著者

Shabana Iqrar Khan Ehab Ahmed Abourashed Ikhlas Ahmad Khan Larry Anthony Walker

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.52, no.4, pp.394-397, 2004 (Released:2004-04-01)

参考文献数

23

被引用文献数

19 21

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This study examined the intestinal transport of five harman alkaloids using the Caco-2 cell monolayer as a model of the human intestinal mucosa. Transport parameters, permeability coefficients and percent transports, were calculated and compared under identical conditions with atenolol. Permeability coefficients were also compared with the reported values for model compounds like mannitol, propranolol and glucose. Sodium fluorescein was used as the marker for paracellular leakage. These alkaloids, in the concentration range of 250—500 μM, demonstrated substantial transport across the monolayer with moderate to high efflux rates and permeability coefficients. The transport was linear with time and was concentration dependent.

著者

Yoshimitsu Yamazaki Yasuhiro Kawano

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.59, no.3, pp.388-391, 2011-03-01 (Released:2011-03-01)

参考文献数

29

被引用文献数

32 43

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It is beneficial to treat chronic inflammatory condition in patients through diets that inhibit the production of proinflammatory cytokines and mediators such as tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Since less attention has been paid to alkaloids in the diets than to polyphenols in this regard, we aimed at investigating anti-inflammatory activity of herb-derived alkaloids through suppression of TNF-α and NO production in lipopolysaccharide (LPS)-stimulated mouse RAW264 and/or human THP-1 cells. A harmala alkaloid, harmine, an opium alkaloid, papaverine, and Lycoris alkaloids, lycorine and lycoricidinol, showed TNF-α suppressive activities stronger than or comparable to that of a reference polyphenol, butein, in RAW264 cells (IC50=4, 10, 2.1, 0.02, and 8 μM, respectively). Other alkaloids showed no or marginal to moderate inhibitory activities. Similar tendency of inhibition was found for NO production in RAW264 cells and TNF-α production in THP-1 cells. In addition, harmine was found to suppress interleukin-6 (IL-6) production in RAW264 cells. The above four inhibitory alkaloids had essentially no antioxidative property in the superoxide anion scavenging assay. Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR) showed that harmine caused neither prevention of nuclear factor-κB (NF-κB) translocation into the nucleus nor inhibition of p38 mitogen activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation, while that the LPS-induced transcription of TNF-α and inducible NO synthase was dose-dependently attenuated by harmine. This result suggests that the molecular mechanism of harmine action is different from those of many other anti-inflammatory phytochemicals. In conclusion, some herbal alkaloids like harmine, in spite of lacking antioxidative property, have potential as anti-inflammatory agents that strongly suppress TNF-α and NO production by a unique mechanism.

著者

Kazuma Shioe Shingo Ishikura Yoshikazu Horino Hitoshi Abe

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.61, no.12, pp.1308-1314, 2013-12-01 (Released:2013-12-01)

参考文献数

32

被引用文献数

11 13

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A facile method for the synthesis of dehydrodigallic acid, which is a fundamental structure of ellagitannins, was developed. A classical Ullmann condition was effective for the formation of the highly hindered biaryl ether structure, and we clarified that the suitable protection of the phenolic hydroxy groups was crucial in this reaction. In this way, the synthesis of dehydrodigallic acid and its derivative was successfully performed. The described method would provide a synthetic utility toward ellagitannins.

著者

Takayuki Miyazaki Michiyuki Komiyama Naoki Matsumaru Hideki Maeda Katsura Tsukamoto

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.45, no.4, pp.477-482, 2022-04-01 (Released:2022-04-01)

参考文献数

20

被引用文献数

5

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Early access to novel drugs, regardless of regional differences, is significant for patients worldwide. Although various efforts have been made to reduce the drug lag, it still exists in some regions, including Japan. In this study, we focused on the drug lag of first-in-class drugs in Japan and obtained fundamental information because we considered that first-in-class and me-too drugs are essentially different and should be treated separately. We analyzed 97 first-in-class and 176 me-too drugs in new molecular entity (NME)-approved drugs in Japan and the United States during the fiscal years between 2009 and 2019. Since government policy and the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs (the Committee) have a huge impact on drug lag, we distinguished NMEs developed at the Committee’s request. First-in-class drugs were developed at the Committee’s request significantly more than the me-too drugs (p = 0.0034). Although it was not statistically significant, the approval lags were 498.0 d for first-in-class drugs and 535.0 d for me-too drugs. Multiple regression analysis showed that multi-regional clinical trial (MRCT) development strategy (p = 0.0043) and foreign origin drugs (p = 0.0072) were a reducing factor and a prolonging factor of drug lag, respectively. In conclusion, the drug lag for first-in-class drug approval was one year. Global drug development using MRCT is one of the most effective development strategies for reducing drug lags.

著者

Abdulaziz Ahmed A. Saad Fan Zhang Eyad Abdulwhab H. Mohammed Xin’an Wu

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.45, no.4, pp.382-393, 2022-04-01 (Released:2022-04-01)

参考文献数

106

被引用文献数

2

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The organic cation transporter 2 (OCT2) belongs to the SLC22 family, while the multidrug and toxin extrusion 1 and 2-K (MATE1/MATE2-K) belong to the SLC47 family, are localized to the basolateral and apical membrane of human renal proximal tubular epithelial cells, respectively. They are polyspecific transporters that enable the transit of structurally diversified drugs with overlapping selectivity across plasma membranes. OCT2 and MATE1/2-K are critically involved in renal secretion, pharmacokinetics (PK), and toxicity of cationic drugs. Drug–drug interactions (DDIs) at OCT2 and/or MATE1/2-K have been shown to result in clinical impacts on PK, therapeutic efficacy and are probably involved in the renal accumulation of drugs. Sites of OCT2 and MATE1/2-K expression and function play an essential role in the pharmacokinetics and toxicity of drugs, such as cisplatin. Thus, knowing the sites (basolateral vs. apical) of the interaction of two drugs at transporters is essential to understanding whether this interaction helps prevent or enhance drug-induced nephrotoxicity. In this work, an overview of OCT2 and MATE1/2-K is presented. Primary structure, membrane location, functional properties, and clinical impact of OCT2 and MATE1/2-K are presented. In addition, clinical aspects of DDIs in OCT2 and MATE1/2-K and their involvement in drug nephrotoxicity are compiled.

著者

Hirotaka Sasa Koyo Mori Kotaro Kikushima Yasuyuki Kita Toshifumi Dohi

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.2, pp.106-110, 2022-02-01 (Released:2022-02-01)

参考文献数

48

被引用文献数

8

---

Benzolactams have unique biological activity and high utility in the synthesis of valuable compounds with direct applicability to oxindole alkaloids and antibacterial agents. Despite recent advances in organic chemistry and the growing number of reported methods for synthesizing benzolactams, their preparation still requires a multistep process. C–H amination reactions can convert aromatic C(sp2)–H bonds directly to C(sp2)–N bonds, and this direct approach to C–N bond formation offers effective access to benzolactams. Hypervalent iodine reagents are promising tools for achieving oxidative C–H amination. Motivated by our ongoing research efforts toward the development of useful hypervalent-iodine-mediated oxidative transformations, we herein describe an effective intramolecular oxidative C–H amination reaction based on μ-oxo hypervalent iodine catalysis for the synthesis of benzolactams bearing various functional groups.

著者

Yasutaka Sato Satoshi Sakaguchi Kenshi Takechi Masayuki Chuma Kenta Yagi Chikako Kane Mitsuhiro Goda Hirofumi Hamano Yuki Aoe Hiroshi Nokihara Yoshiaki Kubo Ichiro Hashimoto Hiroaki Yanagawa

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.45, no.3, pp.374-377, 2022-03-01 (Released:2022-03-01)

参考文献数

15

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In April 2018, the Clinical Trials Act pertaining to investigator-initiated clinical trials was passed in Japan. The purpose of this study was to investigate activity in investigator-initiated clinical studies before and after enforcement of the new Clinical Trials Act. This was done by analysing the records of the Ethics Committee of Tokushima University Hospital, which reviews studies based on the Japanese government’s Ethical Guidelines for Medical and Health Research Involving Human Subjects prior to the Clinical Trials Act, and records of the Certified Review Board established at Tokushima University under the Clinical Trials Act in 2018. The number of new applications to these two review boards during fiscal years 2015–2017 (pre-Act) and fiscal years 2018 and 2019 (post-Act) were used as an indicator of activity in investigator-initiated clinical studies. The number of new applications to the Ethics Committee was 303, 261, 316, 303, and 249 in 2015, 2016, 2017, 2018, and 2019, respectively. The data show that the total number of new interventional studies decreased from 50.3 in average in 2015–2017 (pre-Act) to 42 in 2018 and 40 in 2019 (post-Act), respectively. These results suggest that fewer interventional studies were started following enforcement of the new Clinical Trials Act. To confirm this trend and identify contributing factors, further studies are required. In addition, possible way, such as broader contribution of clinical research coordinators, to promote clinical studies in the new Clinical Trials Act era should be examined.

著者

Tatsuhiro Akaishi Shohei Yamamoto Kazuho Abe

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.45, no.3, pp.301-308, 2022-03-01 (Released:2022-03-01)

参考文献数

45

被引用文献数

7

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Neuroinflammation induced by activated microglia is a key feature of neurodegenerative diseases such as Alzheimer’s disease. The natural flavonoid 3′,4′,7-trihydroxyflavone protects nerve cells from oxidative stress-mediated apoptosis and inhibits the aggregation of amyloid β protein in vitro. However, little is known about its effects on microglial activation. In this study, we investigated the effects of 3′,4′,7-trihydroxyflavone on lipopolysaccharide (LPS)- or interferon-γ (IFN-γ)-induced neuroinflammatory responses in MG6 microglial cells. 3′,4′,7-Trihydroxyflavone inhibited LPS- or IFN-γ-mediated nitric oxide (NO) generation and the upregulation of inducible NO synthase (iNOS) in MG6 cells. 3′,4′,7-Trihydroxyflavone also suppressed LPS- or IFN-γ-mediated phosphorylation of signal transducer and activator of transcription 1 (STAT1), which is crucial for iNOS expression. LPS stimulation induced rapid phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase (ERK) in MG6 cells. 3′,4′,7-Trihydroxyflavone significantly inhibited the LPS-mediated phosphorylation of JNK, but not that of ERK and p38 MAPK. The inhibitory effect of 3′,4′,7-trihydroxyflavone on NO generation was mimicked by pharmacological inhibition of the JNK signaling pathway with SP600125. Furthermore, SP600125 significantly inhibited LPS- or IFN-γ-mediated phosphorylation of STAT1 in MG6 cells. These results suggest that 3′,4′,7-trihydroxyflavone exerts anti-neuroinflammatory effects via inhibition of the JNK-STAT1 pathway in microglia.

著者

Show Ishikawa Haruna Ishikawa Atsushi Sato

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.45, no.3, pp.284-291, 2022-03-01 (Released:2022-03-01)

参考文献数

27

被引用文献数

1

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Recently, we developed a platform strategy for hinge-deficient human immunoglobulin G1 (IgG1) Fc fusion as a non-immunostimulatory Fc fusion system. As a starting point to establish a promising approach for generating hinge-deficient Fc fusion proteins in Escherichia (E.) coli, we selected a CH2-CH3 scaffold as a model protein for evaluation. Recombinant CH2-CH3, expressed as inclusion bodies, was solubilized with various denaturants (urea, sarkosyl, sodium dodecyl sulfate (SDS), 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), or Triton X-100) in neutral (phosphate-buffered saline (PBS), pH 8) or alkaline (50 or 500 mM N-cyclohexyl-3-aminopropanesulfonic acid (CAPS), pH 11) buffer at 25 °C. Similar to the authentic CH2-CH3 produced in Chinese hamster ovary (CHO) cells, all denaturants, except urea in CAPS buffer but not in PBS, were found to elicit the dimer formation of solubilized CH2-CH3 on SDS-polyacrylamide gel electrophoresis (PAGE). After dialysis with PBS, sarkosyl-soluble CH2-CH3 inclusion bodies were successfully purified using protein G-Sepharose, indicating their successful refolding. Compared to the purified CH2-CH3 from its sarkosyl-soluble inclusion bodies in neutral buffer, that in 500 mM CAPS alkaline buffer revealed substantial structure-related similarities, such as secondary structures and thermal stabilities, as measured by circular dichroism spectroscopy, to authentic CH2-CH3. Native PAGE analysis also supported the above data. Therefore, solubilization at alkaline pH is an essential factor that promotes the refolding of CH2-CH3. Dimer formation of CH2-CH3 on SDS-PAGE may act as a surrogate marker for its protein refolding status. Our observations may provide important hints toward downstream processing of Fc-fusion production in E. coli.

著者

Hirohito Ikeda Masatomo Yamanaka Shota Takahashi Tomonori Ohata Miho Yukawa Rie Nakashima Hiroyuki Tsutsumi Masao Fujisawa Hatsumi Aki

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.3, pp.230-234, 2022-03-01 (Released:2022-03-01)

参考文献数

26

被引用文献数

2

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The details of incompatibility between aripiprazole (ARIP) oral solution and green tea were examined. When the ARIP oral solution was mixed with a commercial PET bottled green tea beverage, the residual rate of ARIP in the mixed solution decreased to 15.7–17.6%. Mixing with ARIP reduced the content of gallate-type green tea polyphenols (GTPs) in the mixed solution but not the content of non-gallate-type GTPs. Furthermore, using pH 3.0 lactic acid buffer, 2.23 mM ARIP solution and 2.23 mM GTP solution were prepared, and the same volumes of ARIP solution and GTP solution were mixed. When the gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution decreased. On the other hand, when the non-gallate-type GTP solution was mixed, the residual rate of ARIP in the mixed solution did not decrease. From the above results, it was found that the main reason for the incompatibility between ARIP oral solution and green tea was the formation of an insoluble substance composed of ARIP and gallate-type GTPs in green tea. Furthermore, experimental results using the continuous variation method revealed that ARIP and (−)-epigallocatechin gallate, which is the most representative gallate-type GTP, interact at a molar ratio of 3 : 2.

著者

Shoji Maehara Manami Kobayashi Mari Kuwada Tominari Choshi Hirofumi Inoue Yuhzou Hieda Takashi Nishiyama Toshiyuki Hata

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.70, no.3, pp.195-198, 2022-03-01 (Released:2022-03-01)

参考文献数

17

被引用文献数

4

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We investigated similar compounds to ebselen and tideglusib, which exhibit strong activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using Molecular ACCess System (MACCS) keys. Four candidate compounds were identified. One of them, phenyl-benzothiazol-3-one, showed coronavirus-specific 3C-like (3CL) protease inhibitory activity. The results indicated that a similarity score above 0.81 is a good indicator of activity for ebselen-and-tideglusib-like compounds. Subsequently, we simulated the ring-cleavage Michael reaction of ebselen at the Se center, which is responsible for its 3CL protease inhibitory activity, and determined the activation free energy of the reaction. The results showed that reaction simulation is a useful tool for estimating the activity of inhibitory compounds that undergo Michael addition reactions with the relevant cysteine S atom of 3CL proteases.

著者

Hiroaki Ikesue Haruna Yamamoto Masaki Hirabatake Tohru Hashida Hobyung Chung Tetsuro Inokuma Nobuyuki Muroi

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.45, no.3, pp.333-338, 2022-03-01 (Released:2022-03-01)

参考文献数

29

被引用文献数

1

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Proteinuria is one of the most frequently reported adverse events leading to the discontinuation of lenvatinib treatment in patients with advanced hepatocellular carcinoma (HCC). However, there are no reports regarding the risk factors of proteinuria in patients with HCC or patients receiving lenvatinib. We retrospectively reviewed the medical records of patients with HCC receiving lenvatinib at the Kobe City Medical Center General Hospital between April 2018 and December 2020. The severity of proteinuria was graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A multivariate Cox proportional hazards model was employed to identify the risk factors of developing grade ≥2 proteinuria. Among the 37 patients included, 3 patients had grade-1 proteinuria at baseline and 10 patients had estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at baseline. Grades 1, 2, and 3 proteinuria were observed in 15 (40.5%), 10 (27.0%), and 2 (5.4%) patients, respectively, during lenvatinib treatment. The median value of eGFR was significantly lower in patients who developed grade ≥2 proteinuria than those with grade ≤1 proteinuria (59.6 vs. 78.1 mL/min/1.73 m2, p = 0.045). Multivariate analysis revealed that pre-existing proteinuria at baseline (hazard ratio (HR), 9.72; 95% confidence interval (CI), 1.29–52.21; p = 0.030), and eGFR <60 mL/min/1.73 m2 at baseline (HR, 4.49; 95% CI, 1.32–16.07; p = 0.017) were significantly associated with developing grade ≥2 proteinuria. These patients should be monitored carefully, and our preliminary data should be confirmed by further studies.

著者

Tatsuhiro Ishida Hiroshi Kiwada

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.36, no.6, pp.889-891, 2013-06-01 (Released:2013-06-01)

参考文献数

36

被引用文献数

45 60

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In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance.

著者

Akihisa Itoh Yuuki Akagi Hitoshi Shimomura Takao Aoyama

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.39, no.3, pp.323-328, 2016-03-01 (Released:2016-03-01)

参考文献数

16

被引用文献数

5 9

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Bisphosphonates are antiosteoporotic agents prescribed for patients with osteoporosis. Drug package inserts for bisphosphonate supplements indicate that their bioavailability is reduced by high levels of metal cations (Ca2+, Mg2+, etc.). However, standards for these cations in water used for taking risedronate have not been defined. Here, we examined the effect of calcium and magnesium in mineral waters on the bioavailability of the third-generation bisphosphonate, risedronate, following oral administration in rats. As risedronate is unchanged and eliminated renally, risedronate absorption was estimated from the amount excreted in the urine. Risedronate was dissolved in mineral water samples and administered orally at 0.35 mg/kg. Urine samples were collected for 24 h after dosing. Risedronate was extracted from urine using ion-pair solid-phase cartridges and quantified by HPLC with UV detection (262 nm). Cumulative recovery of risedronate was calculated from the amount excreted in the urine. The 24-h recovery of risedronate from evian® (0.32±0.02% [mean±standard deviation (S.D.)], n=4) and Contrex® (0.22±0.05%) mineral waters was significantly lower than that from tap water (0.47±0.04%, p<0.01). Absorption of risedronate in calcium chloride and magnesium chloride aqueous solutions of the same hardness (822 mg/L) was 54% (0.27±0.04%) and 12% (0.51±0.08%) lower, respectively, compared with ultrapure water; suggesting that absorption of risedronate declines as the calcium concentration of mineral waters increases. Consumption of mineral waters containing high levels of calcium (80 mg/L or above), such as evian® and Contrex®, is therefore not recommended when taking risedronate.

著者

SHOICHIRO OZAKI TOSHIO NAGASE HIROFUMI TAMAI HARUKI MORI AKIO HOSHI MASAAKI IIGO

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.9, pp.3894-3897, 1987-09-25 (Released:2009-10-19)

参考文献数

11

被引用文献数

8 9

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For the purpose of diminishing the toxicity of 5-fluorouracil (1) and obtaining biologically active derivatives of 1 suitable for oral administration, alkylthiomethyl, alkylsulfinylmethyl, alkylsulfonylmethyl, and acylthiomethyl groups were introduced at the 1- and 3-positions of 1. The antitumor activity of these synthetic compounds was tested against L1210 leukemia in mice. 1-Alkylthiomethyl-5-fluorouracils showed weak antitumor activity at a high dose (300 mg/kg).

著者

SUHAIL AHMAD SHOICHIRO OZAKI TOSHIO NAGASE MASAAKI IIGO REIKO TOKUZEN AKIO HOSHI

出版者

The Pharmaceutical Society of Japan

雑誌

Chemical and Pharmaceutical Bulletin (ISSN:00092363)

巻号頁・発行日

vol.35, no.10, pp.4137-4143, 1987-10-25 (Released:2009-10-19)

参考文献数

15

被引用文献数

23 24

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Antitumor-active derivatives of 5-fluorouracil were prepared via a new method by introducing an acyloxymethyl group at the 1-, 3-, or 1, 3-position (s). These derivatives were obtained by condensing 1, 3-bis (hydroxymethyl) -5-fluorouracil with various short-/long-chain carboxylic acids or their derivatives, in the presence of dicyclohexylcarbodiimide and a catalytic amount of N, N-dimethylaminopyridine. Some of the derivatives showed strong antitumor activity against the leukemia L1210 system when administered orally.

著者

Saki Shirako Kenji Sato Saki Moriwaki Yukinobu Ikeya Mikio Nishizawa

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.45, no.2, pp.169-177, 2022-02-01 (Released:2022-02-01)

参考文献数

29

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Many constituents of crude drugs in Japanese Kampo formulas are thought to function as pro-drugs, whose pharmacological activity is manifested after oral administration. Proteins and peptides in crude drugs may be digested and metabolized in the digestive tract and liver. However, few studies have reported the pharmacological activity of peptides in crude drugs. Here, we applied an analysis using LC–tandem mass spectrometry (LC-MS/MS) to identify the compounds derived from six crude drugs that are assumed to have anti-inflammatory effects. To simulate in vivo protease digestion, each water-soluble fraction of the crude drug extracts was treated with proteases, including endoproteinases and exopeptidases. Amines in the resultant digests were modified by 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate and analyzed using LC-MS/MS, which demonstrated the presence of four decarboxylated amino acids (primary amines). In the digest of the hydrophilic fraction of the fruit of Ziziphus jujuba Miller var. inermis Rehder (Taiso), isobutylamine, isoamylamine, and 2-methylbutylamine were identified, which may be derived from valinyl, leucinyl, and isoleucinyl residues, respectively. Additionally, tyramine possibly derived from tyrosyl residues was identified in the digests of all the crude drugs. In primary cultured rat hepatocytes treated with interleukin-1β, all these decarboxylated amino acids suppressed the production of nitric oxide, a proinflammatory mediator. Our approach, i.e., in vitro protease digestion and LC-MS/MS analysis, suggests that decarboxylated amino acids may be formed in vivo from peptides and may be responsible for the anti-inflammatory effect of crude drugs included in Kampo medicine.

著者

Yihan Wang Yang Liu Jieting Liu Min Wang Yingbin Wang

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.45, no.1, pp.27-33, 2022-01-01 (Released:2022-01-01)

参考文献数

40

被引用文献数

1

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This study aimed to explore the effect of curcumin and hydromorphone hydrochloride (HH) cotreatment on postoperative pain in rats. An incision + formaldehyde-induced pain rat model was established. Rats were treated with vehicle, curcumin, HH, or curcumin + HH. Paw mechanical withdrawal threshold and thermal withdrawal latency were measured at 1 d before surgery as well as 1 , 2 h, 1 , 3 , and 7 d after surgery to assess pain sensitivity. The L4-6 region of the spinal cord was collected from each rat at 2 h, 1 , 3 , and 7 d after surgery. Western blot analysis and immunohistochemical staining were carried out to detect the protein expression of pain-related genes. Quantitative real-time PCR and enzyme-linked immunosorbent assay were conducted to measure the expression and production of proinflammatory mediators. Compared with other groups, Curcumin + HH significantly reduced pain sensitivity in the model rats. Mechanistically, curcumin + HH suppressed protein expression of stromal cell-derived factor-1 (SDF-1), CXC chemokine receptor 4 (CXCR4), p-Akt, and c-fos while enhancing protein expression of nerve growth factor (NGF) in the dorsal root ganglia (DRG) of model rats. Curcumin + HH inhibited the expression and production of interleukin 1β (IL-1β), cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), and p65 nuclear factor kappa B (NF-κB) in the DRG. Coadministration of curcumin and HH alleviates incision + formaldehyde-induced pain in rats, possibly by suppressing the SDF-1/CXCR4 pathway and the production of proinflammatory mediators. Our results provide curcumin and HH cotreatment as a promising therapeutic strategy in the management of postoperative pain.

著者

Jae-Suk Choi Min-Hee Jeon Woi-Sook Moon Jin-Nam Moon Eun Jin Cheon Joo-Wan Kim Sung Kyu Jung Yi-Hwa Ji Sang Wook Son Mi-Ryung Kim

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.37, no.1, pp.44-53, 2014-01-01 (Released:2014-01-01)

参考文献数

45

被引用文献数

19 30

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The potential hair growth-promoting activity of rice bran supercritical CO2 extract (RB-SCE) and major components of RB-SCE, linoleic acid, policosanol, γ-oryzanol, and γ-tocotrienol, were evaluated with the histological morphology and mRNA expression levels of cell growth factors using real-time reverse transcriptase-polymerase chain reaction (PCR) in C57BL/6 mice. RB-SCE showed hair growth-promoting potential to a similar extent as 3% minoxidil, showing that the hair follicles were induced to be in the anagen stage. The numbers of the hair follicles were significantly increased. In addition, mRNA expression levels of vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), and keratinocyte growth factor (KGF) were also significantly increased and that of transforming growth factor-β (TGF-β) decreased in RB-SCE-treated groups. Among the major components of RB-SCE, linoleic acid and γ-oryzanol induced the formation of hair follicles according to examination of histological morphology and mRNA expression levels of cell growth factors. In conclusion, our results demonstrate that RB-SCE, particularly linoleic acid and γ-oryzanol, promotes hair growth and suggests RB-SCE can be applied as hair loss treatment.

著者

Toshihiro Akihisa Keiichi Tabata Norihiro Banno Harukuni Tokuda Reiko Nishihara Yuji Nakamura Yumiko Kimura Ken Yasukawa Takashi Suzuki

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.29, no.9, pp.1976-1979, 2006 (Released:2006-09-01)

参考文献数

20

被引用文献数

46 56

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Fifteen triterpene acids, viz., seven of the β-boswellic acids (ursane-type) (1—7), two of the α-boswellic acids (oleanane-type) (8, 9), two of the lupeolic acids (lupane-type) (10, 11), and four of the tirucallane-type (12—14, 16), and two cembrane-type diterpenes (17, 18), isolated from the MeOH extract of the resin of Boswellia carteri (Burseraceae), together with a triterpene acid 15 (the acetyl derivative of 14), were examined for their inhibitory effects on the induction of Epstein–Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and on activation of (±)-(E)-methyl-2[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitrogen oxide (NO) donor, and cytotoxic activities against three human neuroblastoma cell lines, IMR-32, NB-39, and SK-N-SH in vitro. On evaluation against the EBV-EA activation induced by TPA, seven compounds, 2, 10, 11, and 13—16, showed potent inhibitory effects on EBV-EA induction. Upon evaluation against activation of NOR 1, five compounds, 7, 13, and 14—16, showed potent inhibitory effects. Further, fifteen compounds, 1—7, 9—11, 13—15, 17, and 18, exhibited potent cytotoxic activities with IC50 values of 4.1—82.4 μM against all of the three human neuroblastoma cells tested.