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Vestnik FEB RAS. 2018. № 6 Supplement
September 4-8, the 3rd International Symposium "Life Sciences" took place in the G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Sciences (PIBOC FEB RAS). Scientists from Germany, the Republic of Korea, China and Taiwan, as well as members of scientific organizations from Moscow, Krasnoyarsk, Novosibirsk, were invited to participate in the Symposium. A total of 55 oral presentations and 26 poster presentations were made on research in various fields of the science of wildlife, in particular, biologically active compounds of natural origin. Representatives of the sponsors -"General Electric" and "Shimadzu", who made presentations on their activities and presented an exhibition of their products, took part in the Symposium. The preparation of the Symposium was partially funded by the RFBR (project No. 18-04-20060) and the FANO RF, as well as the endowment fund PIBOC FEB RAS.
As part of the Symposium, the accompanying symposium "K0RUS-2018" was also held, which was attended by leading scholars from several universities of the Republic of Korea: Adju University (Suwon), Catholic University of Daegu, Injo University, Kosin University and Pusan and National University (Pusan), Catholic University (Seoul). This symposium is held regularly in order to summarize the results of joint Russian-Korean research.
UDC 577.1 DOI: 10.25808/08697698.2018.202.6S.001
VALENTIN STONIK
Some Results
of International Collaboration of G.B. Elyakov Pacific Institute of Bioorganic Chemistry of the Far-Eastern Branch of the Russian Academy of Sciences
During its more than fifty years history the G.B. Elyakov Pacific Institute of Bioorganic Chemistry (PIBOC) was successfully collaborating with many scientific organizations. Some examples of this cooperation and their scientific significance are discussed in this paper.
In the next 2019, 55 years from the day of the foundation of our institute will be celebrated. Decision of the Council of Ministers of the Soviet Union about organization of Institute of Biologically Active Substances of the Siberian Branch of Academy of Sciences of the USSR (now Pacific Institute of Bioorganic Chemistry, PIBOC) in Vladivostok was made on Octobers, 3, 1963. President of the Academy of Sciences of the USSR, Academician Mstislav Keldysh had signed Resolution No. 79 on the establishment of this Institute on March 6, 1964. Georgy Elyakov, 35-year-old scientist, candidate of chemical sciences, graduate of the Moscow State University became director of this new Institute. After the defense of the master's thesis
* STONIK Valentin Aronovich - Academician of RAS, Chairman of the Organizing Committee of the 3rd International Symposium on Life Sciences, Research Superviser (G.B. Elyakov Pacific Institute of Bioorganic Chemistry, FEB RAS, Vladivostok, Russia).
he did some work in the Central Research Military-Technical Institute and from 1959 worked in the Department of physiology and biochemistry of the Far-Eastern Filial Branch of Academy of Sciences of the USSR, passing on Far East of Russia a way from a senior scientific researcher to the Director of Institute (1964-2001), Academician (1987), Chairman of the Presidium of the Far Eastern Branch (FEB) and Vice-president of the Russian Academy of Sciences (RAS) (1990-2001).
I was fortunate enough to be the second Director of PIBOC of the next period from 2001 to 2017.
Collaboration with Japan
In the first years of its existence, the main activity of our Institute was related to the studies on biologically active substances from the Far-Eastern terrestrial plants, including the famous ginseng. At that time the Institute collaborated with not only Soviet scientific organizations, primarily the Institute of Chemistry of Natural Compounds (now M.M Shemyakin and Ju. A. Ovchinnikov Institute of Bioorganic Chemistry RAS) and the N.D. Zelinsky Institute of Organic Chemistry RAS, but also with Japanese scientific groups headed by Prof. Shoji Shibata and Osamu Tanaka at the Tokyo University and University of Hiroshima, respectively. Since the first isolation of six panaxosides (ginsenosides) from P. ginseng in the 1960s by the scientists of our Institute [6], plenty of ginsenosides have been isolated and identified from different species belonging to the genus Pana-n. Currently, more than a dozen plants have been recognized as members of the genus Panax. Some of them have common names, which stem from their places of origin: P. ginseng, P. japonicus, P. notoginseng, P quinquefolius, and P vietnamensis are also called Korean ginseng, Japanese ginseng, Chinese ginseng, American ginseng, and Vietnamese ginseng, respectively. Creative competition of Japanese and Soviet chemists from PIBOC led to the establishment of structures of a large series of triterpene glycosides responsible for the biological activity of extracts from ginseng [7, 24, 32] (Figure 1). This had contributed to the widespread use of ginseng extracts in medicine and other fields. Totally, >6,000 articles regarding the traditional uses, chemical structures of constituents, and biological and pharmacological effects of ginseng have been published since W. Petkov reported the pharmacological properties of extracts of the Far-Eastern species P ginseng for the first time in the 1950s [21].
Panaxoside A (Ginsenoside Rg1) Ginsenoside Rh2 Ginsenoside F1
Figure 1. Structures of some ginsenosides from Panax ginseng
Many years later joint studies with Japanese microbiologists were initiated with participation of Dr. Naito Tanaka from Tokyo University of Agriculture, see for example [23].
Collaboration with Australia
In the beginning the seventies PIBOC has started the studies on marine natural products.Thesestudie s are now developing in many countries. They resulted in discovery of ew classes of natural products and creation of new drugs against dangerous diseases. More than 30,000 new natural compounds (low molecular weight compounds and biopolymers), describedin approximatelyl0,000 scientific articles were isolated by natural products chemists
from marine macro-andmicroorganismsdimng allthe j^eriodc^fthce studies. Discoveiyof new marine bioactive compounds has opened new directions of bioregulation in living organisms, stimulated the devdnpme nt of phyeicochenucalwetdads toebtdbiishve rycompOinated cheBtal structures of biomolecules. Modern techniques to separate complex mixtures of natural products existing in naturewrreappeared. New chemicP rcaations add rengeheswere eiabOTased tidecide problems concerning total synthesis of natural compounds of particular interest.
Marine expeOeeons and Marina Expedmenlal Statlon oh onr ieptiiute, ereated rn thn shorn of Trinity Bay 100 km southward of Vladivostok played an important role in the development of this scientific direbtion. Dpgng aumerouimarinn expeditionhin diifeeenw ^^^e^^^g^careae ob Indian, Pacific and Atlantic oceans many groups of scientists from USA, Australia, Socialistic Republic of Vietnam, Rephblrc ohKwreagndnthcr cpuniries were aarCpeeating idjoint smhtes onboard of the research vessel "Akademik Oparin". Scientific cooperation continued after the return of these sclentisls in tdcir hon^eroi^i^^its. Thisiedto anumben aO^oigt peblirattohs ;rnd fairly visible scientific discoveries.
For example,a potentadtitnwdtagenlwasdoscdveredtodnmeowitnAuslrali;мL scieniisls from an ascidian, collected in the Great Barrier Reef area. During several years Drs Sergei Fedoreev and OiachehdvNhvikov from PIBOC together with Australian scientists Peter Murphy and Rick Willis from Australian Institute of Marine Science (Townsville) had been studying this new marine alkaloid named as polycarpin (Figure 2). Biotesting in the National Cancer Institute (USA) showed a potent cytotoxicity of this alkaloid against tumor cells as well as the capability to inhibit reverse transcriptase, a key enzyme in the search for antiviral compounds. Polycarpin as well as its derivatives and analogs were synthesized [22]. Up to now some obtained derivatives belonging to this series retain to be good model compounds to develop a leader compound and create new anticancer and/ or antiviral drugs on their basis.
An outstanding Australian scientist Professor Joe Baker (1926-2017) was supporting the collaboration and brotherhood between PIBOC and Australian scientists quite a ^rcqotiWetime. inspientionalteader of
the Australian marine science community. After his academic career in chemistry at James Cook University and foUowrngtea^rsM.) oh lyeRocnhResrarcgtnshtnleafMarine Plhfmpcflfк Prof. J. Baker founded marine biodiversity research at the Australian Institute of Marine Science (AIMS)infbwnrsbПe. As a resplt, AIMS hre contwbntediinntficantiy do thegrawt. o. aquaculture industry in Queensland and several highly active natural compounds from sponges and ascidians were c°icavereO.
Marine microbiology is another scientific field of joint interest of Russian and Australian scientists. The corresponding studies were activated after migration of Professor Elena Ivanova from PIBOC to Swinburne University of Technology in Melbourne. Many new species of marine bacteria were discovered in result of joint efforts and their properties described in a series of scientific articles. For example, in one of recent papers a novel species of gramnegative, non-pigmented, motile bacteria Thalassospira australica was described on the basis of phylogenetic and genomic analysis and analysis of physiological and biochemical properties of two strains isolated from a sea water sample collected at St. Kilda Beach, Port Philip Bay, Victoria, Australia. A study, based on a 16S rRNA gene sequencing, indicated that strains NP 3b2(T) and H 94 belong to the genus Thalassospira. The sequence similarity of the 16S rRNA gene between the two new isolates is 99.8 % and between these strains and all known validly named Thalassospira species was found to be in the range of 95-99.4 % [9].
Polycarpin
Figure 2. Structure of polycarpin
Last years, Professor Elena Ivanova is also well known in the scientific world by the studies oninteractionof different nature surfaces witiibacteria. For example, whenincubatedon cicada wings, Pseudomonas aeruginosa cells are not repelled; instead they are penetrated by the nanoptflar artays peesunton thewmf surfaec. rcssihing mtocterMceUrluathTterefore^kwdo wings are effective antibacterial, as opposed to antibiofouling, surfaces.
CallaborationwUd USA
Aetive coHabaratianwtth A^mericaasokftiste was mitiatedafter ^c^te^itff Amrritan scientist, novelist and playwright professor Carl Djerassi (1923-2015) into our Institute and its Mmine StationielDSWeeDjorossna wetr katcm as anaulsHndingscientirtwHomade a ereat contribution into the wide application of mass-spectrometry and circular dichroism spectroscopy in argDucahemistry Coe^c^ie^ton^e isoaaaknownoor Ms ccotriOutiante she A^^^r^iannseu of oral contraceptive pills for the birth control and as developer first antihistamines. In that time C. ^erar siwas studying^ too s" nteak o^nusa^tecok incurine o^roitms аgdprrtletsаriytn tpanges andsercuccmbeas. Wc^get^^n^ifi sc^iraAete iaoi^ PiBOC,fe rndO^s collaboratorsfrom Stanford University have published a paper concerning unusual sterols from the sea cucumber ErpentactafroaOatrix (giguteЗfandlheirbiarypteesis -e6B Dlsspaper war riU^(2il more i^an 40 times and stimulated further studies on biosynthesis of marine steroids.
Figure 3. Unusual methyl sterols from the sea cucumber Eupentacta fraudatrix
An important example of USA-Russia collaboration was concerned the studies on marine natural ursducts no sressiug conccr-preventiveaelivctics.Taacoacscandinf projeateasronieB out together with scientists from the Hormel Institute of University of Minnesota (Prof. Zigang Dono)inthetegmWan of 21st century. Duricp seperalaeres Dr.Serari Fedortn hfdbpen ttpdyena cancer-preventive properties of several marine natural products isolated in PIBOC using different rapceronduoemolroihUarlinesinlhe Homrcnnrtnite. Tliasertudicshavr lcU patents and publications, for example [8]. Moreover, similar studies were continuing at PIBOC aotcrrjruminu Dt S^ectorov toourjrfSiCutfc
Long-term collaboration with Professor Ted Molinski (now working at the Scripps Institute of Oceanography, San Diego) on structures and properties of new marine natural products has OW tothedeprltpoenjoranewaoprtswn tathe eete^^otiop orabsolhte c^^id^gnritio^r af asymmetric centers in very complicated natural compounds [18].
Dr. VaieryVenwv,one oe meinour speeiahrSsin вass-sнfotramenD)])attoeesitworkmh arc the Department of Chemistry, Oregon State University together with Professor Duglas Borofski. ln roopcratiapwctn oнrrnsSituty,tD-s whppaardcoujveh'lmpartautshtdiessonceAanнtne development of electron capture dissociation (ECD), a mass-spectrometric method that has come tote re^^d us apotoнtialldnowerflil todl forrihfnnoti ng protainsaructures. ThrhHeнpntHajen that a radio-frequency-free electromagnetostatic cell could be retrofitted into a triple quad mass spectrometer to allow electron-capture dissociation without the aid of cooling gas or phase-specific electron injection into the cell. It may be concluded that their recent attempts to optimize ECD for protein analysis were very successful, see, for example [31].
CW/aAoraiiVw withSocialistic Republic of Vietnam.
The jomtstudiesonmarinenaiei^ produets ^fh\tietoasiesesc^^nti^t^^ f erebased on marine expeditions in Vietnamese waters on board of the research vessel "Akademik Oparin" and activated after 2004. Although the first Russian-Vietnamese marine expedition using eeeegcUvessel "M:sdeonkOperin" was organizehbs PIBOCmorethan SOpbSire ege,m 1987 (September 30 - November 29), only after 2004 such expeditions became systematic and many dozens hi Vietncmtse scienticis took part in tiem.ic fachsuchenpcditionshcdbeen cceraang in Vietnamese waters from December, 24 through February, 3, 2004; from May, 04 through June 18, h0e7; mNovember-Decamoec,2016; anil in Jofy-Anjpan, 20th.Vietn;edestpmticipania ef our ehpadiWonabepeesented ^^-^^eel scVe^teU^ orpepizjiiens bdengmi io Actdsmyce Sbtenbb and Technology of Vietnam, namely Institute of Oceanography (Nha Trang), Institute of Chemistry ofNaSuraf Prodht^ss (E^^bh, instihiteof l^afs Biochemiejry SA^e^^id, NhatranpliAhtute of Technology Research and Application, Institute of Marine Environment and Resources
A number of new bioactive marine natural products were discovered (for examples, see [12] widFnalseo) as wellefAahonbwвtccAs o^erioemicroof^msmiwere collected fusSomtetud-ies. Morecoer, sb tertisli hrc^rc PIBOC (Prof. reTtf^c^^ Kc^rf tsohirMibhail
Kusaikin, Mikhail Pivkin, Alla Kicha, Natalia Ivanchina, Sergei Fedoreev, Natalia Mischenko anaothbIfi vtsitbd VibthembSb IrotiPited)PeVibnCbrJyinffinite otChemistecef Nitcra! Propucts (Hanoi) and Institute of Technology Research and Application (Nha Trang), to carry out joint ibve stigbtkmssnmerine ][mcroergArsms,polysarchariHei serin fuco.danr frem ^owp al-nab,Foаymbs from VtetI0iSbsemoliвsAs,sterold glnbcsiPecfiomriai"nsA, annаtnnoid pigmbnts from sea urchins. As result, fucoidans from Vietnamese algae have found a wide application in MedibinbeeVibtdam.An owceoltebtton of mariub mibroorgamsmiwas CTb^^ei^^ieiins b^^ntry and species identification of marine fungi from this collection was carried out by Dr. M. Pivkin. The Ooiieetion of Marieb MisroordosmfofPSBOCwes rbwlbmshb0wlthmanyppA ^beee s of marine bacteria and fungi.
Figure 4. Structure of some natural products from a sponge Penares sp.
Presidbnt of Vtetnam Abadbmy of Sbibnbb and Tbbhnology (VAST) Prof. Chau Van Minli has played an important role in the development of this Russian-Vietnamese cooperation in Marine Sciences. He is also coauthor of several joint publications (for example [14, 15]) with scientists from PIBOC. Professor Chau Van Minh was born in 1961 in one of the Northern Vietnamese hroomres. In IS8S, leb pradutbbdM . V. Lomenasoi Mostow ette rebdved
PhD level in Chemistry from the same University. Chau Van Minh is full professor in chemistry, hovinomотeihanr 50aetidifpnbltshed inIntesla0on;aepd Vtetoaiee^e^deASi0hsenmdj . As President of VAST, he is responsible person in Vietnam for scientific strategy and development hflmnc>rtanthrojeeis,plвnnjng-finanoiai rntrvitibs,orgawzaSloвeieadcdmfmsiratsvb artrnties, international cooperation management and inspection.
Collaboration with Republic of Korea
Very active collaboration was organized between PIBOC and several Universities from the Republic of Korea. Numerous low molecular weight and biopolymer natural compounds, discovered in our Institute became a good basis for the development of modern studies on their molecular mechanisms of action in the Republic of Korea.
Many years fucoidans and algal polysaccharides as well as bioactive glycosides from sea cucumbers are attracting a great attention in Asian countries as immunomodulators and anticancer agents. Studies on different fucoidans including those obtained from our Institute were carried out in Dong-A University School of Medicine, Busan, by Professor Jong Young Kwak. He was the Director of Immune-network Pioneer Research Center, sponsored as one of the Pioneer Research Center Program by the National Research Foundation of Korea. Taking into attention results of more than fifteen scientific articles published together with Russian scientists, Prof. J. Kwak was elected as Doctor Honoris Causa in the Russian Academy of Science in 2012. He was appointed as Professor at Department of Pharmacology, Ajou University School of Medicine, Korea from 2015 and continued scientific contacts with PIBOC.
As an example of joint studies with his group, action of fucoidans on dendritic cells may be mentioned. Dendritic cells are the most potent antigen-presenting cells for naive T cells. It was shown that scavenger receptor class A type I and type II (SR-A) are expressed by peripheral blood and monocyte-derived dendritic cells. The binding of anti-SR-A antibody to these cells was lower in the presence of fucoidan, which is an SR-A agonist [11].
Studies on anticancer properties of fucoidans from some brown algae have been carried by Dr. Svetlana Ermakova and Professor Tatyana Zviagintseva with their students in collaboration with College of Pharmacy, Chosun University, Gwangju. The inhibitory effects of Costaria costata fucoidan were examined on UVB-induced matrix metalloprotein-1 promoter, mRNA, and protein expression in vitro using the immortalized human keratinocyte (HaCaT) cell line. Pretreatment with fucoidan significantly inhibited this enzyme expression compared to UVB irradiation alone. Therefore, this fucoidan may be a potential therapeutic agent to prevent and treat skin photoaging [19].
Professor Joo-In Park from the same Dong-A University has carried out several very impressive studies on sea cucumber glycosides isolated at PIBOC as potent antileukemic agents.Acute myeloid leukemia is a disorder exhibiting the accumulation of immature myeloid progenitors in the bone marrow and peripheral blood. Standard antileukemic healing requires intensive combination chemotherapy, often leading to significant treatment-related toxicity. Low toxic marine secondary metabolites, inducing the generation of ceramide in leukemic cells are new anticancer agents to improve the therapy of leukemia. The antitumor activity, related to ceramide metabolism, of some marine metabolites, including stichoposides extracted from sea cucumbers of the family Stichopodiidae, was recently reviewed in a joint Korean-Russian paper [17]. Very potent antileukemic activity in vivo was reported for a series of glycosides, including holotoxin Aj from the sea cucumber Apostichopus japonicus [28].
Impressive results were obtained in result of joint studies on pigments from sea urchins, particularly echinochrome A, an active substance of medical drugs belonging to the series "Gistochrome" (Figure 5). Two drug forms, so-called "Gistochrome for ophthalmology" and "Gistochrome for cardiology" have been permitted for application and industrial production in the Russian Federation. Echinochrome A was reported to have antioxidant properties and a cardio protective effect against ischemia reperfusion injury. Together with Korean scientists from Jnje University, Busan (Laboratory of Professor Jin Han), its potent effects on mitochondrial activities and metabolisms in heart tissues were established. Actually, this natural product enhances the mitochondrial biogenesis and oxidative phosphorylation in rat cardio myoblast H9c2 cells, increases the mitochondrial mass, level of oxidative phosphorylation, and mitochondrial biogenesis regulatory gene expression. The treatment with echinochrome A did not induce cytotoxicity, but enhanced oxygen consumption rate and other mitochondrial functions [10].
Echinochrome A Neopetroside A Monanchomycalin A
Figure 5. Some natural compounds, studied together with Korean scientists
Moreover, joint studies with this Korean group have shown that male Sprague-Dawley rats after administration of echinochrome A [0.1 mg/kg, daily 30 min before each exercise training (swimnung)] increased theexercise capacity significctlylugher compared tocontrol groups. The rats carried out more work and were capable to more enduring swimming. There were no significant ctoiges m theplasma laids amorng die ggisorin^e^nt)^l amd g^oaps. Hawever,
tie muscto m^tstnh^ct^i^ria content cats netter io echinoohromr treated stups. ^^asa findings show that this natural product enhances exercise capacity, which is associated with an increase mitochfndria)ranOySS2a].
It is of particular interest that another natural product, so-called neopetroside A, an unusual ribos.de tFi°ure y) isylctedatPtCOCfrom 1ue oponge nnddhpreoinsp.war bltt rkswn by Profes sorJin dan topossess etimnlat:oty actian on mitonhotdrial functions in cardiomyocytes [25].
Alongneim cottnborfCnnwien grouo fromlheMarine Уfturolproduc1r laboratoty iiN.Hyi-Seung Lee) of Korea Ocean Research and Development Institute led to strucheue elucogetion of a series of new marine alkaloids from Pacific sponges, see, for example, studies on monmcgamycahl1У (Fittee Sir!?].
Joint studies in the field of marine microbiology between PIBOC and Republic of Korea were searted ia tpe e^gimyu^ of ehi 19ecs. New Kirea Rle^c^ IcsOiMe rf Blasc1enceand Biolectmakises,naнeiyOs Biotohifa1ResaurcfConter ts onooathe matn our pcwalprr dor teese studies. For example, very recently a gram-stain-negative, rod-shaped, yellow-pigmented bacteriumldcsonntedrSnLn DAia 139 (T)and lrolotedfrom Ur UeceiScred aiycCUnfeltia tobuchiensis, was investigated. The phylogenetic analysis based on 16S rRNA gene sequences skrwedtoal ihenueglsttoin befongrd to the genus Polaribacter. This new isolate and the type strains of recognized species of the genus Polaribacter were readily distinguished based on a number of phenotypic characteristics. A combination of the genotypic and phenotypic data showedrhesehee bi^^te^^m regresgnesanoeel spccies nS the genus Polaribacter, named as Polaribacter staleyi sp. nov. [20]
CoUyUnenrion wrthPaople'j RepublrcgfChma
Dr.Li WriУglshedfnst-eroduatestudiehgtPIBOC its tUeendif lar0silnperihe ktS^^i^^hip of Prof. P.A. Lukyanov and last years was working at Dalian Ocean University. During long-term sC^ias ao tedim from mariwelnvertobratesandalnne his grouoey)1aborateo w^^O-eel:^^i^atory ofWLcmistrnoCNoninfcftioue rnenoWtyof PПrOC.aLed reeent)wtogpthrr w)-c scientistaOrom several scientific organizations of Taiwan (such as Institute of Biological Chemistry, Taiwan Natlnnal Umvereiiyanh etllsrs))-legrepprted diesgacestmc ttre cti Cucctiour oOs^ m
the sea mollusk Crenomytilus grayanus (CGL) collected from the sublittoral zone of Peter the Great Bay of the Sea of Japan. The crystal structure of this lectin was solved to a resolution of 1.08 angstrom, revealing a beta-trefoil fold that dimerizes into a dumbbell-shaped quaternary structure. CGL is capable to bind globotriose on the surface of breast cancer cells, leading to cell death. These findings suggest the use of this lectin in cancer diagnosis and treatment [13].
Another point of the Russian-Chinese cooperation is the Biology Institute of Shandong Academy of Science. Drs. Mikhail Kusaikin, Svetlana Ermakova, and collaborators from the Laboratory of Enzyme Chemistry of PIBOC together with Chinese scientists recently studied water-soluble polysaccharides from two specimens of brown alga Sargassum muticum, which synthesized heterogeneous sulfated fucoidans. Two of three fucoidan fractions from this alga collected in April 2014 contained mannogalactofucans, one - galactofucan (Fuc-Gal, 2:1). The alga specimen collected in June 2015 afforded two galactofucans of different structures (Fuc-Gal, 1:1 and 3:1). Studies on the antitumor activity of the obtained fucoidans and their modified derivatives showed a lack of cytotoxicity and the manifestation of activity against DLD-1 human colon carcinoma cells [30]. This collaboration concerned also anti-radiation properties of some algal polysaccharides.
Collaboration with Germany.
Joint studies with German scientists on marine bioactive compounds, possessing by immunomodulatory and anticancer properties are an important part of international scientific collaboration of our Institute. It is well known that spleen is a prime organ, in which immunostimulation takes place in mammalians. Proteome analysis was used by Drs Dmitry Aminin and Pavel Dmitrenok in joint studies with Proteome Center Rostock at University of Rostock (Germany) with participation of Oregon State University (USA) to investigate the elicited effects on mouse splenocytes upon exposure to sea cucumber triterpene glycosides cucumarioside A2-2 and frondoside A (Figure 6) . These compounds have been used to in vitro stimulate primary splenocyte cultures. Differential protein expression was monitored by 2D gel analysis and proteins in spots of interest were identified by MALDI ToF MS and nano LC-ESI Q-ToF MS/MS, respectively. Approximately thirty protein spots were differentially expressed. Prime examples of differentially expressed proteins were NSFL1 cofactor p47 and hnRNP K (down-regulated), as well as Septin-2, NADH dehydrogenase (ubiquinone) iron-sulfur protein 3, and GRB2-related adaptor protein 2 (up-regulated). Together with results from proliferation and cell adhesion assays, these data showed that cellular proliferation is stimulated by the studied triterpene glycosides. The studied triterpene glycosides were proposed to express their immunostimulatory effects by enhancing the natural cellular defense barrier that is necessary to fight pathogens and for which lymphocytes and splenocytes have to be recruited constantly [1].
Joint studies with Laboratory of Experimental Oncology, University Medical Center Hamburg Eppendorf, which is one of the largest hospitals in Germany, were very productive
Figure 6. Structures of some marine metabolites studied together with German scientists
as result of post-graduate studies of Drs. Sergei Dyshlovoy and Ekaterina Menchinskaya in this Center. A series exceeding a dozen of joint articles in high level scientific journals was published. As a very recent example, the investigation of anticancer properties of rhizochalinin (Figure 6), obtained at PIBOC from bipolar lipid rhizochalin, which was also discovered by our scientists, may be mentioned. Rhizochalinin (Rhiz) shows promising in vitro and in vivo activities in human castration-resistant prostate cancer. A global proteome screening approach was applied to investigate molecular targets and biological processes affected by Rhiz in this model system. Bioinformatical analysis of the obtained data predicted an antimigratory effect of Rhiz on cancer cells. Validation of proteins involved in the cancer-associated processes, including cell migration and invasion, revealed down regulation of specific isoforms of stathmin and LASP1, as well as up regulation of Grp75, keratin 81, and precursor IL-1 beta by Rhiz. A combination of Rhiz with MEK/ERK inhibitors PD98059 (non-ATP competitive MEK1 inhibitor) and FR180204 (ATP-competitive ERK1/2 inhibitor) resulted in synergistic anticancer effects [5].
Collaboration with Italy
Institute of Biomolecular Chemistry in Napoly (Italy) elaborates similar scientific directions when compared with PIBOC. Long-term collaboration with scientists from this Institute included exchange of scientists and joint studies on some marine biological objects collected in the Mediterranean Sea. For example, triterpene glycosides of three species of the Mediterranean Sea cucumbers Holothuria polii, Holothuria tubulosa, and Holothuria sp. were studied. Three new monosulfated biosides, holothurins B2, B3, and B4, along with the previously known holothurins A and B were isolated from the sea cucumber H. polii. Triterpene glycosides belonging to holothurin A and B groups were found in H. tubulosa, while only one individual glycoside, holothurin A, was isolated from Holothuria sp. The significance of holothurins as chemotaxonomic markers of the animals belonging to the genus Holothuria was confirmed [29].
Collaboration with France
Joint studies with the Station Biologique, Roscoff, France are connected with the establishment of the structure of hybrid algal polysaccharides carrageenans with the help of specific enzymes - carrageenases. The French side provided carrageenases and carried out partial enzymatic hydrolysis of polysaccharides. From the Russian side, carrageenans of the hybrid structure were obtained and structures of the products of enzymatic hydrolysis were established. In addition, within the frameworks of this cooperation, a search for bacterial strains, potential producers of enzymes capable of cleavage of carrageenans having a hybrid structure was carried out [3].
Collaboration with Poland
In the frameworks of agreement on scientific cooperation between PIBOC (Dr. Irina Ermak and collaborators) and the Ya. Kochanowski University, Kielce, Poland (Dr. Wieslaw Kaca) the interaction of the well-known polysaccharide chitosan with bacterial lipopolysaccharides of various structures was studied. A corresponding joint project was successfully developed. The Polish side provided samples of endotoxins of wild and mutant strains of bacteria of the genus Proteus and their structural components. The parameters of their binding with chitosans of different molecular weights were determined. The acute toxicity of the complexes obtained was determined [4].
The inhibitory effects of natural polysaccharides (carrageenans and chitosans) on the immunobiological properties of endotoxic lipopolysaccharides of bacteria belonging to the genus Proteus were established [2]
International Life Science symposiums
A great contribution in the development of international contacts of PIBOC was made by International Symposiums on Life Sciences which took a place in Vladivostok. The First International Symposium on Life Sciences was held from 2 to 7 September, 2008. About 70 its participants represented seven countries, including Poland, Germany, Republic of Korea, Socialistic Republic of Vietnam, People's Republic of China, France and Russian Federation. Scientists from PIBOC, A.V. Zhirmunski Institute of Marine Biology FEB RAS, N.D. Zelinsky Institute of Organic Chemistry RAS, Far Eastern State University, G.M. Somov Institute of Epidemiology and Microbiology SB MAS, Institute of Automation and Control Processes FEB RAS, Far-Eastern State Technical University, Seaside Research Veterinary Station, Vladivostok were among Russian participants. About 30% participants were young scientists and post-graduate students. Fifteen plenary lectures, 25 oral, and 20 poster presentations were delivered.
The lecture "Structure and biosynthesis of carrageenan: the main component of red algal cell wall structures" by professor William Helbert from University Piere and Marie Curie-CNRS, Station Biologique, Roscoff, France, stimulated the following joint studies on these polysaccharides in the both countries France and Russia.
The presentation "Studies on chemical constituents of Vietnamese starfish Anthenea pentagonala" by scientists from the Professor Pham Quoc Long Laboratory of Institute of Natural Products Chemistry VAST (Vietnam) demonstrated a great interest of Vietnamese scientists to bioactive compounds from marine invertebrates. The corresponding joint studies are continuing more than last 10 years.
Professor Jong-Young Kwak (Dong A-University, Republic of Korea) in his lecture"Antitumor and immunomodulating effects of fucoidan" reported very interesting results, which were later described in several joint publications.
An excellent presentation "Metabolites - the chemical language of microbe" was presented by Professor Hartmut Laatsch from the Department of Organic and Biomolecular Chemistry, University of Gottingen, Gottingen, Germany. He said "We just begin to understand this language of nature and try to compile the vocabulary and to decipher the grammar. Natural products are weapons and defense systems, attractants or repellents, or just communication signals, which are important for the survival of species. Also, resistance development of bacteria against antibiotics is such a logical and unavoidable reply on environmental effects, which we can only overcome by a better understanding of the 'microbial conversation'."
The Second International Symposium on Life Sciences was held from 4 to 9 September, 2013, and attracted more than 80 participants from the same countries and Thailand, delivered 10 plenary lectures, 39 oral and 28 poster presentations.
Before the beginning of the symposium, the Chairman of the Presidium of Far Eastern Branch RAS, Academician Valentin Sergienko and Chief Scientific Secretary of the Presidium, Corresponding Member of RAS Vuacheslav Bogatov wished the symposium participants fruitful work. Valentin Sergienko has noted: "It is symbolic that the symposium is held on the eve of the 50th anniversary of the PIBOC and the 85th anniversary of its founder and long-time leader, Academician Georgy Elyakov, who laid the foundations of the scientific directions, which will be discussed at this conference. These scientific directions have not lost their relevance up to now".
In her lecture, Dr. Min Qu (Dalian Ocean University) reported how, using the model of toxic hepatitis, the favorable effects of low molecular weight lipopeptides, obtained from the giant Chinese salamander mucus were established. The corresponding studies have opened up prospects for the development of new therapeutic drugs for the treatment of viral and toxic hepatitis and cirrhosis of the liver. These and other investigations of Chinese biochemists from Dalian were then continued in collaboration with Professor Pavel Lukyanov and his collaborators from PIBOC.
The lecture of Dr. Andrei Imbs from A.V. Zhirmunsky Institute of Marine Biology FEB RAS was devoted to the Russian-Vietnamese studies on distribution and biosynthesis of coral lipids, which participate in most of the biochemical and physiological processes of these marine animals.
The lecture of Professor Rita Bernhardt (Saarland University, Saarbrucken, Germany) was about the structural studies on cytochromes P450, key enzymes of biosynthesis of steroid hormones and in detoxification of xenobiotics, including drugs. They are widely used in the pharmaceutical industry for the production of steroid hormones and their modified analogues. Bioinformatic studies of Professor Bernhardt can be the basis for the creation of mutant forms of the corresponding proteins with enhanced enzymatic activity, which is of great importance for increasing the yield and quality of artificially produced steroids.
The studies, presented at the symposium by Professor Narongsaka Chayabutra (Institute of the Memory of Queen Sayyawabhi, Bangkok, Thailand) were of considerable practical interest. They were devoted to the molecular mechanisms underlying the development of renal failure in human poisoning with the poison of the Viper Russell (Dabola siamensis), widespread in Thailand.
During the breaks between the sessions, the symposium participants got acquainted with the research work in PIBOC, discussed plans for future joint studies. In his closing speech, the Chairman of the Organizing committee of the symposium, the Director of PIBOC, Academician Valentin Stonik noted that the reports presented at the forum demonstrated the high scientific potential of research conducted by scientists from different countries in the field of chemistry of marine natural compounds, biochemistry and biotechnology.
The Third International Symposium on Life Sciences of this series was held from 4 to 8, 2018. Communications of all the participants of this scientific meeting are published in this Issue of the scientific journal "Herald of the Far-Eastern Branch of the Russian Academy of Science". It is hoped that they will be of interest and useful to those who are involved in research in the field of bioorganic chemistry, biochemistry, molecular biology and biotechnology.
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