2,3-Dihydrosorbicillin and chrysopanol stimulate insulin secretion in INS-1 cells.

Pancreatic ß-cell function and insulin secretion are important in antidiabetic drug development. In an effort to discover small molecules to regulate insulin secretion, an endophytic fungus, Penicillium sp. SSP-1CLG, was selected for chemical investigation. Large scale cultures of the strain followed by extraction and chromatographic analysis led to the isolation of 10 anthraquinone and alkaloid-type compounds. The isolated compounds were identified by comprehensive analysis of NMR, MS, and ECD data. The effect of compounds 1-10 on insulin secretion in INS-1 cells was investigated. 2,3-Dihydrosorbicillin (1), chrysophanol (2), and glandicolin B (10) at non-cytotoxic concentrations resulted in an increase of glucose-stimulated insulin secretion (GSIS) in rat INS-1 pancreatic ß-cells. Furthermore, we investigated the signaling pathway involved in 2,3-dihydrosorbicillin (1) and chrysophanol (2) action in the activation of peroxisome proliferator-activated receptor γ (PPARγ), pancreatic and duodenal homeobox-1 (PDX-1), insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and Akt. Treatment of INS-1 cells with 2,3-dihydrosorbicillin (1) and chrysophanol (2) increased the expression of these proteins. Our findings indicate that 2,3-dihydrosorbicillin and chrysophanol may play roles in the regulation of insulin secretion in pancreatic ß-cells, at least in part, by targeting PPARγ and PDX-1 via the IRS-2/PI3K/Akt signaling pathway.

In Vitro Estrogenic and Breast Cancer Inhibitory Activities of Chemical Constituents Isolated from Rheum undulatum L.

We investigated the estrogenic and breast cancer inhibitory activities of chemical constituents isolated from Rhei undulati Rhizoma (roots of Rheum undulatum L.), which is used as a laxative, an anti-inflammatory, and an anti-blood stagnation agent. Estrogen-like activity was studied using the well characterized E-screen assay in estrogen receptor (ER)-positive MCF-7 cells. The mechanism underlying the breast cancer inhibitory activity of the compounds was studied using human ER-negative MDA-MB-231 and ER-positive MCF-7 cells. The activation of apoptosis pathway-related proteins was investigated by western blotting, using extracts of R. undulatum prepared in three solvent conditions (EX1, EX2, and EX3). The R. undulatum chemical constituents (compounds 1⁻3) showed estrogen-like activity in the concentration range of 10 to 50 µM, by increasing the proliferation of human ER-positive MCF-7 cells. These effects were attenuated by co-treatment with 100 nM fulvestrant, an ER antagonist. Compounds 1⁻3 decreased the viability of MCF-7 cells in a concentration-dependent manner. Compounds 1 (aloe emodin) and 2 (rhapontigenin) induced mitochondria-independent apoptosis by activating the caspase-8 pathway, whereas the cytotoxic effect of compound 3 (chrysophanol 1-O-ß-d-glucopyranoside) was mediated through the mitochondria-dependent apoptotic pathway.

Highly reliable field electron emitters produced from reproducible damage-free carbon nanotube composite pastes with optimal inorganic fillers.

Highly reliable field electron emitters were developed using a formulation for reproducible damage-free carbon nanotube (CNT) composite pastes with optimal inorganic fillers and a ball-milling method. We carefully controlled the ball-milling sequence and time to avoid any damage to the CNTs, which incorporated fillers that were fully dispersed as paste constituents. The field electron emitters fabricated by printing the CNT pastes were found to exhibit almost perfect adhesion of the CNT emitters to the cathode, along with good uniformity and reproducibility. A high field enhancement factor of around 10,000 was achieved from the CNT field emitters developed. By selecting nano-sized metal alloys and oxides and using the same formulation sequence, we also developed reliable field emitters that could survive high-temperature post processing. These field emitters had high durability to post vacuum annealing at 950 °C, guaranteeing survival of the brazing process used in the sealing of field emission x-ray tubes. We evaluated the field emitters in a triode configuration in the harsh environment of a tiny vacuum-sealed vessel and observed very reliable operation for 30 h at a high current density of 350 mA cm(-2). The CNT pastes and related field emitters that were developed could be usefully applied in reliable field emission devices.

A vacuum-sealed compact x-ray tube based on focused carbon nanotube field-emission electrons.

We report on a fully vacuum-sealed compact x-ray tube based on focused carbon nanotube (CNT) field-emission electrons for various radiography applications. The specially designed two-step brazing process enabled us to accomplish a good vacuum level for the stable and reliable operation of the x-ray tube without any active vacuum pump. Also, the integrated focusing electrodes in the field-emission electron gun focused electron beams from the CNT emitters onto the anode target effectively, giving a small focal spot of around 0.3 mm with a large current of above 50 mA. The active-current control through the cathode electrode of the x-ray tube led a fast digital modulation of x-ray dose with a low voltage of below 5 V. The fabricated compact x-ray tube showed a stable and reliable operation, indicating good maintenance of a vacuum level of below 5 × 10(-6) Torr and the possibility of field-emission x-ray tubes in a stand-alone device without an active pumping system.

Protopanaxadiol ameliorates palmitate-induced lipotoxicity and pancreatic ß-cell dysfunction in INS-1 cells.

Background: Free fatty acid-induced lipotoxicity is considered to play an important role in pancreatic ß-cell dysfunction. The effect of ginsenosides on palmitic acid-induced pancreatic beta-cells cell death and failure of glucose-stimulated secretion of insulin (GSIS) was evaluated in this study. Methods: Enzyme-linked immunosorbent assay kit for a rat insulin was used to quantify glucose-stimulated insulin secretion. Protein expression was examined by western blotting analysis. Nuclear condensation was measured by staining with Hoechst 33342 stain. Apoptotic cell death was assessed by staining with Annexin V. Oil Red O staining was used to measure lipid accumulation. Results: We screened ginsenosides to prevent palmitic acid-induced cell death and impairment of GSIS in INS-1 pancreatic ß-cells and identified protopanaxadiol (PPD) as a potential therapeutic agent. The protection effect of PPD was likely due to a reduction in apoptosis and lipid accumulation. PPD attenuated the palmitic acid-induced increase in the levels of B-cell lymphoma-2-associated X/B-cell lymphoma 2, poly (ADP-ribose) polymerase and cleaved caspase-3. Moreover, PPD prevented palmitic acid-induced impairment of insulin secretion, which was accompanied by an increase in the activation of phosphatidylinositol 3-kinase, peroxisome proliferator-activated receptor γ, insulin receptor substrate-2, serine-threonine kinase, and pancreatic and duodenal homeobox-1. Conclusion: Our results suggest that the protective effect of PPD on lipotoxicity and lipid accumulation induced by palmitic acid in pancreatic ß-cells.

Inhibitory effect of ginsenglactone A from Panax ginseng on the tube formation of human umbilical vein endothelial cells and migration of human ovarian cancer cells.

Background: Here, we aimed to assess the inhibitory effect of a new compound from Panax ginseng on the migration of human ovarian cancer cells and tube formation of human umbilical vein endothelial cells (HUVECs). Methods: A new compound, ginsenglactone A (1), was isolated from ginseng roots, together with seven known compounds (2-8). Spectroscopic data were used to elucidate the chemical structure of 1. The tubular structure formation in HUVECs was assessed by Mayer's hematoxylin staining. The migration of A2780 cells was evaluated using the scratch wound healing assay. Results: HUVECs treated with 1 had the statistically significant decrease in tubular structure formation compared to the HUVECs treated with compounds 2-8. This effect was enhanced by co-treatment with inhibitors for phosphatidylinositol 3-kinase (PI3K) (LY294002) and extracellular signal-regulated kinase (ERK) (U0126). Treatment with 1 decreased the expression of phosphorylation of ERK, PI3K, vascular endothelial growth factor receptor2 (VEGFR2), Akt, and mammalian target of rapamycin (mTOR). In addition, the ability of A2780 cells to cover the scratched area were also decreased. This effect was enhanced by co-treatment with U0126. Lastly, treatment with 1 decreased the phosphorylation of ERK, matrix metalloproteinase-9 (MMP-9), and MMP-2. Conclusion: These results suggest that ginsenglactone A is a potential inhibitor of HUVEC tubular structure formation and A2780 cellular migration, which may be helpful for understanding its anticancer mechanism.

Suppressive Effects of Flavonoids on Macrophage-Associated Adipocyte Inflammation in a Differentiated Murine Preadipocyte 3T3-L1 Cells Co-Cultured with a Murine Macrophage RAW264.7 Cells.

The suppressive effects of flavonoids on macrophage-associated adipocyte inflammation in a differentiated murine preadipocyte cell line (3T3-L1) co-cultured with a murine macrophage cell line (RAW264.7) were evaluated. Extracellular lipid accumulation was investigated via Oil Red O staining. The expression levels of adipogenesis- and inflammation-associated proteins, including CCAAT/enhancer-binding protein (C/EBP)-α, inducible nitric oxide synthase (iNOS), C/EBPß, peroxisome proliferator-activated receptor γ (PPARγ), and cyclooxygenase-2 (COX-2), were determined via Western blotting. Proinflammatory cytokines, including monocyte chemoattractant protein 1 (MCP-1) and interleukin-6 (IL-6), were assessed using enzyme-linked immunosorbent assay kits. We found that silybin, formononetin, and diosmetin inhibited lipid accumulation and production of proinflammatory cytokines in the co-cultures of 3T3-L1 and RAW264.7 cells. Moreover, they inhibited the protein expression of PPARγ, C/EBPα, COX-2, C/EBPß, and iNOS in the co-cultures of 3T3-L1 and RAW264.7 cells. These data support that silybin, formononetin, and diosmetin inhibit macrophage-associated adipocyte inflammation and lipid accumulation.

Molecular Mechanism of Cinnamomum cassia against Gastric Damage and Identification of Active Compounds.

Cinnamomum cassia is a natural product found in plants that has been used as a folk remedy for inflammation. In this study, we investigated the mechanism underlying the anti-inflammatory and antioxidant properties of C. cassia extract (ECC) in lipopolysaccharide (LPS)-induced murine RAW 264.7 cells, in comparison with 4-hydroxycinnamaldehyde, a C. cassia extract component. ECC and 4-hydroxycinnamaldehyde inhibited the production of nitrite oxide in a dose-dependent manner and did not show any change in cellular toxicity when treated with the same dose as that used in the nitrite assay. Moreover, they attenuated ROS accumulation after lipopolysaccharide (LPS) stimulation. ECC and 4-hydroxycinnamaldehyde decreased the mRNA and protein expression levels of inflammatory mediators (iNOS and COX-2) and cytokines such as TNF and IL-6. We also found that ECC and 4-hydroxycinnamaldehyde mitigated the phosphorylation of ERK, JNK, and transcription factors, such as NF-κB and STAT3, suppressing NF-κB nuclear translocation in LPS-activated macrophages. In addition, administration of ECC in a Sprague Dawley rat model of acute gastric injury caused by indomethacin significantly increased the gastric mucus volume. Analysis of serum and tissue levels of inflammatory mediators revealed a significant decrease in serum PGE2 and myeloperoxidase levels and a reduction in gastric iNOS, COX-2, and p65 protein levels. Collectively, these results suggest that ECC has antioxidant and anti-inflammatory effects and is a potential candidate for curing gastritis.

Protective Effect of Osmundacetone against Neurological Cell Death Caused by Oxidative Glutamate Toxicity.

Oxidative stress is one of the main causes of brain cell death in neurological disorders. The use of natural antioxidants to maintain redox homeostasis contributes to alleviating neurodegeneration. Glutamate is an excitatory neurotransmitter that plays a critical role in many brain functions. However, excessive glutamate release induces excitotoxicity and oxidative stress, leading to programmed cell death. Our study aimed to evaluate the effect of osmundacetone (OAC), isolated from Elsholtzia ciliata (Thunb.) Hylander, against glutamate-induced oxidative toxicity in HT22 hippocampal cells. The effect of OAC treatment on excess reactive oxygen species (ROS), intracellular calcium levels, chromatin condensation, apoptosis, and the expression level of oxidative stress-related proteins was evaluated. OAC showed a neuroprotective effect against glutamate toxicity at a concentration of 2 µM. By diminishing the accumulation of ROS, as well as stimulating the expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), OAC triggered the self-defense mechanism in neuronal cells. The anti-apoptotic effect of OAC was demonstrated through its inhibition of chromatin condensation, calcium accumulation, and reduction of apoptotic cells. OAC significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 kinases. Thus, OAC could be a potential agent for supportive treatment of neurodegenerative diseases.

Efficacy of Alpinumisoflavone Isolated from Maclura tricuspidata Fruit in Tumor Necrosis Factor-α-Induced Damage of Human Dermal Fibroblasts.

The skin is an important organ in the human body that protects the body from environmentally hazardous substances. Reactive oxygen species (ROS) cause inflammatory reactions and degradation of the extracellular matrix leading to skin aging and various cutaneous lesions. This study evaluated the potential of isoflavones isolated from Maclura tricuspidata fruit to prevent TNF-α-induced skin inflammation in normal human dermal fibroblasts (HDFs). It focused on alpinumisoflavone (AIF) that suppressed the accumulation of ROS and nitric oxide (NO) in tumor necrosis factor-alpha (TNF-α)-treated HDFs. AIF inhibited the TNF-α-induced increase in matrix metalloproteinase-1, decreased procollagen I α1, and suppressed pro-inflammatory mediators and pro-inflammatory cytokines, including NO synthase, cyclooxygenase-2, interleukin (IL)-1ß, IL-6, and IL-8 that trigger inflammatory responses. AIF inhibited nuclear factor-κB and activating protein 1 mitogen-activated protein kinases that were increased by TNF-α stimulation. These results suggest that AIF may protect skin from aging and various cutaneous lesions.

Evaluation of Anti-Colitis Effect of KM1608 and Biodistribution of Dehydrocostus Lactone in Mice Using Bioimaging Analysis.

Inflammatory bowel disease (IBD) is a chronic relapsing disorder modulated by numerous factors. Recent failures of drugs targeting single factors suggest that multitargeting drugs could be useful for the treatment of IBD. Natural medicines may be an alternative option for the treatment of IBD, owing to the complex nature of the disease. However, most natural medicines have poor in vitro and in vivo translational potential because of inadequate pharmacokinetic study. KM1608, a mixture of the medicinal plants Aucklandia lappa, Terminalia chebula, and Zingiber officinale, was examined for its anti-colitis effects and biodistribution using bioimaging. Dehydrocostus lactone, as a marker compound, was analyzed to assess the biodistribution of KM1608. KM1608 significantly attenuated the disease activity of dextran sodium sulfate-induced colitis in mice and suppressed inflammatory mediators such as myeloperoxidase, proinflammatory cytokines (TNF-α and IL-6), and the Th2-type cytokine IL-4 in the colon. Optical fluorescence imaging revealed that KM1608 was distributed in the intestinal area as a target organ. Collectively, our findings suggest that KM1608 is a potential therapeutic formulation for IBD.

Patterns of Integrative Korean Medicine Practice for Anxiety Disorders: A Survey among Korean Medicine Doctors (KMDs) in Korea.

Anxiety disorder is known as the most common disease among psychiatric disorders. However, many studies have not been conducted in the Korean medicine area. This study explores the current state of anxiety disorder treatments of Korean medicine through a survey research. The survey for Korean medicine doctors (KMDs) on Korean medicine (KM) diagnosis and treatments for anxiety disorder was conducted online from December 21, 2016, to December 29, 2016. The results were divided into two groups, KMDs and Korean medicine neuropsychiatric specialists (KMNPS), and comparatively analyzed. Self-evaluation and counseling were the most common in both diagnostic methods and evaluation of treatment effects, and KMNPS tended to make extensive use of objective indicators. There was no difference in the rate of psychiatric medication use among the patients between KMD and KMNPS. The main reason for patients wanting KM treatment was the tapering cessation of psychiatric medications. The most common treatments were acupuncture, herbal medicine, and moxibustion, in addition to dry cupping in KMD and psychotherapy in KMNPS. The most important factor for treatment was herbal medicine treatment, followed by rapport formation in KMD and patient's temperament in KMNPS. Opinions on various items were presented as treatment barriers, and KMNPS tended to think more importantly about the patient's family problems. For the items to be additionally trained in the future, KMD chose the diagnostic tools and KMNPS chose psychotherapies. This study is the first study to analyze the clinical patterns for anxiety disorder in KMDs. KMD and KMNPS showed similar patterns in the perception, diagnosis, and treatment of anxiety disorders, but KMNPS tended to use objective indicators and psychotherapy more actively. Further clinical studies for the development of clinical guidelines should be additionally required.

Protective Effect of Shikimic Acid against Cisplatin-Induced Renal Injury: In Vitro and In Vivo Studies.

Nephrotoxicity is a serious side effect of cisplatin, which is one of the most frequently used drugs for cancer treatment. This study aimed to assess the renoprotective effect of Artemisia absinthium extract and its bioactive compound (shikimic acid) against cisplatin-induced renal injury. An in vitro assay was performed in kidney tubular epithelial cells (LLC-PK1) with 50, 100, and 200 µg/mL A. absinthium extract and 25 and 50 µM shikimic acid, and cytotoxicity was induced by 25 µM cisplatin. BALB/c mice (6 weeks old) were injected with 16 mg/kg cisplatin once and orally administered 25 and 50 mg/kg shikimic acid daily for 4 days. The results showed that the A. absinthium extract reversed the decrease in renal cell viability induced by cisplatin, whereas it decreased the reactive oxidative stress accumulation and apoptosis in LLC-PK1 cells. Shikimic acid also reversed the effect on cell viability but decreased oxidative stress and apoptosis in renal cells compared with the levels in the cisplatin-treated group. Furthermore, shikimic acid protected against kidney injury in cisplatin-treated mice by reducing serum creatinine levels. The protective effect of shikimic acid against cisplatin-mediated kidney injury was confirmed by the recovery of histological kidney injury in cisplatin-treated mice. To the best of our knowledge, this study is the first report on the nephroprotective effect of A. absinthium extract and its mechanism of action against cisplatin-induced renal injury.

Unique Triterpenoid of Jujube Root Protects Cisplatin-induced Damage in Kidney Epithelial LLC-PK1 Cells via Autophagy Regulation.

Chronic exposure to cisplatin is associated with irreversible kidney impairment. In this present study, we explored the protective effects of 3-dehydroxyceanothetric acid 2-methyl ester (3DC2ME) isolated from roots of jujube (Ziziphus jujuba, Rhamnaceae) against cisplatin-induced damage in vitro. In kidney epithelial LLC-PK1 cells, western blotting and staining with specific autophagy epifluorescent dye CytoID were used to determine the molecular pathways involving autophagy. Treatment with 3DC2ME reduced the increased Cyto-ID-stained autophagic vesicles and reversed the protein expressions of 5' AMP-activated protein kinase subunit ß-1 (AMPK)/mammalian target of rapamycin (mTOR)-dependent signaling pathway in cisplatin-induced cell death. Additionally, treatment with autophagy inhibitor 3-methyladenine (3-MA) and with or without 3DC2ME attenuated the cisplatin-induced apoptosis. Although further research is necessary to substantiate the effects, we evaluated the potential mechanism of action of 3DC2ME as an adjuvant for cancer patients.

Enhanced photo-assisted electrical gating in vanadium dioxide based on saturation-induced gain modulation of erbium-doped fiber amplifier.

By incorporating saturation-induced gain modulation of an erbium-doped fiber amplifier (EDFA), we have demonstrated a high-speed photo-assisted electrical gating with considerably enhanced switching characteristics in a two-terminal device fabricated by using vanadium dioxide thin film. The gating operation was performed by illuminating the output light of the EDFA, whose transient gain was modulated by adjusting the chopping frequency of the input light down to 1 kHz, onto the device. In the proposed gating scheme, gated signals with a temporal duration of approximately 40 micros were successively generated at a repetition rate of 1 kHz.

Induced high-temperature ferromagnetism by structural phase transitions in strained antiferromagnetic γ-Fe50Mn50 epitaxial films.

Strain effects in epitaxial films can substantially enhance individual functional properties or induce properties which do not exist in corresponding bulk materials. The bcc α-Fe50Mn50 films are a ferromagnetic with a Curie temperature between 650 K and 750 K, which do not exist in nature can be manipulated through the tensile strain. In this study, γ-Fe50Mn50 epitaxial films grown on GaAs(001) using molecular beam epitaxy are found to structural transition from the face-centered-cubic (fcc, a = 0.327 nm) γ-phase to the body-centered-cubic (bcc, a = 0.889 nm) α-phase. For α-Fe50Mn50 epitaxial films, ferromagnetism is accompanied by structural phase transition due to the tensile strain induced by the differences of the thermal expansion between the film and the substrate. Moreover, by realizing in epitaxial films with fcc structure a tensile strain state, phase transitions were introduced Fe-Mn alloy system with bcc structure. These findings are of fundamental importance to understanding the mechanism of phase transition and properties of epitaxial CuAu-I type antiferromagnetic alloy thin films under strain.

Identification and Isolation of Active Compounds from Astragalus membranaceus that Improve Insulin Secretion by Regulating Pancreatic ß-Cell Metabolism.

In type 2 diabetes (T2D), insufficient secretion of insulin from the pancreatic ß-cells contributes to high blood glucose levels, associated with metabolic dysregulation. Interest in natural products to complement or replace existing antidiabetic medications has increased. In this study, we examined the effect of Astragalus membranaceus extract (ASME) and its compounds 1-9 on glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells. ASME and compounds 1-9 isolated from A. membranaceus stimulated insulin secretion in INS-1 cells without inducing cytotoxicity. A further experiment showed that compounds 2, 3, and 5 enhanced the phosphorylation of total insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and Akt, and activated pancreatic and duodenal homeobox-1 (PDX-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ), which are associated with ß-cell function and insulin secretion. The data suggest that two isoflavonoids (2 and 3) and a nucleoside (compound 5), isolated from the roots of A. membranaceus, have the potential to improve insulin secretion in ß-cells, representing the first step towards the development of potent antidiabetic drugs.

Protocol for a systematic review and meta-analysis of the efficacy of acupuncture and electroacupuncture against chemotherapy-induced peripheral neuropathy.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) occurs in approximately 30% to 40% of patients who receive chemotherapy; however, standardized treatment for CIPN has not yet been developed. Acupuncture is widely used to treat CIPN in Korea, but its efficacy has not been investigated. The purpose of this study is to review the current literature on the efficacy of acupuncture and electroacupuncture (EA) in treating CIPN. MATERIALS AND METHODS: We will perform a literature review using the relevant databases, including MEDLINE, Embase, the Allied and Complementary Medicine Databases (AMED), and China National Knowledge Infrastructure (CNKI), as well as Korean databases, including the National Digital Science Library (NDSL), Oriental Medicine Advanced Searching Integrated System (OASIS), DBpia, and Korean studies Information Service System (KISS). Randomized controlled trials describing treatment of CIPN symptoms with acupuncture or EA will be included. The primary outcomes will be scores on a visual analog scale and a numeric rating scale for neuropathic pain. We will also assess the risk of bias by evaluating the available studies using the tools of the Cochrane Collaboration and carry out a meta-analysis. ETHICS AND DISSEMINATION: Ethical approvals and patient consent are not necessary because the meta-analysis will be based on published research. We will submit our meta-analysis to a peer-reviewed journal for publication. PROSPERO REGISTRATION NUMBER: CRD42018111509.

Acupuncture for anxiety: A protocol for a systematic review of controlled trials.

BACKGROUND: Acupuncture has been widely, used in Asian countries since the Yuan Dynasty in China. Moreover, acupuncture has been reported to exhibit anti-allergy effects in many clinical trials. This systematic review will assess the effectiveness, and safety of acupuncture for anxiety treatment. METHODS: Eleven databases, including Asian databases, will be searched for studies conducted through December in the year 2017. We will include randomized controlled trials (RCTs) assessing acupuncture for anxiety. The risk of bias will be evaluated using the Cochrane risk of bias assessment tool, and confidence in the cumulative evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) instrument. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal. It will also be disseminated electronically, and in print. The review will be updated to inform, and guide healthcare practices. REGISTRATION NUMBER: PROSPERO 2018 under number CRD42018080034.

Curcuzedoalide contributes to the cytotoxicity of Curcuma zedoaria rhizomes against human gastric cancer AGS cells through induction of apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Curcuma zedoaria Roscoe (Zingiberaceae), also known as white turmeric or zedoaria, has been used in Ayurveda and traditional Chinese medicine to treat various cancers, and it possesses several sesquiterpenoid compounds. OBJECTIVE: This study aimed to evaluate the therapeutic effects of a methanolic (MeOH) extract of C. zedoaria rhizomes, as well as its active constituents, against gastric cancer, which is a frequently diagnosed cancer in South Korea. MATERIALS AND METHODS: Repeated column chromatography, together with semi-preparative HPLC purification, was used to separate the bioactive constituents from the C. zedoaria MeOH extract. The cytotoxic effects of the C. zedoaria MeOH extract and its active compounds were measured in human gastric cancer AGS cells. Expression of proteins related to apoptosis was evaluated using Western blotting analysis. RESULTS: The MeOH extract of C. zedoaria rhizomes exerted a cytotoxic effect on AGS cells (IC50: 96.60 ± 4.87µg/mL). Based on the bioactivity-guided fractionation for antiproliferative activity, a chemical investigation of the MeOH extract led to the isolation of five sesquiterpenes including isoprocurcumenol (1), germacrone (2), curzerenone (3), curcumenol (4), and curcuzedoalide (5). Among these, curcuzedoalide demonstrated the strongest effect in suppressing gastric cancer cell proliferation in a dose-dependent manner with an IC50 value of 125.11±2.77µM. Western blotting analysis showed that curcuzedoalide inhibited AGS human gastric cancer cell viability by activating caspase-8, caspase-9, caspase-3, and PARP, which contributed to apoptotic cell death in AGS human gastric cancer cells. CONCLUSION: These data indicate that curcuzedoalide contributed to the cytotoxicity of C. zedoaria by activating the cleavage of caspases and PARP, which are representative markers for apoptosis. Therefore, curcuzedoalide is a positive candidate for the development of novel chemotherapeutics.