Valentine Day: 有名「国立大学」入試向け "英語" の出題例

本日は "バレンタイン=デー"。欧米の習慣によれば、恋人宛てに、熱い愛の囁き (メッセージ) をカードにたくして送る日。そこで、この日に因んで、間もなく迫る国立大学入試向けの (しゃれた) 英語の出題例 (記述問題) を受験生諸君へ送ろう。


出題問題:  恋人から、Valentine Card に添えて、"I  LOVE YOU" というメッセージをもらった。 この恋人に、返信すべき英語 を、Two Words で、記述せよ！

ヒント:  目下、欧米では、過去に上司から「セクハラ」などを受けた被害者 (主に女性たち) が、こぞって「       」運動を始めた。その結果、(トランプ大統領を除く) 有名な映画監督や政治家が失脚し始めた。 この 「     」 に入る Two Words が正解である。

2017 Lasker Award to Prof. Mike Hall, the Father of "TOR" (Target of Rapamycin)

Rapamycin is among antibiotics isolated by a Canadian team from a soil bacterium in Rapa, Nui, Easter Island, in 1975.  Originally, its was recognized as an anti-fungal compound. However, later it was found to be a potent "immune suppressor" useful for organ transplantation. Interestingly, it has an anti-cancer activity as well. However, because of its immuno-suppressive activity, it has never been a favorable anti-cancer drug. To a big surprise, however, around 2009, Rapamycin was found by a US team led by Dr. David Harrison to extend significantly (by 9-14%) the lifespan of old (20 months) mice. Thus, it is among natural elixirs (longevity-promoters).

 In 1991, a Swiss team led by Prof. Mike Hall at University of Basel (Biozentrum), identified its direct target, a kinase,  in yeast. Since then, this kinase is called "target of rapamycin" (TOR), and a mammalian homolog of TOR is called mTOR. In other words, mTOR is an oncogenic/ ageing kinase, as is PAK1. Is TOR essential for melanogenesis as well, as is PAK1?  According to 2016 article by a Taiwanese group, Hinokitiol (heptagonal ring compound) inhibits melano-genensis of B16F10 melanoma cells by inactivating mTOR.  Thus, it is most likely that mTOR is a melanogenic kinase. The PAK1-blockers called ivermectin causes autophagy through PAK1-mTOR pathway, clearly indicating that mTOR is down-stream of PAK1.

However, according to 2012 article by a Korean group, rapamycin promotes melanogenesis, instead of suppressing it.  Thus, there must be another target of rapamycin (called TOR2) in mammals, in addition to mTOR. Furthermore, KO (knock-out) of PAK1 promotes immune system, suggesting that PAK1 is immuno-suppressive, just like rapamycin.  Thus, immuno-suppressive effect of rapamycin must be due to a third target called TOR3, which is not down-stream of PAK1. Therefore, for cancer therapy it would be desirable to develop a new rapamycin derivative which does not interact with TOR3. 

Nevertheless, Prof. Mike Hall became a 2017 Lasker awardee.  Thus, it is most likely that PAK1 pioneer(s) would also join the "Lasker Club" or "Nobel Club" in a not-distant future.  

PAK family kinases come of age: Celebrating 40 years of discovery.

2018 Commentary to J. Cell Signal., accepted for publication (5/01/2018)

Hiroshi Maruta, PAK Research Center, Melbourne, Australia.

e-mail:  maruta20420@yahoo.co.jp

Introduction

Since our team at NIH found the very first member of PAK family kinases (called “myosin I heavy chain kinase”) in a soil amoeba in 1977 (1), this family of RAC/CDC42-dependent Ser/Thr kinases kept expanding their territory during the last four decades. Among this unique family, however, PAK1 has been most extensively studied so far, mainly because it is essential for malignant trans-formation of mammalian cells, but non-essential for normal cell growth (2), and shortens the healthy lifespan of small animals such as C. elegans (3), and is involved even in PDGF/a-MSH-dependent melanogenesis (4). For this reason, a variety of PAK1-blockers/inhibitors have been developed or identified since the turn of this century, and some of them such as propolis and 15K could be potentially useful for therapy of solid tumors, promoting the longevity by suppressing a variety of other PAK1-dependent diseases/disorders such as AD (Alzheimer’s disease), hyper-tension and diabetes (type 2), and even for the cosmetic treatment of hyper-pigmentation (so-called “skin-whitening”). Thus, the potential market value of these PAK1-blockers would be huge in both pharmaceutical and cosmetic industries. In this commentary, I shall briefly highlight the uniqueness of PAK1-blockers useful for signaling therapy causing no serious side effect, in contrast to conventional anti-cancer drugs such as DNA/RNA/microtubule poisons which clearly cause serious side effects such as hair-loss, suppression of immune system and loss of appetite. Rather surprisingly, these PAK1-blockers such as propolis and 15K promote hair growth and boost even our immune system (5, 6), easing the damaging side effects caused by conventional anti-cancer drugs.

References 

1. Maruta H, Korn ED. Acanthamoeba cofactor protein is a heavy chain kinase (PAK) required for actin activation of the Mg2+-ATPase activity of Acanthamoeba myosin I. J Biol Chem. 1977 ; 252: 8329-8332.
2. Maruta, H. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity. Phytother Res. 2014 ; 28: 656-672.
3. Yanase, S, Luo, Y, Maruta, H. PAK1-deficiency/down-regulation reduces brood size, activates HSP16.2 gene and extends lifespan in C. elegans. Drug Discov Ther. 2013; 7: 29-35.
4. Be-Tu PT, Nguyen BC, Tawata S, Yun CY, Kim EG, Maruta H. The serum/ PDGF-dependent “melanogenic” role of the minute level of the oncogenic kinase PAK1 in melanoma cells proven by the highly sensitive kinase assay, Drug Discov. Ther. 2016. 10:  314–322.
5. Nguyen BC, Taira N, Maruta H, Tawata S. Artepillin C and Other Herbal PAK1-blockers: Effects on Hair Cell Proliferation and Related PAK1-dependent Biological Function in Cell Culture. Phytother Res. 2016; 30: 120-127.
6. Huynh N, Wang K, Yim M, et al. Depletion of p21-activated kinase 1 up-regulates the immune system of APC∆14/+ mice and inhibits intestinal tumorigenesis. BMC Cancer. 2017; 17: 431.

 

Minocycline (MC) is a PAK1/MLK-inhibitor: Useful for therapy of brain tumors such NF

A brief review in “Brain Tumors” issue:

Is an old antibiotic “Minocycline” useful for NF therapy? 

Hiroshi Maruta, PAK Research Center, Melbourne, Australia.

ABSTRACT:

So far no effective FDA-approved drug useful for NF (neurofibromatosis) therapy is available on the market.  However, there emerged a good possibility that an old antibiotic called “Minocycline” (MC) could be used (prescribed) for NF therapy at least on a so-called “compassionate” ground. Why?  MC is a tetracyclin derivative, and has been used for therapy of a variety of infectious diseases (including cerebral malaria) as well as thrombosis during last 4 decades without any serious side effect. Besides the generic drug MC is far less expensive than Gleevec, the ABL/PDGFR/KIT-inhibitor, approved by FDA only for therapy of rare cancers such as CML and GIST. Recently a number of both preclinical and clinical studies strongly suggest that MC possesses a relatively strong anti-cancer, anti-inflammatory, anti-AIDS, anti-AD (Alzheimer’s disease), anti-PD (Parkinson’s disease), anti-schizophrenia, anti-depressive, and anti-melanogenic effects, all of which are closely associated with anti-PAK1 activity. Furthermore, it is obvious that, unlike FK228, MC passes effectively through BBB (blood brain barrier). Most recently, there emerged a paper by a US group clearly indicating that MC could be a direct PAK1-inhibitor, as is CEP-1347.  Lastly, it has been reported that MC indeed inhibits the growth of MPNST (NF1-deficient cancer) cells. Thus, it would be worth testing its anti-PAK1 activity in vitro first, and then its anti-NF2 (tumor) activity in cell culture as well as in vivo (against human NF tumor xenograft in mice) to get the FDA approval for NF therapy. 

Discussion

Tetracyclin (TC) is an anti-bacterial antibiotic developed in late 1940s, and inhibits the ribosome-based protein synthesis in bacteria, but not in mammals.  Thus, it selectively kills pathognenic bacteria without any serious side effect on mammals. However, bacteria gradually developed TC-resistance, and therefore TC is no longer used nowadays for therapy of infectious diseases.

According to a recent review on minocycline (MC), an old (long-lasting) TC derivative developed in 1961, the antibiotic MC has been successfully used for therapy of a wide variety of infectious diseases and thrombosis as well for more than 4 decades without any serious side effects (1).  However, since MC is now a “generic” drug, and is available on the market extremely inexpensive (100 mg costs only 30 cents), if you take 100 mg twice a day, it would cost you only 60 cents daily.

Furthermore, over 4 decade study has revealed that MC can be used beyond the ordinal antibiotics killing only pathogenic bacteria.  A wide range of other diseases appear to be among targets of MC (1), such as cancer, a variety of inflammatory diseases, AD (Alzheimer’s disease), PD (Parkinson’s disease), schizophrenia, depression, autism, obesity, hyper-pigmentation, and so forth. All of these diseases/disorders are among typical PAK1-dependent symptoms. Thus, there is a good possibility that MC is a PAK1-blocker.

In support of this notion, just like CEP1347 that inhibits both PAK1 and MLK (2), MC inhibits thrombosis (platelet aggregation) (3).  Most interestingly, MC enhances sleep and memory in clinical trials, clearly indicating that unlike FK228, MC passes through BBB (blood brain barrier) (4). In support of this notion, MC is effective for therapy of “cerebral” malaria in mice as well (5).   Thus, it is quite possible that MC would be useful for therapy of brain tumors in general.

How about NFs (neurofibromatosis type 1 and 2)?  Sadly so far no effective FDA-approved therapeutic is available on the market for NF patients as yet, except for propolis, natural PAK1-blockers made by honey bees.  Very recently, a group in Taiwan reported that MC is effective to suppress the growth of MPNST (Nf1-deficient cancer) cells (6). Thus, like propolis such as Bio 30 from New Zealand which has been successful for therapy of both NF1 and NF2 clinically, MC would be potentially useful for NF2 therapy as well. 
 
I should remind you that “Gleevec”, which blocks PAK1 by inhibiting Tyr-kinases (PDGFR/KIT), is also useful for NF therapy (7), but is very expensive. So MC could replace “Gleevec” soon.

References:

1. Garrido-Mesa N, Zarzuelo A, Galvez, J. Minocycline: far beyond an antibiotic. Brit. J. Pharmacol. 169 (2013). 337-352.

2. Neu TV, He, H. Hirokawa Y. et al. The K252a derivatives, Inhibitors of PAK/MLK kinase family selectively block the growth of RAS transformants.

3. Joseph W. Jackson, Affiliation Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America ⨯ Meera V. Singh, Vir B. Singh, et al. Novel Antiplatelet Activity of Minocycline Involves Inhibition of MLK3-p38 Mitogen Activated Protein Kinase Axis. PloS ONE 11 (2016), e0157115. 

4. Besedovsky L, Schmidt EM, Linz B, Diekelmann S, Lange T, Born J. Signs of enhanced sleep and sleep-associated memory processing following the anti-inflammatory antibiotic minocycline in men. J Psychopharmacol.  2017 ; 31(2): 204-210.

5. Apoorv TS, Babu PP. Minocycline prevents cerebral malaria, confers

neuroprotection and increases survivability of mice during Plasmodium berghei

ANKA infection. Cytokine. 2017 ; 90 :113-123.

6. Ko JC, Wang TJ, Chang PY, et al. Minocycline enhances mitomycin C-induced cytotoxicity through down-regulating ERK1/2-mediated Rad51 expression in human non-small cell lung cancer cells. Biochem Pharmacol. 2015 ; 97(3): 331-40.

7. Mukherjee J, Kamnasaran D, Balasubramaniam A, Radovanovic, Zadeh G, Kiehl TR, Guha A. Human schwannomas express activated platelet-derived growth factor receptors and c-kit and are growth inhibited by Gleevec (Imatinib Mesylate). Cancer Res. 2009 ; 69(12): 5099-107.