Publications by authors named "Kaoru Umehara"

42 Publications

Association between ionized magnesium and postoperative shivering.

J Anesth 2021 Mar 7. Epub 2021 Mar 7.

Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Purpose: Ionized magnesium (iMg) is considered to be the biologically active fraction of circulating total serum Mg (tMg). However, only the relationship between tMg and postoperative shivering has been studied. To our knowledge, hitherto no clinical studies have investigated the association between serum ionized magnesium concentration ([iMg]) and postoperative shivering. Therefore, we aimed to retrospectively examine this association, focusing on hypomagnesemia and depletion of [iMg].

Methods: This retrospective study involved 421 patients who underwent pancreaticoduodenectomy under general anesthesia at our center from December 2012 to September 2019. Logistic regression analysis was performed to estimate the odds ratio (OR) for the incidence of postoperative shivering.

Results: Postoperative shivering developed in 111 out of 421 patients. The post-surgical concentration of [iMg] was significantly associated with postoperative shivering in the non-adjusted model, but not in the multivariable-adjusted model. In multivariable-adjusted analysis, progressive decrease of [iMg] by 0.1 mmol/L significantly increased the risk of postoperative shivering (OR: 1.64, 95% CI 1.02-2.64, p = 0.04). The multivariable-adjusted OR for postoperative shivering was 3.65 (95% CI 1.25-13.55, p = 0.02) in subjects with post-surgical [iMg] less than 0.6 mmol/L and decrease in [iMg] during surgery compared with those with post-surgical [iMg] more than 0.6 mmol/L and constant or increased of [iMg] during surgery.

Conclusion: A decrease in the [iMg] during surgery was significantly associated with postoperative shivering. Subjects who had an [iMg] lower than 0.6 mmol/L post-surgery and decreased [iMg] during surgery had a significantly higher risk of postoperative shivering. Intraoperative depletion of [iMg] was significantly associated with shivering.
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http://dx.doi.org/10.1007/s00540-021-02914-yDOI Listing
March 2021

Evaluation of postoperative kidney function after administration of 6% hydroxyethyl starch during living-donor nephrectomy for transplantation.

J Anesth 2021 Feb 14;35(1):59-67. Epub 2020 Oct 14.

Department of Anesthesiology and Critical Care Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Purpose: We aimed to investigate whether 6% HES 130/0.4 was associated with postoperative reduction of estimated glomerular filtration rate (eGFR) in donor patients who underwent nephrectomy for living kidney transplantation.

Methods: This retrospective study included 213 living kidney transplant donors treated at Kyushu University Hospital in Japan from April 2014 to March 2018. Patients who were administered 6% HES 130/0.4 were allocated in the HES group (n = 108), and those who were not were allocated in the control group (n = 105). The postoperative decrements in estimated glomerular filtration rates (eGFRs) from preoperative values were calculated on postoperative days (PODs) 1, 3, and 14. Decline in kidney function (DKF) according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification were analyzed by multivariable-adjusted ordinal logistic regression to estimate odds ratios (ORs) for postoperative DKF.

Results: In HES group, administration amount of HES was median 9.4 [interquartile range: 8.2-14.3] ml/kg. Postoperative decrements in eGFR were similar in the control and HES groups on POD 1 (control group: mean 32.0 vs. HES group: 33.0 mL/min/1.73 m), same as POD 3 (21.1 vs. 22.4 mL/min/1.73 m) and POD 14 (26.0 vs. 25.9 mL/min/1.73 m), even after adjusting for confounding factors. The multivariable-adjusted ORs for postoperative DKF did not significantly increase in the HES group on POD 1 (OR: 0.88), POD 3 (OR: 0.96), and POD 14 (OR: 0.52) compared with the control group.

Conclusion: Six percent HES 130/0.4 is not associated with postoperative renal dysfunction in donor patients undergoing nephrectomy for kidney transplantation.
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http://dx.doi.org/10.1007/s00540-020-02862-zDOI Listing
February 2021

Incidence of postoperative shivering decreased with the use of acetaminophen: a propensity score matching analysis.

J Anesth 2020 06 21;34(3):383-389. Epub 2020 Mar 21.

Department of Anesthesiology and Critical Care Medicine, Kyushu University Graduate School of Medicine, Fukuoka, Japan.

Objectives: The incidence of postoperative shivering is known to be inversely associated with core body temperature. However, previous studies have pointed out that the threshold of shivering could be affected by peripheral temperature or anesthetic agents. These reports pointed specific drugs, though, anesthesia techniques have since advanced considerably. This study aimed to investigate factors associated with postoperative shivering in the context of the current body warming practice.

Methods: The institutional clinical research ethics committee of Kyushu University approved the study protocol (IRB Clinical Research number 2019-233). This retrospective study involved 340 patients who had undergone radical surgery for gynecological cancer treatment under general anesthesia at our center from December 2012 to June 2019. Logistic regression analysis was performed to estimate the odds ratio (OR) for the incidence of postoperative shivering.

Results: Postoperative shivering developed in 109 out of 340 patients. After multivariate-adjusted logistic regression, the incidences of postoperative shivering decreased significantly with increasing patient age (OR = 0.96; 95%CI: 0.93-0.98; p = 0.0004). Volatile anesthesia technique was less inclined to shiver after surgery than TIVA (OR = 0.55; 95%CI: 0.30-0.99; p = 0.04). Acetaminophen was much less used in the shivering group than in the non-shivering group (OR = 0.49; 95%CI: 0.25-0.94; p = 0.03).

Conclusions: This study indicated that the development of shivering in patients receiving the anesthetic technique currently used in our hospital was associated with use of acetaminophen or volatile agents, and patient age.
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http://dx.doi.org/10.1007/s00540-020-02763-1DOI Listing
June 2020

Effects of Puerarin on the Ovariectomy-Induced Depressive-Like Behavior in ICR Mice and Its Possible Mechanism of Action.

Molecules 2019 Dec 13;24(24). Epub 2019 Dec 13.

Division of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.

Daily treatment of ovariectomized (OVX) ICR mice with puerarin, a glycosyl isoflavone isolated from the root bark of var. , and 17β-estradiol attenuated ovariectomy-induced depression-like behavior, as indicated by a decrease in immobility times in the tail suspension test (TST) and the forced swimming test (FST), an increase in the uterine weight and volume, a decrease in serum corticosterone levels, and dose-dependently normalized the downregulated transcription of the brain-derived neurotrophic factor (BDNF) and estrogen receptor (Erβ and Erα) mRNAs. Like 17β-estradiol, puerarin also inhibited ovariectomy-induced suppression of neurogenesis in the dentate gyrus of the hippocampus (increased the number of doublecortin (DCX)-immunosuppressive cells). These results suggest that puerarin exerts antidepressant-like effects in OVX animals, possibly by attenuating the OVX-induced hyperactivation of the HPA axis and/or normalizing the downregulated transcription of BDNF and ER mRNA in the brain.
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http://dx.doi.org/10.3390/molecules24244569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943479PMC
December 2019

Serum 1,25-Dihydroxyvitamin D Level Is Inappropriate for Use in Prospective Studies of Cancer Incidence - Reply.

Circ J 2018 07 11;82(8):2216. Epub 2018 Jul 11.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University.

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http://dx.doi.org/10.1253/circj.CJ-17-0909DOI Listing
July 2018

Correlation between the Potency of Flavonoids on Mushroom Tyrosinase Inhibitory Activity and Melanin Synthesis in Melanocytes.

Molecules 2018 06 9;23(6). Epub 2018 Jun 9.

Natural Product Biotechnology Research Unit, Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.

Twenty-seven flavonoids isolated from with vast structural diversity were screened for inhibitory activity against mushroom and murine tyrosinases using l-DOPA as the substrate. Among the flavonoids tested, only four—khrinone (), cajanin (), (3)-3′-hydroxy-8-methoxy vestitol (), and (6a,11a)-3,8-dihydroxy-9-methoxy pterocarpan ()—reacted with mushroom tyrosinase, with IC values of 54.0, 67.9, 67.8, and 16.7 μM, respectively, and only compound showed inhibitory activity against murine tyrosinase. With cell-based assays, only compounds and effectively inhibited melanogenesis in B16-F10 melanoma cells (by 34% and 59%, respectively), at a concentration of 15 μM, without being significantly toxic to the cells. However, the crude extract of and some of the flavonoid constituents appeared to increase melanin production in B16-F10 cells, suggesting that there are flavonoids with both inhibitory and stimulatory melanogenesis in the crude extract. Studies on the correlation between the enzyme-based and cell-based assays showed that only the flavonoids with IC values below 50 μM against mushroom tyrosinase could inhibit the mammalian tyrosinase, and thus, reduce melanogenesis in B16-F10. Flavonoids with the IC values greater than 50 μM, on the other hand, could not inhibit the mammalian tyrosinase, and had either no effect or enhancement of melanogenesis. In conclusion, the tyrosinase enzyme from mushroom is not as selective as the one from mammalian source for the enzyme-based melanogenesis inhibitory screening, and the mammalian cell-based assay appears to be a more reliable model for screening than the enzyme-based one.
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http://dx.doi.org/10.3390/molecules23061403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100075PMC
June 2018

α-Keto tetrahydrofuran lignan glucosides from the Bangladeshi medicinal plant Terminalia citrina inhibit estradiol (E2) induced proliferation in cancer cells.

Phytochemistry 2018 Jan 14;145:161-167. Epub 2017 Nov 14.

School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.

EtOAc extract from the leaves of Terminalia citrina collected in Bangladesh were separated, and seven previously undescribed α-keto tetrahydrofuran lignan glucosides (terminalosides Q to W) were isolated and characterized. NOESY analysis of H NMR spectra and ECD spectroscopic data analysis revealed the absolute stereochemistry of the tetrahydrofuran ring of the isolated constituents as being a (7S,8R,8'S)- configuration in terminalosides Q to U and a (7R,8R,8'S)- configuration in terminalosides V and W. All of the isolated compounds were evaluated for their estrogenic and anti-estrogenic properties using two types of estrogen-responsive human breast cancer cell lines (MCF-7 and T47D). Terminaloside R, which has a dioxymethylene group in its aromatic ring, inhibited 90% of estradiol-enhanced cell proliferation in T47D and MCF-7 cells at concentrations of 0.01 μM and 0.1 μM, respectively. On the other hand, terminaloside T, the analogous compound which has two oxymethyl groups in place of dioxymethylene, suppressed 90% of cell proliferation selectively in T47D cells at a concentration of 0.01 μM. However, terminaloside W, the 7R-stereoisomer of terminaloside R, only showed moderate activity.
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http://dx.doi.org/10.1016/j.phytochem.2017.10.011DOI Listing
January 2018

Naphthalene glycosides in the Thai medicinal plant Diospyros mollis.

J Nat Med 2018 Jan 10;72(1):220-229. Epub 2017 Oct 10.

School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, 422-8526, Japan.

This study evaluated methanol extracts from the leaves and branches of the Thai medicinal plant Diospyros mollis (Ebenaceae). Seven triterpenes and 22 aromatic compounds, including five new compounds, were isolated, and their structures were determined. The new compounds had the following structures: diospyrol glycoside (makluoside A, 1), 8,8'-di-O-6-β-D-apiofuranosyl-β-D-glucopyranosyl-6,6'-dimethyl-2,3'-binaphthalene-1-ol-1',4'- dione (makluoside B, 2), and 3-methyl-1,8- naphthalenediol glycosides (makluosides C-E, 3-5). Makluoside B is the first example of a naphthoquinone glycoside that has both a 3-methyl-1,8-naphthalenediol unit and a 5-hydroxy-7-methyl-1,4-naphthoquinone unit. The hyaluronidase inhibitory activity of the isolates was evaluated, revealing that one of the triterpene derivatives possessed moderate inhibitory activity.
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http://dx.doi.org/10.1007/s11418-017-1134-1DOI Listing
January 2018

Design and synthesis of benzoacridines as estrogenic and anti-estrogenic agents.

Bioorg Med Chem 2017 10 24;25(20):5216-5237. Epub 2017 Aug 24.

Department of Chemistry, Faculty and Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan.

Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERβ (IC < μM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).
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http://dx.doi.org/10.1016/j.bmc.2017.07.067DOI Listing
October 2017

Association Between Serum Vitamin D and All-Cause and Cause-Specific Death in a General Japanese Population - The Hisayama Study.

Circ J 2017 Aug 20;81(9):1315-1321. Epub 2017 Apr 20.

Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University.

Background: Few studies have investigated the association between serum vitamin D levels and mortality in general Asian populations.Methods and Results:We examined the association of serum 1,25-dihydroxyvitamin D (1,25(OH)D) levels with the risk of all-cause and cause-specific death in an average 9.5-year follow-up study of 3,292 community-dwelling Japanese subjects aged ≥40 years (2002-2012). The multivariable-adjusted hazard ratio (HR) for all-cause death increased significantly with lower serum 1,25(OH)D levels (HR 1.54 [95% confidence interval, 1.18-2.01] for the lowest quartile, 1.31 [0.99-1.73] for the 2nd quartile, 0.94 [0.70-1.25] for the 3rd quartile, 1.00 [Ref.] for highest quartile; P for trend <0.001). A similar association was observed for cardiovascular and respiratory infection death (both P for trend <0.01), but not for cancer death or death from other causes. In the stratified analysis, the association between lower serum 1,25(OH)D levels and the risk of respiratory infection death was stronger in subjects with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 mthan in those with eGFR ≥60 mL/min/1.73 m; there was a significant heterogeneity in the association between eGFR levels (P for heterogeneity=0.04).

Conclusions: The findings suggested that a lower serum 1,25(OH)D level is a potential risk factor for all-cause death, especially cardiovascular and respiratory infection death, in the general Japanese population, and that lower serum 1,25(OH)D levels greatly increase the risk of respiratory infection death in subjects with kidney dysfunction.
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http://dx.doi.org/10.1253/circj.CJ-16-0954DOI Listing
August 2017

Isolation of a new compound, 2-butanone 4-glucopyranoside 6'-O-gallate and other 8 compounds from the anti-inflammatory leave extracts of Memecylon edule Roxb.

Nat Prod Res 2017 Jun 7;31(12):1370-1378. Epub 2016 Nov 7.

c School of Pharmaceutical Sciences , University of Shizuoka , Shizuoka , Japan.

This present study was designed to isolate the compounds of Memecylon edule. The chemical compounds were purified by chromatographic methods and their structures were established on the basis of spectroscopic analyses (UV, MS and NMR). The major isolated compounds were tested for anti-inflammatory activity. The methanolic extracts of M. edule leaves gave a new compound 2-butanone 4-glucopyranoside 6'-O-gallate (1) with eight known compounds, namely, 3,3'-di-O-methylellagic acid 4-O-β-d-glucopyranoside (2), epigallocatechin-3-O-gallate (EGCG) (3), (2R, 3R)-dihydromyricetin-4'-β-d-glucopyranoside (4), myricetin-3-O-α-l-rhamnopyranoside (5), benzyl-(6-O-α-L arabinofuranosyl) O-β-d-glucopyranoside (6), benzyl-(6-O-α-l-rhanmopyranosyl) O-β-d-glucopyranoside (7), 2-phenylethyl-(6-O-β-d-apiofuranosyl)-O-β-d-glucopyranoside (8) and methyl benzoate 2-(6-O-α-l-rhamnosyl)-O-β-d-glucopyranoside (9). All compounds were isolated for the first time from this plant. The major compounds (2, 3 and 5) exhibited significant anti-inflammatory activity. In conclusion, M. edule was recognised to be a good source for phenolic compounds and these compounds may contribute to anti-inflammatory activity of the extract.
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http://dx.doi.org/10.1080/14786419.2016.1253074DOI Listing
June 2017

A novel steroid and cytotoxic constituents from Dioscorea membranacea Pierre against hepatocellular carcinoma and cholangiocarcinoma cells.

J Ethnopharmacol 2016 Dec 24;194:91-97. Epub 2016 Aug 24.

Department of Applied Thai Traditional Medicine, Faculty of Medicine, Thammasat University, Klongluang, Pathumthani 12120, Thailand; Center of Excellence in Applied Thai Traditional Medicine Research (CEATMR), Faculty of Medicine, Thammasat University, Klongluang, Pathumthani 12120, Thailand.

Ethnopharmacological Relevance: The rhizomes of Dioscorea membrancea Pierre have been used in Thai traditional medicine as an ingredient formula for liver cancer and cholangiocarcinoma treatment.

Aim Of The Study: To investigate the cytotoxic activity of ethanolic extract and constituents of D. membrancea to support its traditional use.

Materials And Methods: The SRB assay was used to determine the cytotoxic activity against hepatocellular carcinoma (HepG2), cholangiocarcinoma (KKU-M156) cells and one normal human keratinocyte immortal cells (HaCaT) with its ethanolic extract and isolated compounds. Bioassay guided isolation was used for isolating cytotoxic compounds.

Results: The ethanolic extract of D. membranacea rhizome showed weak cytotoxic against KKU-M156 and HepG2 (IC at 72h exposure=30.49±0.82 and 38.97±2.04µg/mL respectively). A new steroid [epipanthogenin B (1)], a known steroid [panthogenin B (2)], two napthofuranoxepins [dioscorealide A (3) and dioscorealide B (4)], phenanthraquinone [dioscoreanone (5)] and two phenanthrene [5,6-dihydroxy-2,4-dimethoxy-9,10-dihydrophenanthrene (6) and 2,5,6-trihydroxy-3,4-dimethoxy, 9, 10-dihydrophenanthrene (7)] were isolated from active chloroform fraction. Compound 4 showed the highest cytotoxicity against HepG2 (IC at 72h exposure=2.87±0.21µM) and KKU-M156 (IC at 72h exposure=1.67±0.10µM) and less toxicity against normal cell line (HaCaT) (IC at 72h exposure>100µM). Compound 5 showed selective cytotoxic activity against KKU-M156 (IC at 72h exposure=3.46±0.11µM). Compounds 6 and 7 showed weak cytotoxic activity against HepG2 (IC at 72h exposure=24.96±2.32 and 51.31±3.52µM). Compounds (1-3) showed no cytotoxic activity against HepG2 and KKU-M156 cell lines (IC at 72 h exposure>100µM).

Conclusion: Seven compounds were isolated from active chloroform fraction of the ethanolic extract of D. membranacea rhizomes. Only dioscorealide B (4) might be served as a good anticancer agent for liver cancer and cholangiocarcinoma cancer because it can kill cancer cell but not toxic on normal cell. This research support Thai traditional medicine use of D. membranacea for liver cancer and cholangiocarcinoma cancer treatment.
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http://dx.doi.org/10.1016/j.jep.2016.08.037DOI Listing
December 2016

Five furofuranone lignan glucosides from Terminalia citrina inhibit in vitro E2-enhanced breast cancer cell proliferation.

Fitoterapia 2016 Sep 15;113:74-9. Epub 2016 Jul 15.

School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.

Five new polyalkoxylated furofuranone lignan glucosides, terminalosides L-P (1-5), were isolated from EtOAc extracts of the leaves of Terminalia citrina, a Bangladeshi medicinal plant. The structures of the isolates were deduced primarily by NMR spectroscopy, and four of the isolates were found to contain rare tetraoxygenated aryl groups in their structures. The absolute configurations and conformations of the furofuranone ring were confirmed by ECD spectroscopy. All of the isolates were evaluated for their estrogenic and/or antiestrogenic properties using two estrogen responsive breast cancer cell lines, T47D and MCF-7. At a concentration of 10nM, terminaloside L (1) suppressed E2-enhanced T47D cell proliferation by 90%, while terminaloside M (2) showed 90% antiestrogenic activity against MCF-7 cells. Compared to 2, the antiestrogenic activity of terminaloside O (4) and P (5) was weak, possibly due to the different attachment positions of the sugar moiety that they share in common. This is the first report of furofuranone lignans from any Terminalia species, and also of their antiestrogenic activity.
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http://dx.doi.org/10.1016/j.fitote.2016.07.004DOI Listing
September 2016

Abietane-type diterpenoids from the roots of Caryopteris mongolica and their cholinesterase inhibitory activities.

Phytochemistry 2016 Oct 10;130:152-8. Epub 2016 Jun 10.

School of Engineering and Applied Sciences, National University of Mongolia, POB-617, Ulaanbaatar-46A, 14201, Mongolia.

Eleven abietane-type diterpenoids and two known abietanes were isolated from the roots of Caryopteris mongolica, and their structures were characterized. The absolute configurations at C-5 and C-10 were determined from the NMR data, including from the nuclear Overhauser effect and CD spectra, and the absolute configuration of C-16 in the hydroxypropyl group was determined via a modified Mosher's method. Furthermore, the previously unknown absolute configuration of the C-15 of cyrtophyllone B was determined to be in an R-configuration using X-ray crystallography. To estimate the preventive effects of the isolates for neurodegenerative disease development, their inhibitory activities against acetylcholinesterase (AChE) from human erythrocytes and butyrylcholinesterase (BChE) from horse serum were evaluated.
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http://dx.doi.org/10.1016/j.phytochem.2016.05.011DOI Listing
October 2016

Furofuran Lignan Glucosides with Estrogen-Inhibitory Properties from the Bangladeshi Medicinal Plant Terminalia citrina.

J Nat Prod 2016 05 25;79(5):1298-307. Epub 2016 Apr 25.

School of Pharmaceutical Sciences, University of Shizuoka , 52-1 Yada, Shizuoka 422-8526, Japan.

Extracts from the leaves of the Bangladeshi medicinal plant Terminalia citrina were prepared, and 13 new furofuran lignan glucosides, terminalosides A-K (1-4, 6-12), 2-epiterminaloside D (5), and 6-epiterminaloside K (13), were characterized using various spectroscopic techniques. Twelve of the isolates were found to contain rare tetraoxygenated aryl groups in their structures. Analysis of the NMR chemical shifts for the oxymethine signals in the furofuran ring suggested a pragmatic approach to determining the relative configuration of these compounds. The ECD and NOESY spectroscopic data obtained allowed for the deduction of the absolute configurations and conformations of the compounds. The isolates were tested for their estrogenic/antiestrogenic activity using the MCF-7 and T47D estrogen-responsive human breast cancer cell lines. Terminalosides B (2) and G (8) exhibited inhibitory effects for both cell lines, and estradiol-enhanced cell proliferation was suppressed by 90% at concentrations lower than 10 μM. Terminaloside E (6) showed inhibitory activity against the T47D cell line, whereas terminalosides C (3), F (7), and I (10) and 6-epiterminaloside K (13) displayed antiestrogenic activity against MCF-7 cells.
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http://dx.doi.org/10.1021/acs.jnatprod.5b01042DOI Listing
May 2016

Phenolic constituents of the Bangladeshi medicinal plant Pothos scandens and their anti-estrogenic, hyaluronidase inhibition, and histamine release inhibitory activities.

Phytochemistry 2016 Jan 2;121:30-7. Epub 2015 Nov 2.

School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.

Extracts from the stem and roots of the Bangladeshi medicinal plant Pothos scandens L. (Araceae) were isolated, and three hemiterpene glucoside aromatic esters, pothobanosides A (1), B (2), and C (3), and a phenylisobutanoid, pothobanol (4), along with 14 known compounds, were characterized. The isolates were tested for their estrogenic/anti-estrogenic activity using the estrogen-responsive human breast cancer cell lines MCF-7 and T47D, and syringoyl derivatives (2, 3, and canthoside B) showed strong inhibitory activity against both cell lines. Their less oxygenated analogs (1, and markhamioside F) were almost inactive. The isolates were also evaluated for hyaluronidase and histamine release inhibitory activities, and pothobanoside A (1) showed significant hyaluronidase inhibitory activity among the isolated compounds, which was similar to that of the positive control rosmarinic acid. Because hyaluronidase produces an angiogenic response that has been implicated in tumor invasiveness and metastasis, 1 could be valuable as an anti-tumor compound with a different mechanism of action from related compounds (2, 3). Pothobanoside C (3) and pothobanol (4) were also found to inhibit histamine release to a similar degree to the positive control epigallocatechin 3-O-(3"-O-methyl)-gallate. The histamine release inhibitory potency of these isolates may support the traditional uses of this plant in folk medicine.
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http://dx.doi.org/10.1016/j.phytochem.2015.10.009DOI Listing
January 2016

Flavonoids: separation and quantitation.

ScientificWorldJournal 2015 1;2015:874148. Epub 2015 Mar 1.

Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA.

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http://dx.doi.org/10.1155/2015/874148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359849PMC
April 2016

Effect of miroestrol on ovariectomy-induced cognitive impairment and lipid peroxidation in mouse brain.

Phytomedicine 2014 Sep 25;21(11):1249-55. Epub 2014 Jul 25.

Division of Medicinal Pharmacology, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

Miroestrol (MR) is a phytoestrogen isolated from Pueraria candollei var. mirifica (KwaoKrueaKhao), a Thai medicinal plant used for rejuvenation. We examined the effects of MR on cognitive function, oxidative brain damage, and the expression of genes encoding brain-derived neurotrophic factor (BDNF) and cyclic AMP-responsive element-binding protein (CREB), factors implicated in neurogenesis and synaptic plasticity, in ovariectomized (OVX) mice. OVX decreased serum 17β-estradiol level and uterine weight. OVX also impaired object recognition performance in the novel object recognition test and spatial cognitive performance in the Y-maze test and the water maze test. Daily treatment of MR dose-dependently attenuated OVX-induced cognitive dysfunction. Moreover, OVX mice had a significantly increased level of thiobarbituric acid-reactive substances, and down-regulated expression levels of BDNF and CREB mRNAs in the hippocampus and frontal cortex. MR treatment as well as hormone replacement therapy with 17β-estradiol significantly reversed these neurochemical alterations caused by OVX. These results suggest that MR ameliorates cognitive deficits in OVX animals via attenuation of OVX-induced oxidative stress and down-regulation of BDNF and CREB mRNA transcription in the brain. Our findings raise the possibility that MR and Pueraria candollei var. mirifica, the plant of origin of MR, may have a beneficial effect on cognitive deficits like AD in which menopause/ovariectomy are implicated as risk factors.
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http://dx.doi.org/10.1016/j.phymed.2014.06.012DOI Listing
September 2014

Identification of a new angiotensin-converting enzyme (ACE) inhibitor from Thai edible plants.

Food Chem 2014 Dec 22;165:92-7. Epub 2014 May 22.

Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand; Phytomedicine and Pharmaceutical Biotechnology Excellent Center, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla 90112, Thailand. Electronic address:

Eight Thai edible plants were tested for their inhibitory activity against an angiotensin-converting enzyme (ACE) using an in vitro assay. The methanol extract of Apium graveolens exhibited significant ACE inhibitory activity with an IC50 value of 1.7 mg/ml, and was then subjected to an isolation procedure that resulted in identification of a pure active constituent, junipediol A 8-O-β-d-glucoside (1-β-d-glucosyloxy-2-(3-methoxy-4-hydroxyphenyl)-propane-1,3-diol) (1), which had good ACE inhibitory activity with an IC50 value of 76 μg/ml. Another eight known compounds, isofraxidin-β-d-glucoside (2), roseoside (3), apigenin-7-O-β-d-glucoside (4), luteolin-7-O-β-d-glucoside (5), icariside D2 (6), apiin (7), chrysoeriol-7-O-β-d-apiosylglucoside (8), and 11,21-dioxo-3 β,15 α,24-trihydroxyurs-12-ene-24-O-β-d-glucopyranoside (9) were also identified. Although each of these five constituents (2-6) isolated from the same fraction as 1 showed no activity at concentrations of 500 μM, together, when each was present at 300 μg/ml, they enhanced the inhibitory activity of 500 μM of 1 from 64% to 81%.
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http://dx.doi.org/10.1016/j.foodchem.2014.05.080DOI Listing
December 2014

Structure and antioxidant activity relationships of isoflavonoids from Dalbergia parviflora.

Molecules 2014 Feb 20;19(2):2226-37. Epub 2014 Feb 20.

Department of Pharmacognosy and Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.

The antioxidant activities of 24 isoflavonoids that were previously isolated as pure compounds from Dalbergia parviflora were evaluated using three different in vitro antioxidant-based assay systems: xanthine/xanthine oxidase (X/XO), ORAC, and DPPH. The isolates consisted of three subgroups, namely isoflavones, isoflavanones, and isoflavans, each of which appeared to have diversified substituents, and were thus ideal for the study of their structure-activity relationships (SARs). The SAR analysis was performed using the results obtained from both the inter-subgroup isoflavonoids with the same substitution pattern and the intra-subgroup compounds with different substitution patterns. The inter-subgroup comparison showed that the isoflavones exhibited the highest antioxidant activities based on all three assays. The intra-subgroup analysis showed that the additional presence of an OH group in Ring B at either R3' or R5' from the basic common structure of the R7-OH of Ring A and the R4'-OH (or -OMe) of Ring B greatly increased the antioxidant activities of all of the isoflavonoid subgroups and that other positions of OH and OMe substitutions exerted different effects on the activities depending on the subgroup and assay type. Therefore, based on the structural diversity of the isoflavonoids in D. parviflora, the present study provides the first clarification of the detailed antioxidant SARs of isoflavonoids.
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http://dx.doi.org/10.3390/molecules19022226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271601PMC
February 2014

Diastereomers of lithospermic acid and lithospermic acid B from Monarda fistulosa and Lithospermum erythrorhizon.

Fitoterapia 2013 Dec 23;91:51-59. Epub 2013 Aug 23.

Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.

Monardic acids A (1) and B (2), which are (7R,8R) diastereomers of lithospermic acid (LA) and lithospermic acid B, respectively, were isolated from Monarda fistulosa. A (7S,8R) isomer (3) of LA was also isolated from this plant, and a (7R,8S) isomer (7) of LA was obtained from Lithospermum erythrorhizon. The absolute configuration of 1 was confirmed by analysis of its hydrolysates, 7-epiblechnic acid and 2R-3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid. The configuration in the dihydrobenzofuran moieties of 2, 3, and 7 was extrapolated by using the phenylglycine methyl ester method and a Cotton effect at approximately 250-260 nm in their electronic circular dichroism spectra. Diastereomers (1-3 and 7) displayed moderate hyaluronidase inhibitory and histamine release inhibitory activities.
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http://dx.doi.org/10.1016/j.fitote.2013.08.009DOI Listing
December 2013

Cytotoxic and immunomodulatory effects of polyhydroxyoctane isolated from Lentinus polychrous mycelia.

J Nat Med 2014 Apr 15;68(2):302-9. Epub 2013 Aug 15.

Faculty of Agricultural Technology, Burapha University Sakaeo Campus, Sakaeo, 27160, Thailand.

A polyhydroxyoctane, 6-methylheptane-1,2,3,4,5-pentaol (MHP), was first isolated from mycelia of the Thai edible mushroom Lentinus polychrous. MHP was evaluated for its cytotoxic and immunomodulatory effects in vitro. MHP was slightly cytotoxic to murine splenocytes but not to RAW264.7 cells or peripheral blood mononuclear cells. MHP decreased nitric oxide and intracellular O2 (-) production from lipopolysaccharide- and phorbol-12-myristate-13-acetate-activated RAW264.7 cells at levels of 78.98 ± 4.72 and 78.48 ± 2.41 % of controls, respectively. The mRNA expression of pro-inflammatory mediators, including iNOS, TNF-α, IL-1β, IL-6, COX-1 and COX-2, were significantly suppressed by MHP. In addition, MHP significantly increased the proliferation of phytohemagglutinin and pokeweed mitogen-induced splenocytes. These results indicate that MHP is able to modulate inflammatory responses and the proliferation of both T- and B-lymphocyte cells, suggesting that MHP may be a good natural immunomodulator.
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http://dx.doi.org/10.1007/s11418-013-0797-5DOI Listing
April 2014

Flavonoid glycosides from Botrychium ternatum.

Chem Pharm Bull (Tokyo) 2012 ;60(12):1561-73

Institute for Environmental Sciences, University of Shizuoka, 52–1 Yada, Suruga-ku, Shizuoka 422–8526, Japan.

The MeOH extract from dried whole Botrychium ternatum plants yielded 33 compounds, including seventeen new flavonoid glycosides and sixteen known compounds. The structures of new compounds were established using NMR spectroscopic analysis and chemical evidence.
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http://dx.doi.org/10.1248/cpb.c12-00744DOI Listing
May 2013

Bioactive ergostanoids and a new polyhydroxyoctane from Lentinus polychrous mycelia and their inhibitory effects on E2-enhanced cell proliferation of T47D cells.

Nat Prod Res 2013 19;27(18):1611-9. Epub 2012 Nov 19.

a Faculty of Pharmaceutical Sciences, Center for Research and Development of Herbal Health Products , Khon Kaen University , 123 Mitrapap Rd. , Khon Kaen , 40002 , Thailand.

From mycelia of Lentinus polychrous, a Thai local edible mushroom cultured under solid-state fermentation, a new compound, 6-methylheptane-1,2,3,4,5-pentaol (1), and five ergostanoids, namely (22E,24R)-ergosta-7,22-dien-3β,5α,6β-triol (2), 3β,5α-dihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (3), ergosta-4,6,8(14),22-tetraen-3-one (4), (3β,5α,8α,22E)-5,8-diepoxy-ergosta-6,22-dien-3-ol (5) and 5,8-epidioxy-(3β,5α,8α,22E)-ergosta-6,9(11),22-trien-3-ol (6), was isolated and characterised. The compounds were determined for their oestrogenic and anti-oestrogenic activities by using human breast cancer T47D cells. All compounds had no oestrogenic activity but exhibited suppressive effect on oestradiol-enhanced cell proliferation. Among these compounds, only 4 significantly competed with oestradiol in the binding to oestrogen receptors (ERs) with higher selectivity to ERα than ERβ. These results may suggest that most compounds suppressed this oestradiol-enhanced T47D proliferation via other mechanisms rather than ER binding.
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http://dx.doi.org/10.1080/14786419.2012.742079DOI Listing
April 2014

Flavonoid and stilbenoid production in callus cultures of Artocarpus lakoocha.

Phytochemistry 2012 Sep 5;81:42-9. Epub 2012 Jul 5.

Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.

Callus cultures of Artocarpus lakoocha Roxb., established from seedling explants and maintained on woody plant medium containing 1mg/l 2,4-dichlorophenoxyacetic acid and 1mg/l benzyladenine, were studied for their chemical constituents and biosynthetic potential of secondary metabolites. Four prenylflavones and prenylated stilbenes, along with nine known polyphenolic compounds, were isolated and elucidated for their structures through extensive analysis of their NMR and MS data. Among the 13 isolates, it appeared that seven of them are prenylated derivatives of 5,7,2',4'-tetrahydroxyflavones, and four are prenylated derivatives of 2,4,3',5'-tetrahydroxystilbene (oxyresveratrol), suggesting that the biosynthetic pathways of these two polyphenolic groups and their prenylating enzymes are highly expressed in A. lakoocha callus cultures. A study on the growth-product relationship of the callus cultures showed that the secondary metabolites were all formed simultaneously during the rapid growth phase of the culture cycle, with various prenylflavones, and a prenylated stilbene as major constituents. In assays for DPPH free radical scavenging activity and tyrosinase inhibitory potential, the stilbenoids appeared to possess moderate effects, whereas the flavonoids showed only weak activity.
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http://dx.doi.org/10.1016/j.phytochem.2012.05.031DOI Listing
September 2012

Constituents from the roots of Taraxacum platycarpum and their effect on proliferation of human skin fibroblasts.

Chem Pharm Bull (Tokyo) 2012 ;60(2):205-12

Institute for Environmental Sciences, University of Shizuoka, 52–1 Yada, Suruga-ku, Shizuoka, Japan.

A MeOH extract from the roots of Taraxacum platycarpum has shown significant effects on the proliferation of normal human skin fibroblasts. Chemical analysis of the extract resulted in the isolation of 26 compounds, including eight new triterpenes, one new sesquiterpene glycoside, and seventeen known compounds. The structure of each new compound was established using NMR spectroscopy. Some triterpenes had a significant effect on the proliferation of normal human skin fibroblasts.
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http://dx.doi.org/10.1248/cpb.60.205DOI Listing
June 2012

8,12;8,20-diepoxy-8,14-secopregnane glycosides from roots of Asclepias tuberosa and their effect on proliferation of human skin fibroblasts.

Phytochemistry 2011 Oct 22;72(14-15):1865-75. Epub 2011 Jun 22.

Institute for Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.

A pregnane glycoside fraction from the roots of Asclepias tuberosa L. caused normal human skin fibroblasts to proliferate. This fraction contained 21 pregnane glycosides whose structures were established using NMR spectroscopic analysis and chemical evidence. The aglycones of most of these compounds were identified as 8,12;8,20-diepoxy-8,14-secopregnanes, such as tuberogenin or 5,6-didehydrotuberogenin, the same aglycones as constituents of the aerial parts of this plant. Some of these compounds also caused proliferation of skin fibroblasts.
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http://dx.doi.org/10.1016/j.phytochem.2011.05.012DOI Listing
October 2011

The quenching effect of flavonoids on 4-methylumbelliferone, a potential pitfall in fluorimetric neuraminidase inhibition assays.

J Biomol Screen 2011 Aug 2;16(7):755-64. Epub 2011 Jun 2.

Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.

Many assays aimed to test the inhibitory effects of synthetic molecules, and naturally occurring products on the neuraminidase activity exploit the hydrolysis of 2'-O-(4-methylumbelliferyl)-N-acetylneuraminic acid (4-MUNANA). The amount of the released product, 4-methylumbelliferone (4-MU), is then measured fluorimetrically. The authors attempted an analysis of the inhibitory properties of 35 naturally occurring flavonoids on neuraminidase N3, where only 29 of them were sufficiently soluble in the assay medium. During the analysis, the authors noticed a strong quenching effect due to the test compounds on the fluorescence of 4-MU. The quenching constants for the flavonoids were determined according to the Stern-Volmer approach. The extent of fluorescence reduction due to quenching and the magnitude of the fluorescence reduction measured in the inhibition assays were comparable: for 11 of 29 compounds, the two values were found to be coincident within the experimental uncertainty. These data were statistically analyzed for correlation by calculating the pertinent Pearson correlation coefficient. Inhibition and quenching were found to be positively correlated (r = 0.71, p(uncorr) = 1.5 × 10(-5)), and the correlation was maintained for the whole set of tested compounds. Altogether, the collected data imply that all of the tested flavonoids could produce false-positive results in the neuraminidase inhibition assay using 4-MUNANA as a substrate.
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http://dx.doi.org/10.1177/1087057111409221DOI Listing
August 2011

QSAR study of natural estrogen-like isoflavonoids and diphenolics from Thai medicinal plants.

J Mol Graph Model 2011 Apr 19;29(6):784-94. Epub 2011 Jan 19.

Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand.

Two species of Thai medicinal plants, Dalbergia parviflora R. (Leguminosae) and Belamcanda chinensis L. (Iridaceae), used traditionally for the regulation of menstrual disorders, have been found to contain a large number of potential estrogen-like compounds. A set of some 55 isolated isoflavonoids and diphenolics showed a wide range of estrogen activity as determined in breast cancer MCF-7 and T47D cell proliferation assays. This set of compounds was studied by means of computational techniques including quantitative structure-activity relationships (QSAR) and molecular modeling. It was found that the estrogenic potencies of the studied compounds depend mainly upon the presence/absence of hydroxyl groups attached to 3' and 5' positions of B ring of the isoflavone scaffold and the inter-atomic distance between the hydroxyl groups attached to the outer terminal positions 7 of A ring and 4' of B ring. In a QSAR model employing ligand-receptor interaction energy descriptors, the LigScore scoring function of Cerius(2) virtual screening module, which describes the receptor affinities of simultaneous binding to estrogenic receptors α and β (ER(α) and ER(β)), led to the best correlation between the observed estrogenic activities and computed descriptors. Consideration of independent binding to ER(α) and ER(β) did not result in statistically significant QSAR models. It was thus concluded that simultaneous and possibly competitive interaction of the compounds with the ER(α) and ER(β) receptors, in which the presence of hydroxyl groups at the abovementioned positions of the isoflavonoids and diphenolics molecular scaffold plays a dominant role, may determine the estrogenic potency of the considered phytochemicals.
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http://dx.doi.org/10.1016/j.jmgm.2011.01.001DOI Listing
April 2011

Estrogenic and anti-estrogenic compounds from the Thai medicinal plant, Smilax corbularia (Smilacaceae).

Phytochemistry 2011 Apr;72(6):495-502

School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.

From the rhizomes of Smilax corbularia Kunth. (Smilacaceae), 11 compounds, (2R,3R)-2″-acetyl astilbin, (2R,3R)-3″-acetyl astilbin, (2R,3R)-4″-acetyl astilbin, (2R,3R)-3″-acetyl engeletin, (2R,3S)-4″-acetyl isoastilbin, 2-(4-hydroxyphenyl)-3,4,9,10-tetrahydro-3,5-dihydroxy-10-(3,4-dihydroxyphenyl)-(2R,3R,10R)-2H,8H-benzo [1,2-b:3,4-b'] dipyran-8-one, 2-(4-hydroxyphenyl)-3,4,9,10-tetrahydro-3,5-dihydroxy-10-(3,4-dihydroxyphenyl)-(2R,3R,10S)-2H, 8H-benzo [1,2-b:3,4-b'] dipyran-8-one, 3,4-dihydro-7-hydroxy-4-(3,4-dihydroxyphenyl)-5-[(1E)-2-(4-hydroxyphenyl) ethenyl]-2H-1-benzopyran-2-one, 3,4-dihydro-7-hydroxy-4-(3,4-dihydroxy-phenyl)-5-[(1E)-2-(3,4-dihydroxyphenyl) ethenyl]-2H-1-benzopyran-2-one, 3,4-dihydro-7-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-5-[(1E)-2-(4-hydroxyphenyl) ethenyl]-2H-1-benzopyran-2-one, and 5,7,3',4'-tetrahydroxy-3-phenylcoumarin along with 34 known compounds were isolated and characterized as 19 flavonoids, 14 catechin derivatives, 6 stilbene derivatives, and 6 miscellaneous substances. All isolates had their estrogenic and anti-estrogenic activities determined using the estrogen-responsive human breast cancer cell lines MCF-7 and T47D. The major constituents were recognized as flavanonol rhamnosides by the suppressive effect on estradiol induced cell proliferation at a concentration of 1μM. Meanwhile, flavanonol rhamnoside acetates demonstrated estrogenic activity in both MCF-7 and T47D cells at a concentration of 100μM, and they enhanced the effects of co-treated E2 on T47D cell proliferation at concentrations of more than 0.1μM.
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http://dx.doi.org/10.1016/j.phytochem.2010.12.018DOI Listing
April 2011