS (9%). For receptor tyrosine kinases, amplifications detected by immunohistochemistry were higher than sequencing (HER2, 9.1% vs. 5.8%; EGFR, 11.2% vs. 6.1%; FGFR2, 4.6% vs. 3.9%, c-MET, 3.4% vs. 0.9%). PTEN protein loss (22%) correlated well with underlying PTEN alterations while ATM loss (27%) was not significantly correlated with genetic alterations of ATM. p53 protein expression predicted alterations of TP53 with high sensitivity (97.8%) and low (15.9%) specificity. The poorly cohesive histology/CDH1-mutant GC subgroup showed the worst survival (p < 0.001). PD-L1 expression was significantly associated with MSI-H, MLH1 loss, ATM loss, MET positivity, higher host immune response, and genetic alterations of ARID1A, BRD3, PIK3CA, KRAS, MAP3K13, CDH2, PTEN and ESR1. The merged clinical, pathology and genomics of GC provide a better understanding of GC and new insights into the treatment of GC.

Sustained stimulation of ß2- and ß3-adrenergic receptors leads to persistent functional pain and neuroinflammation.

Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral ß2- and ß3-adrenergic receptors (ß2- and ß3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Here, we first sought to investigate the role of ß2- and ß3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15 mg/kg/day) or vehicle for 14 days. The ß2AR antagonist ICI118551 and ß3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNFα inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35 days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3 weeks after OR486 cessation. Corresponding increases in spinal TNFα, IL-1ß, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14-35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral ß2- and ß3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.

Sophora flavescens Aiton Decreases MPP+-Induced Mitochondrial Dysfunction in SH-SY5Y Cells.

Sophora flavescens Aiton (SF) has been used to treat various diseases including fever and inflammation in China, South Korea and Japan. Several recent reports have shown that SF has anti-inflammatory and anti-apoptotic effects, indicating that it is a promising candidate for treatment of Parkinson's disease (PD). We evaluated the protective effect of SF against neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+)-induced mitochondrial dysfunction in SH-SY5Y human neuroblastoma cells, an in vitro PD model. SH-SY5Y cells were incubated with SF for 24 h, after which they were treated with MPP+. MPP+-induced cytotoxicity and apoptosis were confirmed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling assay. MitoSOX red mitochondrial superoxide indicator, tetramethylrhodamine methyl ester perchlorate and Parkin, PTEN-induced putative kinase 1 (PINK1), and DJ-1 immunofluorescent staining were conducted to confirm the mitochondrial function. In addition, western blot was performed to evaluate apoptosis factors (Bcl-2, Bax, caspase-3 and cytochrome c) and mitochondrial function-related factors (Parkin, PINK1 and DJ-1). SF suppressed MPP+-induced cytotoxicity, apoptosis and collapse of mitochondrial membrane potential by inhibiting the increase of reactive oxidative species (ROS) and DNA fragmentation, and controlling Bcl-2, Bax, caspase-3 and cytochrome c expression. Moreover, it attenuated Parkin, PINK1 and DJ-1 expression from MPP+-induced decrease. SF effectively suppressed MPP+-induced cytotoxicity, apoptosis and mitochondrial dysfunction by regulating generation of ROS, disruption of mitochondrial membrane potential, mitochondria-dependent apoptosis and loss or mutation of mitochondria-related PD markers including Parkin, PINK1 and DJ-1.

Four distinct immune microenvironment subtypes in gastric adenocarcinoma with special reference to microsatellite instability.

INTRODUCTION: Programmed death-ligand 1 (PD-L1) can be overexpressed in tumours other than Epstein-Barr virus (EBV)-positive (EBV+) or microsatellite instability-high (MSI-H) gastric cancer (GC) subtypes. We aimed to determine the tumour immune microenvironment (TME) classification of GC to better understand tumour-immune interactions and help patient selection for future immunotherapy with special reference to MSI-H. METHODS: Immunohistochemistry (IHC) for PD-L1 and CD8+ T cells in three distinct subtypes of GC (43 EBV+, 79 MSI-H and 125 EBV-/MSS) were performed and analysed. In 66 MSI-H GC, mutation counts were compared with PD-L1 expression and survival of the patients. RESULTS: GC TME divided by PD-L1 IHC and tumour-infiltrating lymphocytes (TIL) measured by intratumoural CD8 density showed: (1) about 40% of GC are type I (PD-L1+/TIL+) consisting ~70% of MSI-H or EBV+ GC, and ~15% of EBV-/microsatellite stable (MSS) GC patients show the best survival in both disease-free (HR 2.044) and overall survival (HR 1.993); this type would respond to a checkpoint blockade therapy; (2) almost 30% of GC are type II (PD-L1-/TIL-) with the worst survival; (3) approximately 10% of GC are type III (PD-L1+/TIL-); and (4) up to 20% are type IV (PD-L1-/TIL+) and, unexpectedly, ~25% of EBV+ or MSI-H GC are within this subtype. In MSI-H GC, frequent frameshift mutations were observed in ARID1A, RNF43, NF1, MSH6, BRD3, NCOA3, BCORL1, TNKS2 and NPM1 and the numbers of frameshift mutation correlated significantly with PD-L1 expression (P<0.05). DISCUSSION: GC can be classified into four TME types based on PD-L1 and TIL, and numbers of frameshift mutation correlate well with PD-L1 expression in MSI-H GC.

Tissue recommendations for precision cancer therapy using next generation sequencing: a comprehensive single cancer center's experiences.

To generate accurate next-generation sequencing (NGS) data, the amount and quality of DNA extracted is critical. We analyzed 1564 tissue samples from patients with metastatic or recurrent solid tumor submitted for NGS according to their sample size, acquisition method, organ, and fixation to propose appropriate tissue requirements.Of the 1564 tissue samples, 481 (30.8%) consisted of fresh-frozen (FF) tissue, and 1,083 (69.2%) consisted of formalin-fixed paraffin-embedded (FFPE) tissue. We obtained successful NGS results in 95.9% of cases. Out of 481 FF biopsies, 262 tissue samples were from lung, and the mean fragment size was 2.4 mm. Compared to lung, GI tract tumor fragments showed a significantly lower DNA extraction failure rate (2.1 % versus 6.1%, p = 0.04). For FFPE biopsy samples, the size of biopsy tissue was similar regardless of tumor type with a mean of 0.8 × 0.3 cm, and the mean DNA yield per one unstained slide was 114 ng. We obtained highest amount of DNA from the colorectum (2353 ng) and the lowest amount from the hepatobiliary tract (760.3 ng) likely due to a relatively smaller biopsy size, extensive hemorrhage and necrosis, and lower tumor volume. On one unstained slide from FFPE operation specimens, the mean size of the specimen was 2.0 × 1.0 cm, and the mean DNA yield per one unstained slide was 1800 ng.In conclusions, we present our experiences on tissue requirements for appropriate NGS workflow: > 1 mm2 for FF biopsy, > 5 unstained slides for FFPE biopsy, and > 1 unstained slide for FFPE operation specimens for successful test results in 95.9% of cases.

Acupuncture suppresses kainic acid-induced neuronal death and inflammatory events in mouse hippocampus.

The administration of kainic acid (KA) causes seizures and produces neurodegeneration in hippocampal CA3 pyramidal cells. The present study investigated a possible role of acupuncture in reducing hippocampal cell death and inflammatory events, using a mouse model of kainic acid-induced epilepsy. Male C57BL/6 mice received acupuncture treatments at acupoint HT8 or in the tail area bilaterally once a day for 2 days and again immediately after an intraperitoneal injection of KA (30 mg/kg). HT8 is located on the palmar surface of the forelimbs, between the fourth and fifth metacarpal bones. Twenty-four hours after the KA injection, neuronal cell survival, the activations of microglia and astrocytes, and mRNA expression of two proinflammatory cytokines, interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α), were measured in the hippocampus. Acupuncture stimulation at HT8, but not in the tail area, significantly reduced the KA-induced seizure, neuron death, microglial and astrocyte activations, and IL-1ß mRNA expression in the hippocampus. The acupuncture stimulation also decreased the mRNA expression of TNF-α, but it was not significant. These results indicate that acupuncture at HT8 can inhibit hippocampal cell death and suppress KA-induced inflammatory events, suggesting a possible role for acupuncture in the treatment of epilepsy.

Bee venom protects SH-SY5Y human neuroblastoma cells from 1-methyl-4-phenylpyridinium-induced apoptotic cell death.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by progressive selective loss of dopaminergic neurons in the substantia nigra. Recently, bee venom was reported to protect dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced mice PD model, however, the underlying mechanism is not fully understood. The objective of the present study is to investigate the neuroprotective mechanism of bee venom against Parkinsonian toxin, 1-methyl-4-phenylpyridine (MPP(+)), in SH-SY5Y human neuroblastoma cells. Our results revealed that bee venom pretreatment (1-100 ng/ml) increased the cell viability and decreased apoptosis assessed by DNA fragmentation and caspase-3 activity assays in MPP(+)-induced cytotoxicity in SH-SY5Y cells. Bee venom increased the anti-apoptotic Bcl-2 expression and decreased the pro-apoptotic Bax, cleaved PARP expressions. In addition, bee venom prevented the MPP(+)-induced suppression of Akt phosphorylation, and the neuroprotective effect of bee venom against MPP(+)-induced cytotoxicity was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. These results suggest that the anti-apoptotic effect of bee venom is mediated by the cell survival signaling, the PI3K/Akt pathway. These results provide new evidence for elucidating the mechanism of neuroprotection of bee venom against PD.

Phosphatidylinositol 3-kinase/Akt signaling pathway mediates acupuncture-induced dopaminergic neuron protection and motor function improvement in a mouse model of Parkinson's disease.

It has been reported that acupuncture treatment reduced dopaminergic neuron degeneration in Parkinson's disease (PD) models. However, the mechanistic pathways underlying, such neuroprotection, are poorly understood. Here, we investigated the effects and the underlying mechanism of acupuncture in a mouse model of PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). First, we observed that MPTP-induced impairment of Akt activation, but not MPTP-induced c-Jun activation, was effectively restored by acupuncture treatment in the substantia nigra. Furthermore, we demonstrated for the first time that the brain-specific blockade of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, by intranasal administration of LY294002, a specific inhibitor of PI3K/Akt signaling pathway, significantly blocked acupuncture-induced dopaminergic neuron protection and motor function improvement. Our results provide evidence that PI3K/Akt signaling pathway may play a central role in the mechanism underlying acupuncture-induced benefits in Parkinsonian mice.

Predictive factors for the outcome of nasal septal perforation repair.

OBJECTIVES: The aim of this study was to determine the important predictive factors for successful repair of nasal septal perforation. MATERIALS AND METHODS: In this study, we examined 35 symptomatic patients (27 males and 8 females, aged from 16 to 76 years) with a nasal septal perforation. In order to correlate pre- and intra-operative factors to the respective results, preoperative symptoms, etiologies, size of the perforation, operation methods and postoperative results from the patients were reviewed and analyzed using logistic regression. RESULTS: Nasal obstruction, crust and epistaxis were common preoperative symptoms. In most cases, perforations were observed to evolve after the patients' trauma caused from their previous nasal surgery experience. The overall reperforation rate was 48% and turned out to be associated with both large perforation size and unilateral mucosal flap coverage. However, we found no strong evidence that other factors such as graft materials and medical conditions were related with surgical failure. The surgical operations for our examinees resulted in complete healing of epistaxis and whistling, whereas nasal obstruction and crusting persisted after the surgeries. In addition, symptom improvement was negatively correlated with large perforation size and nasal trauma history including previous nasal surgeries. CONCLUSION: Precise and complete coverage with bilateral flaps might be the most important factor for successful closure in a septal perforation. Moreover, both trauma history and large perforation size might be at risk for persistent symptoms after septal perforation repair.

Cigarette smoking increases risk of recurrence for sinonasal inverted papilloma.

BACKGROUND: Sinonasal inverted papilloma (IP) is a neoplasm in the nasal cavity, characterized by its local aggressiveness and tendency to cause malignancy. Despite the frequent recurrence of IP, few studies have reported the effects of situational parameters including smoking on the recurrence rate of IP. This study was performed to evaluate clinical and environmental factors including smoking that can predict neoplasm recurrence after surgery in patients with IP. METHODS: This study was conducted retrospectively on 132 patients who were diagnosed with IP between November 1985 and September 2007. The study focused on the risk factors of recurrence, such as smoking behaviors, diabetes mellitus (DM), hypertension (HTN), allergic rhinitis (AR), the sites of tumor origin and involvement, neoplasm staging, and the surgical method. The age of the patients ranged from 22 to 85 years, and among the 132 patients, 39 patients were smokers (29.5%), 17 (13.3%) with DM, 31 (24.4%) with HTN, and 11 (9.3%) with AR. RESULTS: The recurrence rate showed great disparity between the groups of smokers and nonsmokers: 28.2% of smokers suffered recurrence compared with 10.7% recurrence from the nonsmoker group. The Krouse stage IV group experienced more frequent recurrence than the stage I, II, and III groups. Some patients in Krouse stage III (5/72, 6.9%) and IV (3/3, 100%) groups underwent malignant transformation of IP. Histories of DM, HTN, and AR did not exert a statistically meaningful influence on the recurrence and malignant transformation. CONCLUSION: The smoking behavior and tumor with extranasal/sinus extension appear to be associated with recurrence of IP after surgical resection.

Acupuncture inhibits kainic Acid-induced hippocampal cell death in mice.

We examined whether acupuncture can reduce both the incidence of seizures and hippocampal cell death using a mouse model of kainic acid (KA)-induced epilepsy. ICR mice were given acupuncture once a day at acupoint HT8 (sobu) bilaterally during 2 days before KA injection. After an intracerebroventricular injection of 0.1 microg of KA, acupuncture treatment was subsequently administered once more (total 3 times), and the degree of seizure was observed for 20 min. Three hours after injection, the survival of neuronal cells and the expressions of c-Fos, c-Jun, and glutamate decarboxylase (GAD)-67 in the CA1 and CA3 were determined using immunohistochemistry and Western blotting techniques. Acupuncture reduced the severity of the KA-induced epileptic seizure and the rate of neural cell death, and it also decreased the expressions of c-Fos and c-Jun induced by KA in the hippocampus. Furthermore, acupuncture increased GAD-67 expressions in the same areas. These results demonstrated that it could inhibit the KA-induced epileptic seizure and hippocampal cell death by increasing GAD-67 expressions.