Effects of Korean Red Ginseng (Panax ginseng C.A. Meyer) on Menopausal Symptoms in Premenopausal Women After Gynecologic Cancer Surgery: A Double-Blind, Randomized Controlled Trial.

Objectives: Korean red ginseng (KRG) has been widely used as an alternative medicine to relieve menopausal symptoms. However, there is still a lack of clinical studies showing the effects of KRG on menopausal symptoms after gynecologic cancer surgery. Therefore, the authors investigated the effects of KRG on surgical menopause symptoms in premenopausal women with gynecologic cancer. Design: A double-blind, randomized, placebo-controlled clinical trial was conducted. Settings/Location: The study was performed at Severance Hospital at the Yonsei University College of Medicine in Seoul, Korea. Subjects: Fifty-five premenopausal women diagnosed with gynecologic cancer were enrolled in the study. Interventions: Patients were randomly assigned to a KRG (n = 29) or a placebo control group (n = 26). Subjects were administered either KRG (a total of 3 g per day) or placebo supplements for 12 weeks. Outcome measures: Patients' physical measurements (height, weight, and blood pressure) and blood samples (lipid profiles, hormone profiles, biochemical profiles, and neutrophil-to-lymphocyte ratio) at baseline and at 12 weeks were compared. Changes in menopausal symptoms based on the Menopause Rating Scale (MRS) were also compared between these two time points and two groups. Results: After 12 weeks, the MRS score was significantly reduced in each group (p = 0.001 and p = 0.001, respectively), but there were no significant differences between the two groups (p = 0.661). No adverse events were observed in either group. After comparing 11 MRS symptoms between the two groups, the KRG group seemed to be superior to the placebo group on the subscale of sexual complaints (p < 0.05). Conclusions: Through the study, KRG did not show absolute relief of surgical menopause symptoms in premenopausal women after gynecologic cancer surgery. However, the study did demonstrate that KRG may be effective in reducing sexual complaints. Further studies are required to evaluate the long-term effects of KRG in a larger patient population.

Incorporation of paclitaxel-based hyperthermic intraperitoneal chemotherapy in patients with advanced-stage ovarian cancer treated with neoadjuvant chemotherapy followed by interval debulking surgery: a protocol-based pilot study.

OBJECTIVES: We conducted a protocol-based cohort study to evaluate the outcomes of interval debulking surgery (IDS) followed by paclitaxel-based hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of advanced-stage ovarian cancer. METHODS: From October 2015 to May 2018, 65 patients with stages IIIC-IV ovarian cancer were treated according to the study protocol. HIPEC was performed with paclitaxel (175 mg/m²) for 90 minutes, only in cases of optimal cytoreduction. RESULTS: Of 65 patients, 40 (61.5%) patients underwent neoadjuvant chemotherapy (NAC), 34 (52.3%) patients had a high tumor burden with a Fagotti score ≥8 at diagnostic laparoscopy, and 6 (9.2%) had definite stage IV metastasis and/or poor performance status before NAC. Twenty-seven (41.5%) patients underwent IDS followed by HIPEC. The mean duration of IDS with HIPEC was 543.8 (range, 277.0-915.0) minutes. Grade III/IV perioperative complications occurred in 7.4% (n=2)/3.7% (n=1) of patients and no cases of mortality were reported within 30 days postoperatively. The median progression-free survival was 21.3 months, and the median overall survival was not reached for those who received HIPEC. CONCLUSIONS: According to our study protocol, IDS followed by paclitaxel-based HIPEC as a first-line treatment appears to be feasible and safe for the treatment of advanced-stage ovarian cancer. Further evaluations of this procedure are required to assess its survival benefits.

Impact of increased utilization of neoadjuvant chemotherapy on survival in patients with advanced ovarian cancer: experience from a comprehensive cancer center.

OBJECTIVE: The choice between primary debulking surgery (PDS) and neoadjuvant chemotherapy (NAC) in advanced ovarian cancer remains controversial. We evaluated NAC use in our center before and after results from a randomized trial were published, with the aim to determine the impact of changes in the neoadjuvant strategy on survival in advanced-stage ovarian cancer. METHODS: We retrospectively investigated the clinical course of 435 patients with ovarian, tubal, or peritoneal carcinoma (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV). According to the period of treatment, we stratified patients into a control group (n=216; diagnosed between 2006 and 2010; 83.8% underwent PDS) and a study group (n=219; diagnosed between 2011 and 2014; 48.9% received NAC followed by interval debulking surgery [IDS]). RESULTS: There were no between-group differences in age, body mass index, histology findings, or tumor grade. Compared to patients in the control group, those in the study group were more likely to receive NAC followed by IDS as first-line treatment (48.9% vs. 16.2%; p<0.001), cytoreductive surgery to no-residual disease (21.5% vs. 10.2%; p<0.001), or radical surgery (57.5% vs. 35.6%; p<0.001). However, there was no between-group difference in postoperative morbidity. Kaplan-Meier analysis showed no between-group differences in progression-free or overall survival (p=0.449 and 0.952, respectively). CONCLUSION: NAC incorporation resulted in increased optimal cytoreduction rates although no significant differences in survival outcomes were noted. NAC is advantageous for patients with high perioperative morbidity or unresectable disease.

Piperolein B and piperchabamide D isolated from black pepper (Piper nigrum L.) as larvicidal compounds against the diamondback moth (Plutella xylostella).

BACKGROUND: There is growing demand for the development of alternative pest control agents that are effective as well as non-toxic to human health and the environment. Plant protection products derived from plant extracts are an eco-friendly alternative to synthetic pesticides. The aim of this study was to identify larvicidal compounds isolated from a natural source against Plutella xylostella L. In a larvicidal activity assay, several solvent fractions from the methanol extract of Piper nigrum L. fruit showed larvicidal effects against P. xylostella. RESULTS: Screening results indicated that chloroform extract was the most effective against P. xylostella larvae. Two compounds with insecticidal activity in the chloroform fraction were identified as piperolein B and piperchabamide D by spectroscopic analyses, including mass spectrometry and NMR, and by comparison to published data. At applications of 0.1 mg mL-1 concentration, piperolein B and piperchabamide D, respectively, induced 96.7 ± 5.8% and 79.2 ± 16.6% mortality rates of P. xylostella larvae 4 days post-application. CONCLUSION: Our results demonstrate that piperolein B and piperchabamide D isolated from P. nigrum are the major constituents of the extract demonstrating insecticidal properties for the control of P. xylostella larvae. These plant-derived compounds should become useful alternatives to synthetic chemicals after studying their insecticidal mechanisms. © 2017 Society of Chemical Industry.

Inhibition of the Calcineurin Pathway by Two Flavonoids Isolated from Miliusa sinensis Finet & Gagnep.

In order to discover plant-derived signaling pathway inhibitors with antifungal properties, a two-component screening system utilizing the calcineurin and Hog1 mitogen-activated protein kinase pathways responsible for the virulence networks of Cryptococcus neoformans was employed, owing to the counter-regulatory actions of these pathways. Of the 1,000 plant extracts tested, two bioactive compounds from Miliusa sinensis were found to act specifically on the calcineurin pathway of C. neoformans. These compounds, identified as pashanone and 5-hydroxy-6,7-dimethoxyflavanone, exhibited potent antifungal activities against various human pathogenic fungi with minimum inhibitory concentration values ranging from 4.0 to >128 µg/ml.

Pre-clinical in vitro and in vivo safety evaluation of Cimicifuga heracleifolia.

The rhizomes of Cimicifuga species, including Cimicifuga heracleifolia (CH), have been widely used as antipyretic, analgesic, and anti-inflammatory agents in oriental countries. However, information regarding its toxicity, especially long-term toxicity and genotoxicity, is limited. Therefore, we performed the subchronic toxicity and genotoxicity assays of the CH extract in accordance with the test guidelines published by the Organization for Economic Cooperation and Development. In a 13-week repeat-dose oral toxicity study, the CH extract did not influence body weight, food/water consumption, mortality, clinical signs, and urinalysis throughout the study. Noteworthy, the CH extract groups exhibited increased liver weights along with serum alanine transaminase activity rise at doses of 667 and 2000 mg/kg in females. No-observed-adverse-effect-level of the CH extract administered orally was concluded to be 2000 mg/kg body weight/day for male rats and 222 mg/kg body weight/day for female rats. The CH extract did not exert a mutagenic or clastogenic effect in Ames test, in vitro chromosome aberration assay and in vivo micronucleus assay. Overall findings of the subchronic toxicity study indicate for the first time that the CH extract may possess hepatotoxic potential in female rats, suggesting that further mechanistic studies should be performed to have more conclusive results on hepatotoxic potential of the CH extract.

Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons.

Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy. However, use of existing electrode based ACC stimulation has not significantly reduced pain, at least in part due to the lack of specificity and likely co-activation of both excitatory and inhibitory neurons. Herein, we report a dramatic reduction of pain behavior in transgenic mice by optogenetic stimulation of the inhibitory neural circuitry of the ACC expressing channelrhodopsin-2. Electrophysiological measurements confirmed that stimulation of ACC inhibitory neurons is associated with decreased neural activity in the ACC. Further, a distinct optogenetic stimulation intensity and frequency-dependent inhibition of spiking activity in the ACC was observed. Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons. These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

Inhibition of the calcineurin pathway by two tannins, chebulagic acid and chebulanin, isolated from Harrisonia abyssinica Oliv.

In order to discover and develop novel signaling inhibitors from plants, a screening system was established targeting the two-component system of Cryptococcus neoformans by using the wild type and a calcineurin mutant of C. neoformans, based on the counter-regulatory action of high-osmolarity glycerol (Hog1) mitogen-activated protein kinase and the calcineurin pathways in C. neoformans. Among 10,000 plant extracts, that from Harrisonia abyssinica Oliv. exhibited the most potent inhibitory activity against C. neoformans var. grubii H99 with fludioxonil. Bioassay-guided fractionation was used to isolate two bioactive compounds from H. abyssinica, and these compounds were identified as chebulagic acid and chebulanin using spectroscopic methods. These compounds specifically inhibited the calcineurin pathway in C. neoformans. Moreover, they exhibited potent antifungal activities against various human pathogenic fungi with minimum inhibitory concentrations ranging from 0.25 to over 64 µg/ml.

Comparative proteomic analysis of advanced serous epithelial ovarian carcinoma: possible predictors of chemoresistant disease.

To identify specific proteins associated with chemotherapeutic responses, we analyzed protein expression patterns in stage IIIc primary serous epithelial ovarian cancer tissues displaying differential responses to first-line postoperative adjuvant chemotherapy. The expression profiles of five chemoresistant tissues [progression-free survival (PFS) ≤12 months] and five chemosensitive tissues (PFS ≥48 months) were analyzed with 2D electrophoresis, and the spot intensities of differentially expressed proteins were quantified. To validate these proteins as markers for chemoresistant disease, we analyzed tissues from an additional 17 patients. All the patients were allocated to the over- or underexpressing group according to protein spot intensity, and survival analysis was performed. In chemoresistant tissues, four proteins (thioredoxin domain containing four, similar to RIKEN cDNA 1700016G05, tubulin α 1A chain, and the pyruvate dehydrogenase E1-ß subunit precursor) were overexpressed, and seven proteins [keratin 1, vitamin D-binding protein, creatine kinase B, annexin V, SH3-containing guanine nucleotide exchange factor (SGEF), tryptophan-aspartate repeat protein-1 (WDR 1), and WDR 1 isoform 1] were underexpressed. The underexpression of keratin 1, creatine kinase B, annexin V, SGEF, WDR1, and WDR1 isoform 1 were significantly correlated with poor overall survival. A combination of keratin 1 and SGEF showed the highest sensitivity of 0.800, specificity of 0.917, PPV of 0.800, and NPV of 0.917 in predicting chemoresistant disease. These proteins may be useful as predictive markers of chemoresistant disease. However, further analyses in large-scale should be performed before they can be considered reliable predictive markers of chemoresistant disease.

The prognostic significance of ERCC1, BRCA1, XRCC1, and betaIII-tubulin expression in patients with non-small cell lung cancer treated by platinum- and taxane-based neoadjuvant chemotherapy and surgical resection.

OBJECTIVES: The DNA repair pathway and isotype composition of beta-tubulin are known to be associated with resistance to platinum- and taxane-based chemotherapy, respectively. The aim of this study was to identify the clinical significance of excision repair cross-complementation 1 (ERCC1), breast cancer susceptibility gene 1 (BRCA1), X-ray repair cross-complementation 1 (XRCC1) and betaIII-tubulin on the chemotherapy response and overall survival in patients with non-small cell lung cancer (NSCLC) who received neoadjuvant chemotherapy. METHODS: Protein expression profiles were evaluated by immunohistochemistry on surgical specimens of 82 NSCLC patients who underwent platinum- and taxane-based neoadjuvant chemotherapy. The expression levels of proteins were measured semi-quantitatively and the correlation with tumor responses, pathologic cell death rate and survival were evaluated. RESULTS: There were 73 (89.0%) clinical stage III patients. Lobectomy, bilobectomy, and pneumonectomy were performed in 54 (65.0%), 11 (13.4%), and 17 (20.7%) patients, respectively. There was no correlation between clinical response and protein expression. The expression levels of ERCC1, BRCA1, and XRCC1 increased proportionally to the cell death rate (p<0.05); however, betaIII-tubulin expression did not correlate with cell viability. Multivariate analysis demonstrated that early pathologic stage, adjuvant chemotherapy, high ERCC1 and low betaIII-tubulin expression were good prognostic factors for overall survival (p<0.05). CONCLUSIONS: The inverse correlation between DNA repair proteins and cell viability suggests that these protein expression levels can be markers for chemotherapy responsiveness. However, only ERCC1 and betaIII-tubulin were prognostic factors after platinum- and taxane-based neoadjuvant chemotherapy following surgical resection.

Obovatols, new chitin synthase 2 inhibitors of Saccharomyces cerevisiae from Magnolia obovata.

In the course of the search for inhibitors of ScCHS2 from natural sources, we have isolated a new type of chitin synthase 2 inhibitor, obovatol, which has a biphenol skeleton, from Magnolia obovata. Obovatol inhibited chitin synthase 2 activity of Saccharomyces cerevisiae with an IC(50) of 38 microM. Its derivative, tetrahydroobovatol, inhibited chitin synthase 2 activity under the same conditions with an IC(50) of 59 microM. These compounds exhibited no inhibitory activity for ScCHS3, and showed less inhibitory activity for chitin synthase 1 than for chitin synthase 2 (IC(50) > 1 mM). These results indicated that obovatol and tetrahydroobovatol are specific inhibitors of ScCHS2. They also inhibited CaCHS1, which is structurally and functionally analogous to ScCHS2, with similar IC(50)s to ScCHS2 (IC(50) 28 and 51 microM, respectively). The compounds exhibited mixed competitive inhibition with respect to UDP-N-acetyl-D-glucosamine as substrate [inhibition constant (K(i)) 21.8 microM for obovatol and 23.1 microM for tetrahydroobovatol]. Furthermore, they showed antifungal activities against various pathogenic fungi, with a particularly strong inhibitory activity against Cryptococcus neoformans (MIC 7.8 mg/L). The results indicate that obovatol and tetrahydroobovatol can potentially serve as antifungal agents.