平成26年度富山県薬事研究所年報
Contents
1. ICsy lug mL e3ug mLO 22. 219 RTR FNV d 3 9
3. 1 1 FM 100 89 879 886 1969 1988 p 186 2011 D 378 D 387 D 740 C 411 C 2700 216 223 2003 5 PHE 29 j 426 181 187 2007
4. Table Effect of peony extract on lipid peroxidation in mice treated with Fe NTA Dose Blood Kidney TBAR nmole ml TBAR nmole g Control 2 01 0 39 245 12 4 Fe NTA 5mg kg Fe 18 1 1 10 588 26 8 Bonten extract 1g kg 14 8 0 35 530 7 05 Mice were administered perorally with Bonten extract 1g kg 2 times 4 and 0 5hr before the intraperitoneal injection of Fe NTA Mice were sacrificed 1hr after the injection with Fe NTA Each value shows the mean SE of 5 mice 2 Significantly different from Fe NTA at p lt 0 01 0 001 3 1 5
5. ECD FID FID LI E 2 H Jr E 3 26
6. Summary Antioxidative potency of 4 components contained in peony root was compared with the degree of lipid peroxidation in mice treated with iron chelating agent as oxidative stress model Pentagalloylglucose had no effect on the formation of lipid peroxide in this model even when administered with high dosing of 100mg kg but high dose of gallic acid significantly inhibited the formation of them in blood and kidney And methyl gallate inhibited the lipid peroxidation only in kidney but catechin had no effect Furthermore peony root extract had the tendency to inhibit the lipid peroxidation in this model These results suggest that some components in peony root exert the improvement in oxidative stress model but this effect appear to be due to the blend effect of some components Keywords Pentagalloylglucose Gallic acid Methyl gallate
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8. 87 40 GREE X 1 39 69 76 25
9. EK EER DMSO v7 RAHA CO DMSO 0 33 2 twitch ICRA MEE v 7 A SRHEWLETCEOUU 1 2 2 2 TB 651T 1 34C McEwen 130mM NaCl 5 9mM KCl 22mM CaCl 0 9mM NaHzPO4 25 0mM NaHCOs 13 1mM 11 1mM
10. 2 26 9 1 2
11. Mechanism of action of the anti tumor effects of betulin Masaru OGASAWARA Takayuki MATSUNAGA Yoshinori NAGAI Kiyoshi TAKATSU Department of Immunobiology and Pharmacological Genetics Graduate School of Medicine and Pharmaceutical Science for Research University of Toyama LC TGF f d v AX PGE2 B16F10
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13. 1 1 2732 4 26 11 7 1 5 2 0cm 10 12cm TB 057 7 4C 2 2 WERE KALE small food dryer Petit Mini 3 WEE 27 1 5 1 28 23 5 10C 4 30 1 70 47 72
14. DPPH 229ug ml 21 4E REIN FE O PEK O346ug ml 1 g kg 2 TERI O9 PGG RETR
15. b OD Mate c TS 5000Z d e TYU VERY ATAR 358 pis S x 2 QD 27 1
16. lt H20 E 1 RARE Se CUI I H24 26 5 26 3 2 17 1 Qu Ir 26 10 6 H Qu Ir 27 2 H27H 337m 1
17. Summary Peony root is recognized to possess antispasmodic effect on smooth muscle and skeletal muscle Effect of some constituents of peony root and related compounds on the twitch response to electrical stimulation were examined as well as reference drugs Loperamide 0 01 0 1 u M a purgative agent showed the potent twitch inhibitory effect which is antagonized by naloxone 0 34 M an opioid receptor antagonist Nifedipine 0 03 0 3 uM a L type calcium channel blocker and a vasodilator and papaverine 1 104 M a non specific antispasmodic agent showed the remarkable twitch inhibitory effect Adenosine 0 3 3 u g mL showed a relatively short acting twitch inhibition Methyl gallate and pyrogallol showed the twitch inhibitory effect and the contractile effect Tannic acid 10 30 ug mL gallic acid 1 3 u g mL paeonol 30 100 u g mL and benzoic acid 100 u g mL showed the twitch inhibitory effect These results suggest that gallic acid its related compounds paeonol and benzoic acid possess the inhibitory effect on the neurogenic contraction in the mouse vas deferens Key words Tannic acid Me
18. WS 5 6 7 8 9 F LOL TGF PGE B16F10 Jg D 1
19. Summary The cultivation area of Paeonia lactiflora is expanding in Toyama recently The fresh roots harvested by the farmers are shipped to the outside of Toyama prefecture now but it is considered that the farmers ship the dried Peony root in the near future for expansion in a market and adding a high value Therefore test drying of P lactiflora for large scale production was performed in this center using the flat bed dryer improved for peony drying by production conference As a result 390 kg fresh roots were dried in 8 days by this dryer and the obtained Peony roots were suited to the Japanese Pharmacopoeia quality Sixteenth Edition We will study on drying methods further and we will support the farmers by technology transfer WM VASE Key words Peony root Drying Flat bed dryer TAR 16 HUS 16 Paeonia lactiflora Pallas SEE db AES TH 1489
20. Fe NTA Fe 05mg ml 5 Je a Blood Kidney 2 a H i g B a i E ii a mum gt C gt 5 M y r p T f LS S P Ra P S S E d gr gt S s S s f gj D Fig 1 Effect of pentagalloylglucose on lipid peroxidation in mice treated with Fe NTA Mice were administered perorally with 3 doses of pentagalloylglucose 2 times 4 and 0 5hr before the intraperitoneal injection of Fe NTA Mice were sacrificed 1hr after the injection with Fe NTA Each column shows the mean SE of 5 mice Significantly different from Fe NTA Blood _ Kidney f Pu i i 3 pu x z F p x P M gt L a Ld qo Vw f P UO f P P A s e y E B E g y 4 E lt y y P a or F Ly F lt wr Fig 3 Effect of gallic acid on lipid peroxidation in mice treated with Fe NTA Mice were administered pe
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23. GL ILG NLRPS DNA AIM2 GL ILG Ek GL NLRP3 AIM2 ASC ILG NLRP3 ASC ILG IAPP Islet amyloid polypeptide IL 1 NLRP3 ILG ILG n ex vivo IL 1 1
24. en pH L pH 38 Kid pH pH 38 29 32 HPLC 12 5mg HPLC 34 50mg 14 2 26 9 9 10 24 3 27 3 18 HOR VENT pH
25. 4 100mg kg 0 17 1 24 D 1 g kg 1 1995 2 1990 3 BAEZ 1
26. 3 NK TAE RO Summary We have previously reported that betulin a plant constituent restored the reduced cytolysis of splenocytes caused by TGF f or PGE Betulin has been reported to exhibit an antitumor effect their mechanism of action is believed to be an inhibitory effect on cancer cell proliferation In this study we examined whether the restorative activity of betulin is involved in its anti tumor effect in a tumor burden mice model It was confirmed that betulin exhibited the antitumor effect in a mouse model subcutaneously inoculated with B16F10 melanoma To reveal the effects of betulin on the anti tumor immune system the number of leukocytes accumulated in tumor tissues was examined and found to increase to approximately 3 fold by administering of betulin The more detailed analysis clarified that this increased leukocytes were mainly NK cells T cel
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28. 1 Na Fe NTA VE fi PGG Cayman chemical 05 2 AUR CA eK 4 25 10 BER LIZ 3 Balb c HEME 6 7 9 4 Fe NTA Fe NTA 4 30 2 L Fe NTA Fe 5mg kg 1
29. 108 1101 1103 1988 18 a 20 21 3 Basic Studies on dying of Paeonia lactiflora Pallas for large scale production Takayuki TAMURA Masaaki TAKATA Isamu OE 390kg 8 16
30. 0 3 2 64 5 63 I CL 4 62 tiiet 61 9 HA cy F 6 Ad pH 59 58 4 57 5 56 T 0188 E 0188 BB E a206 53 OE 3 0123 45 6 7 amp 9 101212 131445 1617 18 13202122 232425 26 27 2829303132 3334 35 36 37 38 Q zi 3 Oz gt 3 Cy 2 Z 23 Cy 2
31. 5 x x 595x 399 x 229mm 1 13 2 26 15kg 1 390kg 16 40 C 50Hz 1 MOWRY bt 48 OLE 3
32. Ek 2 rpm 30rpm L DOREIR ETC A CL RMR LZ l 2 IL 33 TL 5 ILC2 ER qu WW RR 35 2014 7 1 4
33. 34 65 72 2015 UHPLC HILIC ER WE 1 HPLC UHPLC 20 UHPLC 2 HILIC 4 2
34. HABE Y 8 9 10096 WOR EO CLI Asa EY 453 4 T 05 3 ERARO m EUR 16 73 3 3 7 FERIRE 11 38 16 14 0 IKI 2 83 16 6 5 002 16 0 5 270 16 20 060 26 0E
35. day 1 3 Figs 5 6 Fig 5 NK CD69 NK day 1 C 2 3 Fig 6 NK TH
36. 6 15 s Tcells Neutrophils LJ 4 10 x 2 2 5 il Zz 0 0 30 15 3 Macrophages Eosinophils F 3 20 0 x 10 z 5 I a 5 T A cH Day Day4 DayB Day Day4 DOw8 Days after starting the administration of betulin Fig 6 Comparison of the cell number of each immune cell accumulated to the site of administration of betulin in mice The absolute cell number of each immune cell in the leukocytes accumulated in tumor sites as shown in fig 4 were evaluated by flow cytometry Data are expressed as mean S D of 3 9 mice TGF NK
37. C 1 BEY AT UL 16
38. 9 Ws 3 7 8 DB KERR 1 Sigma
39. 2 26 1 1 pH 12 5mg 50mg PRB pH 20 4 2 1 2 0 1 g
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41. SUE 16 2014 2014 7 30 Chemical Constituents Analysis of the Leaf of Eleutherococcus senticosus Cultivated in Different environment Eu f k 31 2014 8 31 Comparing the contents of main components in the roots of Bonten a medicinal cultivar of Paeonia lactiflora after different post harvestprocessing Zhu S Shirakawa A Shi YH Yu XL Tamura T Yoshimatsu K Komatsu K The 8th JSP CCTCNM KSP Joint Symposium on Pharmacognosy 8 2014 9 13 E RA BE 13 2014 2014 9 20 Son 2014 9
42. 50 30 u g mL 4 ICso DMSO RE 100 g mL ms Fy bic Mik
43. 4 DPPH PGG100mg kg 4 100mg kg PGG Abdelwahed 9 Ek
44. CCL5 TGF HERB SNS C 4 IL 12 Er OT 1 4 OVA IL 2 IFN y IL 12 NK EK IL 2 IFN y CD8 TT if JSPS 24590109 1 Rosenberg S A Yang J C Restifo N P Cancer immunotherapy
45. 1 J Leukoc Biol 96 6 1087 1100 2014 Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet induced adipose tissue inflammation Honda H Nagai Y Matsunaga T Okamoto N Watanabe Y Tsuneyama K Hayashi H Fujii L Ikutani M Hirai Y Muraguchi A and Takatsu K 2 2 1 IL 1 IL 1 NLRP3 NLRP3 ILG LPS NF kB TLR4 ILG NLRP3
46. 38 17 20 2011 4 40 17 21 2013 5 0 39 61 68 2012 6 Luo C Wang H Chen X Cui Y Li H Long J Mo X and Liu J Protection of H9c2 rat cardiomyoblasts against oxidative insults by total paeony glucosides from Radix Paeonia Rubrae Phytomed 21 20 24 2013 7 Su J Zhang P Zhang J J Qi X M Wu Y G and Shen J J Effects of total glucosides of paeony on oxidative stress in the kidney from diabetic rats Phytomed 17 254 260 2010 Abdelwahed A Bouhlel IL Skandrani I Valenti K Kadri M Guiraud P Steiman R Mariotte AM Ghedira K Laporte F Dijoux Franca MG Chekir Ghedira L Study on antimutagenic and antioxidant activities of gallic acid and 8 1 2 3 4 6 pentagalloylglucose from Pistacia lentiscus Confirmation by microarray expression profiling Chem Biol Interact 165 1 13 2007 Zhang J Li L Kim S H Hagerman AE and Lu J Anti cancer antidiabetic and other pharmacological 9 and biological activities of penta galloyl glucose P
47. 40 46 50 2013 gb Loperamide 1 Prostaglandin E1 ak 74 145 154 1978 17 Giagnoni G Casiraghi L Senini R Revel L Parolaro 11 13 14 16 D Sala M Gori E Loperamide evidence of interaction with mu and delta opioid receptors Life Sci 33 Suppl 1 315 318 1983 II 2009 p 227 229 19 k 38 61 68 2011 2 92 750 756 1972 YAR ii 1982 p 286 p 299 22 di
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52. TGF p 7 Fig 2B TGF B D Vaiciw ywated B otzwrroeted No of leukocytes CD45 celsa Day Day4 Dav6 Days after starting the edmunistration ef betin Fig 4 Accumulation of leukocytes to the site of administration of betulin in mice Tumor cells were subcutaneously inoculated into mice Betulin was intratumorally administered for 1 to 8 consecutive days starting 2 days after tumor inoculation On day 1 4 or 8 of post of the initial injection of betulin leukocytes accumulated in tumor sites were analyzed as CD45 positive cells in a flow cytometer The data are expressed as meanz S D of 3 9 mice Fig 4
53. ILG NLRP3 Immunol Letters 163 22 31 2015 Differential Requirements of MyD88 And TRIF Pathways in TLR4 mediated Immune Responses in Murine B Cells Yanagibashi T Nagai Y Watanabe Y Ikutani M Hirai Y and Takatsu K LPS Toal TLR 4 LPS IL 4 TGF Ig Gl IgE IgA IgGl IgA Lot IgG1 IgA TLR4 2 MyD88 TRIF B LPS
54. 81 596 T 2 25 1 22 26 27 KEM CH 5 BAS 26
55. ELZ 120cm 40cm 45rpm 1 20kg 2 1 4 2 26 1 SUS304 1800mm 1800mm 500mm d Q Q
56. Fig 8 Fig 9 Fig 8 30 100 u g mL T twitch Fig 10A 1004 g mL 41 4 A Papaverine B Atropine Tine min Time min 20 10 0 1 0 20 30 4 50 0 20 10 0 0 20 30 40 50 9 20 20 o tral su Control ol 0 10 4M s 20 wl 1gM o 5 2 wt 3 uM eo 80 10 uM 100 100 Fig 4 Effect of papaverine and atropine on the twitch response in the isolated mouse vas deferens Papaverine hydrochloride and atropine sulfate were dissolved in distilled water Each point is presented as a mean S E of 4 6 experiments A Tannic acid B Gallic acid Time erin Time mn 20 10 0 0 20 30 40 S0 v 20 10 0 10 20 30 40 50 60 5 S 20 9 9 Control Control 2 2 Tu g mL 0 104 g mL i 4 0 E LU 80 90 30 u g mL 3 g mL 8 100 Fig 6 Effect of tannic acid and gallic acid on the twitch response in the isolated mouse vas deferens Tannic acid and gallic acid were dissolved in DMSO Each point is presented as a mean S E of 4 experiments ba 10 min Methyl Gallate ES OFF ES OFF 100 4t g mL Wash Fig 8 E
57. 100 1 Wu 16 18 95 2 95 z is 90 x 1 590 60 C 2hr 85 Tas e u i 4 82 3 e 80 e e e 80 THRE 75 75 70 70 1 2 3 4 5 6 7 8 9 1011121314 e 45 2hr MARRS a e x x m
58. 2 1 L pH pH L pH 38 36 0 10 EJ 02 2 M1 3 3 9 6 ELE ELLE ELELLELLELL LT 5 3 8 0188 4 37 1 28B 3 3 6 Zi pH 3 5 NER WI 1 1 34 7 i i 33 n t MARL TALL d 2 9 T co 6 7 de i 3 2 3 9 2 9 n 01234567 amp 9 101012131415 1617 1819202122 23 2425 26 27 28 29 303132 3334353537 38 O V 23 2 gt 3 Ce2 Z 3 Eros SD pH 0 10 pH 0 10 1 L
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62. twitch a gt Ai twitch 19 B Pyrogallol Increase in basal contraction EIL ELLE 20 10 0 10 20 30 40 SO 60 Time min Fig 9 Effect of methyl gallate and pyrogallol on the basal contraction in the electrically stimulated mouse vas deferens Methyl gallate and pyrogallol were dissolved in DMSO Each point is presented as a mean S E of 4 experiments A Control methyl gallate at 30 ug mL A amp or 100 ug mL 49 B Control O pyrogallol at 3 ug mL A amp or 10 ug mL 4 A Paeonol Time min 20 10 0 10 20 30 40 50 60 Control Inhibition amp 301 g mL 100 4 g mL B Benzoic acid Time min 20 10 0 10 20 30 40 50 60 0 Control pense 100 g mL vl ao 100 Fig 10 Effect of paeonol and benzoic acid on the twitch respon
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64. 3 40 22 26 2013 Pfarr K Danciu C Arlt O Neske C Dehelean C Pfeilschifter J M Radeke H H Simultaneous and dose dependent melanoma cytotoxic and immune stimulatory activity of betulin PLoS One 10 3 e0118802 2015 Peg E Comparative Potency of peony components on the lipid peroxidation in oxidative stress induced mouse Takayuki MATSUNAGA Takayuki TAMURA Yoichi YOKOTA and Toru KAWASUJI 4 100mg kg 1 g kg
65. TGF B NS 398 PGE Fig 2A 2 16 150 nmol 17 45 TGF LY2157299 Fig 2B LY2157299 of control Betulin uM Fig 3 Effects of betulin on the in vitro proliferation of B16 melanoma cells Tumor cells were cultured in 10 FBS medium containing various concentrations of betulin for 48 h After that WST 1 solution was added into each well and cells were incubated for an additional 4 h Absorbance of each well was measured at 450 nm Data are expressed as mean S D
66. 3 1 twitch 00L01uMTC twitch Fig 1 Fig 2 60 50 ICso 0 021zx M 0 03uM 03uM Fig 2 L 0 03 0 3 zzM twitch ICso 0 13 uM Fig 3 1 10uM twitch ICs 16 M Fig 4A 10zM ld Fig 4B E 10 min e Loper
67. 30mL 1 msec Hi 0 1Hz twitch Loperamide Time min 20 10 0 10 20 30 40 50 60 20 0 Control 2 001 uM 4 E E 6 0 03 uM 80 0 1 uM 100 Fig 1 Effect of loperamide on the twitch response in the isolated mouse vas deferens Loperamide hydrochloride was dissolved in distilled water Each point is presented as a mean S E of 4 6 experiments B BL 0 15 g 30 1 TOR 30 twitch 60 twitch 0 0 96 100 ELT
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70. 16 50mg NUNN o m N SSS ABR CI 17 50mg 1 D 12 B 1 B 1 Y 13 DPLU 0 18 50mg 3 7 92 185 170 HY 93 180 168 pH pH 0 10
71. BAAPEH EHS L6 5307 COTES OTSE 38 Toru KAWASUJI 00L014M t twitch 03uM TRPE NZ L 0 03 0 3 uM 1 10uM twitch 0 3 3 g mL twitch 100 g mL lOug mL twitch 100 00ug mL L3ug mL 30 100w g mL 100 7 g mL twitch
72. Control 0 1 Tween 0 9 L12157299 45 nmol NS 396 45 mel Tumor volume me 8 Days after tumor oculabon Fig 1 Effects of LY2157299 or NS 398 on the growth of B16 melanoma in mice Tumor cells were subcutaneously inoculated into mice on day 0 LY2157299 or NS 398 was intratumorally administered once daily until day 16 starting 2 days after tumor inoculation Tumor volume was evaluated two or three times a week The data are expressed as mean S D of 8 mice 3 RE x x 2 4 10 FBS DMEM GIBCO B16F10 4 x10 ml 99 Corning 4 x10 37C 596 COs 48 T WST 1 Wako 5 10 FBS DMEM 4 450 nm 5 B16F10
73. NK NK CD69 NK TGF NK 5 NK TGE TGF f X T 48 5199 7 TGF k 0 Mis NK NK TA B NK T CCL4 CCL5
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75. 13 12 5mg 14 12 5mg 2 6 50mg 29 2 3 49 2 Z 32 LL 1 3 1 15 12 5mg 2 14 1 Sb Lv 1 12 2 45C 2 82 3
76. pH 2 L pH 36 B Ex BT Ex 38 B EEDLUNOTE 2 0 hd 3 L pH pH 38 34 010 4 3 4 6 pH Chit
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80. 2009 219484 2012 43815 2014 94917 2013 271897 N y IL 1RUTNFISTEBISEA PCT PCT P2014 084076
81. B16F10 XU TGF PGE B16F10 TGF PGE TGF 1 COX 2 TGF t B16F10 TGF I SB431542 B16F10 TGEF Z TGE I
82. 22 LL 3 27 DPL 0 5 4 9 174 5 5 174 4 173 5 DO 3 EN Ion Fi 173 M Zs i n 1725 zi c n L els M y LJ 9 VR os 0 I 171 5 E 2345 I 789101112814 9 1 e 1 171 DON ea e 2 2 x 1705 rie t m ole 012345678 9 101112131415 1617 18 19 2021 2223 24 25 26 27 2829303132 3 an en Z gt 3 gt 2 Z S38 10 1 29 LL 3 3 27 4 1 0 B12 4 27 1
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88. FBGA ONK UGE amp ae LT TGF PGE ui Betulin treated Vehicle trested NK1 1 B io C 0 O Vehicla treated B Betuln trested D Vehicle treated Bi Betuln treatec 23 2 3 i xz Sw sl s 1 3 OL s x I 7 0 m Day Day4 Day Day Day4 Days after starting the administration of betuln Fig 5 Increase of NK cells in the accumulated leukocytes to the site of administration of betulin in mice Population of NK cells in the leukocytes accumulated in tumor sites as shown in fig 4 were evaluated in their ratio to total leukocyte A the absolute cell number B and the absolute number of CD69 NK cells C by flow cytometry Data are expressed as mean S D of 3 9 mice 3
89. LPS B MyD88 LPS IL 4 TRIF MyD88 34 25 30 2015 HPLC 7 6 Gin SE HPLC 30 6F ERORE Sum 46mm 150 mm C8 3 m 446mm 75mm C8 Inertsil C8 3 YMC Pack C8 Mightysil RP 8GP
90. 8 9H 11 a SALD RO BE b c SALD 2300 SALD 7500nano
91. KA Kenji TAKEBAYASHI Yoichi YOKOTA and Mikiya OHTO 25 3 6 089 1 25 21 D 25 pH HPLC 93 Z 3 USP
92. Extrasynthese 0 1 Tween 80 PBS LY2157299 TGF 1 NS 398 COX 2 Sellecchem 0 1 Tween 80 PBS 2 B16F10 10 100 U ml 0 1 mg ml 55 M 2 RPMI 164085 HHH IC CHEK 3 B16F10 2 x105 0 05 ml PBS 38 80 L C57BL 6 8 ME 8 10 0 05 ml 2 16 1 1 0 1 Tween 80 PBS 50z1 2
93. 2 x105 0 05 ml PBS C57BL 6 8 W 3 6 pe 0 05 ml 2 9 1 1 150 nmol RHE 0 196 Tween 80 PBS 3 6 HH d 10 1 mg ml A 200 U ml DNase I Sigma 37C 30 L Wum THA R Falcon 1500 rpm 10 min 10 ml CD16 32 24G2 TWE d5u 4C 15 min Fc g ml A B 5000 p O Control 0 1 Tween 80 O Control 0 1 Tween 80 4000 amp Betin 15 emo Bets 400 t Bondin 150 nmol a LY2157299 E 3000 Botuin LY1257299 E 3 2 2000 1000 0 0 5 10 15 0 5 10 15 Days after tumor moculton Days after tumor moculabon Fig 2 Effects of betulin alone or the
94. Z 3 pH 0 10 pH 0 10 4 pH f 34 BLL OFt 4 37 E EEOLUMOTE 3 1 6 pH 3 29 4 th HED LW 3 5 7 9 30 60 5
95. 2 13 OUHPLC HILIC AE Aw MAC 34 2015 2 13 EA A GE TAXE AS RA FORK EQ W CA Aqu Best WE 34 2015 2 13 3 Hikosaka K Ikutani M Shito M Kazuma K Gulshan M Nagai Y Takatsu K Konno K Tobe K Kanno H and Nakagawa T Deficiency of Nicotinamide Mononucleotide Adenylyltransferase 3 Nmnat3 Causes Hemolytic Anemia by Altering the Glycolytic Flow in Mature Erythrocytes J Biol Chem 289 14796 811 2014 Katayama H Mori T Seki Y Anraku M Iseki M Ikutani M Iwasaki Y Yoshida N Takatsu K and Takaki S Lnk prevents inflammatory C
96. 30 FA BAE WE HE EA o WO Age WE 16 2014 10 18 Structural Determination and Synthesis of Isoprenoids as Immune Activators via TLR4 MD 2 Mizote K Saeki A Honda H Okamoto N Kimura T Nagai Y Takatsu K Fujimoto Y Fukase K SLB IEIIS 2014 2014 10 23 Salt Lake City USA HE EN DE BFE VE OO CUTE Zee IC BUT BMF ER EIL Z Z FV 0 BRE BENT mus 35 2014 10 24 51 2014 10 24 ABCD1 E RES 56 2014 11 13 15 UPL A RU 7 4 ET V Y
97. KER 12 4 86 92 1991 1 11 3 75 81 1990 2 11 4 70 75 1990 2 JE 3 xw 4 6 7 8 9 m 104 1244 1250 1984 10 Maeda T Shinozuka K Baba K Hayashi M Hayashi E Effect of Shakuyaku kanzoh toh a prescription composed of shakuyaku Paeoniae Radix and Kanzoh Glycyrrhizae Radix on guinea pig ileum J Pharmacobio Dyn 6 153 160 1983 HEAT 110 139 143 1990 12 7 1990 p 67 69 p 185 186 p 229 233 14 1992 p 643 646 3 3 39 51 60 2012 15
98. moving beyond current vaccines Nat Med 10 9 909 915 2004 2 Teicher B A Transforming growth factor beta and the immune response to malignant disease Clin Cancer Res 13 21 6247 6251 2007 2 39 21 25 2012 Tang JJ Li J G Qi W Qiu W W Li P S Li B L Song B L Inhibition of SREBP by a small molecule betulin improves hyperlipidemia and insulin 3 xw 4 t resistance and reduces atherosclerotic plaques Cell Metab 13 1 44 56 2011 5 Jonnalagadda S C Corsello M A Sleet C E Betulin betulinic acid natural product based analogs as anti cancer agents Anticancer Agents Med Chem 13 10 1477 1499 2013 6 02 009719 7 2005 330261 8 1 14832 9 Xu W Zhu C Cheng W Fan X Chen X Yang S Guo Y Ye F Shi J Chemical Constituents of the Roots of Euphorbia micractina J Nat Prod 72 9 1620 1626 2009 10 Soica C Dehelean C Danciu C Wang H M Wenz G Ambrus R Bojin F Anghel M Betulin complex in y cyclodextrin derivatives properties and antineoplasic activities in in vitro and in vivo tumor models Int J Mol Sci 13 11 14992 15011 2012 11 Penafuerte C Galipeau J TGF b
99. 3 1 6 7 8 2 13 9 16 4 095996 48 642 48 56896 54296 529 c 1 0 027 8 Z 48 3 1 3
100. combination of betulin and LY2157299 on the growth of B16 melanoma in mice Tumor cells were subcutaneously inoculated into mice on day 0 A B betulin LY2157299 or their mixture was intratumorally administered once daily until day 16 starting 2 days after tumor inoculation Tumor volume was evaluated two or three times a week The data are expressed as mean S D of 8 10 mice CD19 1D3 CD3e 145 2C11 NK1 1 PK136 CD11b M1 70 Gr 1 RB6 8C5 CD11c HL3 CD45 30 F11 siglec F E50 2440 i amp 025 1254 g ml 4C 05 fH Ee 7 AAD FACSCantol BD ET TGF PGE LY2157299 TGF B NS 398 COX 2 Fig 1 LY2157299 17 50 Z
101. of triplicate wells TGF 7s Fig 2B TGF Fig 2A B16F10 50 13 0 MTh oZ COS TGF p
102. ANDREE ZOD RUE mu 126 2014 11 16 Roles of IL 5 producing ILC2 in vascular pathogenesis Ikutani M Tsuneyama K Nagai Y Takatsu K 43 2014 12 10 Adipocyte derived free fatty acids trigger IL 18 production by neutrophils in mouse adipose tissue Watanabe Y Nagai Y Tsuneyama K Takatsu K 43 2014 12 10 Isoliquiritigenin Is a Potent Inhibitor of NLRP 3 Inflammasome Activation and Diet induced Adipose Tissue Inflammation Honda H Nagai Y Takatsu K 43 2014 12 10 An antibiotics funiculosin derivative is a novel agonist of Toll like receptor 4 Okamoto N Honda H Nagai Y Takatsu K 43 2014 12 11 HPLC 7 WO 61 RAT 34 2015
103. Catechin Oxidative stress model 27 RE 9 SH
104. D8 T cell proliferation and contributes to intestinal homeostasis Eur J Immunol 44 6 1622 32 2014 Mori T Iwasaki Y Seki Y Iseki M Katayama H Yamamoto K Takatsu K and Takaki S Lnk Sh2b3 controls the production and function of dendritic cells regulates the induction of IFN gamma producing T cells J Immunol Aug 15 193 4 1728 36 2014 Tamura K Ikutani M Yoshida T Tanaka Hayashi A Yanagibashi T Inoue R Nagai Y Adachi Y Miyawaki T Takatsu K and Mori H Increased production of intestinal immunoglobulins in Syntenin 1 deficient mice Immunobiology in press 2015 Yamamoto S Niida S Azuma E Yanagibashi T Muramatsu M Ting H T Sagara H Higaki S Ikutani M Nagai Y Takatsu K Miyazaki K Hamashima T Mori H Matsuda N Ishii Y and Sasahara M Inflammation induced endothelial cell derived extracellukar vesicles modulate the cellular status of pericytes Sci Rep 5 Article number 8505 2015 4 0 A 4815421 5548874 2 2009 221191
105. E XR OREO REESE L 1 50H 40C 16 48 if 1 16 1514 2011 2 ik 3 23 24 2015 puis H 26 External quality control for laboratories of pharmaceutical companies in 2014
106. amide c A 0 08 kM ES oFF Naloxone 03 uM Fig 2 Antagonistic effect of naloxone against the twitch inhibition induced by loperamide in the isolated mouse vas deferens Loperamide hydrochloride and naloxone hydrochloride were dissolved in distilled water and were added to the bath at the points indicated Electrical stimulation 1 msec 0 1 Hz was stopped at the period indicated 0 3 3 u g mL twitch 1Cs 2 1 u g mL Fig D 2 twitch 10 30 u g mL twitch ICs 13 7 ug g mL Fig 6A 1 3 g mL twitch ICso 1 6 u g mL Fig 6B 30 100 u g mL twitch Nifedipine Time min 20 10 0 10 20 30 40 50 60 20 v r 0 Control 2 0 03 uM Rus 0 1uM 0 3 uM 80 100 Fig 3 Effect of nifedipine on the twitch
107. eta secreted by B16 melanoma antagonizes cancer gene immunotherapy bystander effect Cancer Immunol Immunother 57 8 1197 1206 2008 Parhar R S Lala P K Amelioration of B16F10 melanoma lung metastasis in mice by a combination 12 therapy with indomethacin and interleukin 2 J Exp Med 165 1 14 28 1987 41 17 20 2014 14 Yang L Pang Y Moses H L TGF beta and immune cells an important regulatory axis in the 13 tumor microenvironment and progression Trends 15 Immunol 31 6 220 227 2010 Castriconi R Dondero A Bellora F Moretta L Castellano A Locatelli F Corrias M V Moretta A Bottino C Neuroblastoma derived TGF f 1 modulates the chemokine receptor repertoire of human resting NK cells J Immunol 190 10 5321 5328 2013 16 Hu S Chao C C Ehrlich L C Sheng W S Sutton R L 17 18 Rockswold G L Peterson P K Inhibition of microglial cell RANTES production by IL 10 and TGF beta J Leukoc Biol 65 6 815 21 1999 EOJPEGE
108. ffect of methyl gallate on the twitch response and the basal contraction in the isolated mouse vas deferens Methyl gallate was dissolved in DMSO and was added to the bath at the point indicated Electrical stimulation 1 msec 0 1 Hz was stopped at the point indicated 100 u g mL twitch Fig 10B se 41 8 twitch 60 A 7s 100ug mL 30ug mL twitch ATP twitch A Methyl Gallate Increase in basal contraction 20 10 0 Time min 10 20 30 40 S0 60 WS twitch Nar BY
109. harm Res 26 2066 2080 2009 1 2002 11 Lapidot T Walker MD And Kanner J Antioxidant and prooxidant effects of phenolics on Da 10 pancreatic beta cells in vitro J Agric Food Chem 50 7220 7225 2002 12 Chedea V S Braicu C Chirila F Ogola H J O Pelmus R S Calin L G and Socaciu C Antioxidant prooxidant and antibacterial probacterial effects of a grape seed extract in complex with lipoxygenase Biomed Res Internat 2014 1 9 2014 13 Zong L Inoue M Nose M Kojima K Sakaguchi N Isuzugawa K Takeda T and Ogihara Y Metabolic fate of gallic acid orally administered to rats Biol Pharm Bull 22 326 329 1999 14 Nakagawa Y Nakajima K Tayama S and Moldeus P Metabolism and cytotoxicity of propyl gallate in isolated rat hepatocytes effects of a thiol reductant and an esterase inhibitor Mol Pharmacol 47 1021 1027 1995 3E Effect of Constituents of Peony Root and Related Compounds on the Twitch Response to Electrical Stimulation in the Isolated Mouse Vas Deferens IE 3
110. ls macrophages and neutrophils From these observations the antitumor effect of betulin is suggested to include the killing activity to tumor cells of these immune cells accumulated into tumor tissues TGF 6 PGE2 Key words Betulin melanoma TGF PGE immunosuppression jm TGF f PGE TGF PGE 800
111. response in the isolated mouse vas deferens Nifedipine was dissolved in DMSO Each point is presented as a mean S E of 4 5 experiments Adenosine Time min 20 10 0 10 20 30 40 50 6 amp 0 20 0 Control 20 0 3 4 g mL ilu g mL 3 3 ug ml eo 80 100 Fig 5 Effect of adenosine on the twitch response in the isolated mouse vas deferens Adenosine was dissolved in DMSO Each point is presented as a mean S E of 3 4 experiments A Methyl Gallate B Pyrogallol Tare rin Tima min 20 10 0 10 20 30 4 0 60 20 10 0 10 20 30 40 0 amp 20 20 0 0 Control Control 2 3 31 g mL i 0 304 g mL j 40 o m 80 100 g mL 80 100 100 10 gg mL Fig 7 Effect of methyl gallate and pyrogallol on the twitch response in the isolated mouse vas deferens Methyl gallate and pyrogalol were dissolved in DMSO Each point is presented as a mean S E of 4 experiments ICso 44 8 g mL Fig 7A 3 10 u g mL twitch ICso 46 g mL Fig 7B IC 10 20
112. rorally with 3 doses of gallic acid 2 times 4 and 0 5hr before the intraperitoneal injection of Fe NTA Mice were sacrificed lhr after the injection with Fe NTA Each column shows the mean SE of 5 mice Significantly different from Fe NTA 6 One way ANOVA Dunnett s test 5 Students ttest 1 PGG Fe NTA PGG Lk Fe NTA 3 PGG100mg kg Ek Fe NTA 12 7 Kidney 3 2 i i i B e 1 4 3 E 2 Pa x F p A S Y x d Ly E d Fig 2 Effect of catechin on lipid peroxidation in mice treated with Fe NTA Mice were administered perorally with 3 doses of catechin 2 times 4 and 0 5hr before
113. se in the isolated mouse vas deferens Paeonol and benzoic acid were dissolved in DMSO Each point is presented as a mean S E of 3 5 experiments A Paeoniflorin Time min 20 10 0 10 20 30 40 SO 60 M or seestsesy Cm 1 a 20 00 gu g mL 4 E 60 s0 100 B Albiflorin Time min 20 10 0 10 20 30 40 50 6 20 0 rir f apii i i E i gy Control 30 u g mL Inhibition 8 8 8 8 8 Fig 11 Effect of paeoniflorin and albiflorin on the twitch response in the isolated mouse vas deferens Paeoniflorin and albiflorin were dissolved in DMSO Each point is presented as a mean S E of 4 experiments 2
114. the intraperitoneal injection of Fe NTA Mice were sacrificed 1hr after the injection with Fe NTA Each column shows the mean SE of 5 mice Significantly different from Fe NTA Blood Kidney x J i i x lt lt Es E 2 gt F 5 f F F x P F 4 S e 7 rd f gt x e M e y d d gt F y y Fig 4 Effect of methyl gallate on lipid peroxidation in mice treated with Fe NTA Mice were administered perorally with 3 doses of methyl gallate 2 times 4 and O 5hr before the intraperitoneal injection of Fe NTA Mice were sacrificed Ihr after the injection with Fe NTA Each column shows the mean SE of 5 mice Significantly different from Fe NTA PGG30 100mg kg Fig 1 100mg kg Fig 2 2 100mg kg
115. thyl Gallate Loperamide Vas deferens Electrical stimulation o 2 4 6 9 twitch m
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