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Monday, February 27, 2017

Natural products for cancer prevention and therapy by targeting the arachidonic acid pathway

Abstract (as presented by the authors of the scientific work):

"Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A2s (PLA2s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA2s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed."

Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Conclusions and future directions (as presented by the authors of the scientific work):

"AA cascade, a metabolic pathway, has been found to have involvement in cancer initiation, promotion and progression. Roles of AA metabolizing enzymes and their products have been well characterized in cancer progression and development. Several chemical carcinogens, UV-radiation, tobacco, and proinflammatory cytokines are involved in carcinogenesis by activating multiple pathways, including AA cascade. PLA2s are a group of enzymes which initiate AA cascade by acting on membrane-bound phospholipids to form LPLs and AA. Further, the released AA is oxygenated by variety of oxygenases, including COXs, LOXs and CYP dependent monoxygenases to form bioactive signaling oxylipids like PGs, LTs and epoxy/hydroxy- eicosatrienoic acids respectively.

sPLA2s are first identified PLA2 isoforms and their roles in cancer have not been well characterized. Accumulated literature suggests that GIIA, GV and GX sPLA2s have key roles in inflammation, but several studies have demonstrated the anti-tumor activities of several sPLA2s isoforms. The role of sPLA2s in cancer is thus controversial and further investigations are required. Among GIV(A-F) cPLA2 isoforms, GIVA cPLA2 plays an important role in initiation and progression of inflammation and cancer and it can be a novel chemopreventive and therapeutic target. Several research findings suggested that iPLA2 is also involved in carcinogenesis, but it has been characterized as housekeeping enzyme. LPLA2 is also necessary for normal physiological functions. Lp-PLA2 does not have significant involvement in cancer. Surprisingly, AdPLA exhibits tumor-suppressive activity.

COX has two important isoforms COX-1 and COX-2. COX-1 is a constitutive enzyme but COX-2 expression is observed in several cancers. As the conventional NSAIDs inhibit both COX-1 and COX-2, they were found to have many side effects as a result of inhibition of cytoprotective COX-1. In this scenario, COX-2 selective inhibitors (COXIBs) have been believed to be safe drugs. However, their clinical utility has been hampered due to their side effects. Several synthetic COX-2 inhibitors were withdrawn from the market due to their severe adverse effects. Although most of the pro-tumorigenic activity of COX-2 is attributed to the generation of PGE2, it is important to highlight that the other COX-2-derived products can also affect tumor development. Accumulating evidences suggest that EP(1-3) have pro-tumorigenic roles in several cancers and their antagonists/genes suppressors can be potential chemopreventive agents. Recent findings suggest that COX-2 and PGs have key role in the development of drug resistance in cancer patients undergoing chemotherapy. In this scenario, inhibition of COX-2 pathway could be a potential strategy to overcome the drug resistance problem. 5-LOX and its major metabolic product, LTB4, have been characterized as novel chemopreventive targets for cancers among other LOX isoforms. Moreover, BLT1&2, receptors for LTB4 have been characterized as protumorigenic mediators. In this context, antagonists for BLT1&2 can be developed as novel chemopreventive agents.

Recent findings suggest that pathway diversion is a major problem in targeting the AA pathway. For instance, COX-2 pathway inhibition caused shunting AA metabolism towards the LOX or CYP pathways. In the same way, 5-LOX inhibition caused shunting AA metabolism towards the COX-2 or CYP pathways. In addition, recently identified HK pathway linked with both 5-LOX and COX-2. Hence, blocking two major pathways involved in carcinogenesis, namely the 5-LOX and COX-2 pathways, can be a plausible approach to better inhibit cancer progression. At the same time, PLA2 initiates the AA cascade and inhibition of PLA2 prevents the liberation of AA and LPLs. Hence, researchers have been considering PLA2s to be a better therapeutic target than the downstream enzymes, namely COX-2 and 5-LOX. However, a fundamental problem in drug development is diversity and redundancy in PLA2 isoforms. Moreover, complete physiological roles of PLA2 isoforms are not clearly known. However, several recent findings suggest that inhibition of AA specific-GIVA cPLA2 is advantageous as it is upstream to COX-2 and 5-LOX and prevents liberation of AA and LPLs. Overall, multi-targeting of AA pathway is highly advantageous for effective prevention and/or treatment of several cancers.

Realizing the role of AA pathway in several cancers, considerable efforts are being made to the discovery and development of inhibitors of AA pathway as cancer preventive and therapeutic agents. NSAIDs have been explored as chemopreventive agents for several cancers. However, several side effects associated with usage of NSAIDs hampered their clinical applications. Natural products have a much better safety profile than synthetic molecules. In this context, research on AA pathway inhibitory natural products has gained momentum to develop them as novel chemopreventive and therapeutic agents. Apigenin (1), anthocyans (2), baicalein (3), berberine (4), curcumin (5), diallyl sulfides (6), ellagic acid (7), epigallocatechin gallate (8), eugenol (9), fisetin (10), garcinol (11), genistein (12), [6]-gingerol (13), guggulsterone (14), indole-3-carbinol (15), lycopene (16), nordihydroguaiaretic acid (17), C-phycocyanin (18), piperine (19), quercetin (20), resveratrol (21), silibinin (22), sulforaphane (23), thymoquinone (24), triptolide (25), ursolic acid (26) and wogonin (27) are some of the important AA pathway targeting natural products which have been identified from natural sources and these are under development as cancer chemopreventive and therapeutic agents at various stages, including their clinical development.

Curcumin, berberine and garcinol blocked multiple COX-2, LOXs and cPLA2 pathways, thereby exhibiting chemopreventive and therapeutic potentials against several cancers. Resveratrol exerted chemopreventive activity by blocking COX-2, LOX and CYP pathways. Thymoquinone, garcinol, lycopene and piperine exhibited dual 5-LOX and COX-2 inhibitory activities. Baicalein showed chemopreventive and anti-cancer activities against several cancers by inhibiting 12-LOX. NDGA exhibited anti-cancer activities by inhibiting the activities of 5-LOX, and other LOXs. Apigenin, cyanidin-3-glucoside, delphinidin, curcumin, diallyl sulfide, fisetin, [6]-gingerol, resveratrol, silibinin, and wogonin prevented UVB radiation-induced skin carcinogenesis by inhibiting COX-2 pathway. Curcumin, guggulsterone and indole-3-carbinol blocked tobacco and its constitutents-induced inflammation and carcinogenesis by down-regulating COX-2. Apigenin, curcumin, genistein, [6]-gingerol, gugglosterone, piperine, resveratrol, silibinin, sulforaphane and ursolic acid prevented chemically-induced tumorigenesis by targeting COX-2 pathway. Berbeine and ellagic acid suppressed cPLA2 expression while garcinol prevented activation of cPLA2 by inhibiting its phosphorylation. Curcum suppressed cPLA2 expression and prevented cPLA2 activation by inhibitiong MAPK-mediated phosphorylation. Rosmarinic acid reported to possess sPLA2 and COX-2 inhibitory activities. Several PLA2-inhibitory natural products have been identified, but their anti-cancer efficacy has not been examined systematically. Metabolic pathway diversion is a major problem in development of AA pathway inhibitors. Seveal studies suggest that either COX-2 or LOX inhibitor are ineffective in countering inflammation and thus inflammation-induced carcinogenesis. Recently we have isolated COX and 5-LOX dual inhibitory compounds dammarane triterpeniod 1 and chebulagic acid from seed coat of B. flabellifer and fruits of T. chebula respectively, and found their anticancer and pro-apoptotic potentials in cancer cells. Also COX-2 and 5-LOX dual inhibitors have been developed by several other groups which are at different stages of clinical development. Futher in vivo anticancer, toxicity and pharmacokinetic studies are required for their clinical developemnt.

Natural products, in genral, are known to exhibit better safety profile in toxicity studies and are non-mutagenic and non-genotoxic in nature. Curcumin is characterized as non-toxic and “Generally Recognized As Safe” (GRAS) by the US FDA. However, recently a committee of the FDA voted to prohibit its use intravenously due to inadequate evidence of safety or efficacy. This decision is not yet law in the US, and is currently being challenged. Recent reports on genotoxic effects of [6]-gingerol are controversial and need futher investigations. Anthocyans are less toxic with anti-oxidant and anti-genotoxic potentials. The available data is not sufficient to conclude that anthocyans are less/non toxic. Further, a detailed and long-term toxicity studies on anthocyans are required. NDGA was once classified as “Generally Recognized As Safe” by US FDA but later this classification was withdrawn due to its toxicity concerns. NDGA was not overtly toxic at low doses. However, high doses of NDGA have been associated with several adverse effects. Further detailed studies are necessary to get clarity on toxic effect of NDGA which is a major problem in clinical use of NDGA. Eugenol, a cancer chemopreventive agent, exhibits genotoxic and carcinogenuc properties. Aspirin eugenol ester, a hybrid molecule, shows comparable anti-inflammatory activity with aspirin and eugenol, but it is no or less toxic. Resveratrol, curcumin, ellagic acid, silibinin and thymoquinone exhibit protective effects against xenobiotic-induced toxicity in addition to their safety profile in toxicity studies. C-Phycocyanin containing water extract of Spirulina, generally recognized as safe by US FDA, is a promising agent as potent anti-oxidant, anti-inflammatory, chemopreventive and chemotherapeutic agent for variety of cancers. However, its high molecular weight and delivery problems limit its further development as a clinical agent. Hence there is need for identifying a fragment of this biliprotein without loosing its therapeutic properties.

Bioavailability of the natural products is a major problem for their clinical development. Several nano-particle based drug delivery methods have been explored for improvement of bioavailability of natural products. Also several analogs of the natural products have been synthesized with enhancement of their bioavailability as well as improving therapeutic potentials. Aspirin, acetyl ester of salicylic acid, is the most successful anti-inflammatory drug developed as a natural product analog targeting COXs. Several analogs of the natural products have been synthesized with enhancement of their bioavailability. Internal metabolization is one of the reasons for low bioavailability of curcumin, resveratrol and other natural products. Piperine enhances the bioavailability of curcumin as well as resveratrol by inhibiting internal metabolization of these phytochemicals.

Combinatorial therapy using AA pathway-inhibitory natural products may also be advantageous not only for improving the chemopreventive efficacy, but also useful in overcoming the several problems, including bioavailability and drug resistance. Combinations of piperine with curcumin or resveratrol caused enhancement of bioavailability of both compounds and exhibit better chempeventive efficacy. Combinations of indole-3-carbinol and silibinin effectively prevented carcinogen-induced lung tumorigenesis in mouse by suppressing pro-inflammatory and pro-carcinogenic mediators, including COX-2, than alone. Ursolic acid in combination with resveratrol effectively prevented TPA-induced skin tumor promotion by suppressing inflammatory mediators, including COX-2. Several studies proved that eugenol and combination with sulforaphane or gemcitabine can be useful for chemoprevention of cervical cancer. Lycopene and fish oil acted synergistically as chemopreventive agents against colon carcinogenesis by blocking COX-2 pathway. Therefore, various combination/formulation of AA pathway-inhibitory natural products may be useful to improve its efficacy towards cancer prevention and therapy.

Drug resistance is a major problem in current chemotherapy for cancers. We and others have suggested that COX-2 and PGs have key roles in drug resistance in cancer and their inhibitors can be useful to reverse the drug resistance and sensitize the chemoptherpeutic drugs. C-phycocyanin, a COX-2 selective inhibitor, inhibited MDR1-mediated drug resistance in HepG2 cells. Drug resistance-inhibitory potency of C-phycocyanin was due to its COX-2 inhibition activity and by inhibiting ROS generation. Similarly it was shown by several investigators have shown that celecoxib and guggulsterone overcome imatinib resistance and induces apoptosis in imatinib-resistant leukemic cells by inhibiting COX-2 and P-glycoprotein. Hence, researchers may explore COX-2 inhibitory natural products as sensitizers of drugs and/or inhibitors of drug resistance.

Overall, research on development of AA pathway inhibitory natural products in cancer prevention and therapy is in good progress. Safety profile of AA pathway inhibitory natural products in toxicity studies represents an advantage for their clinical development. However, poor bioavailability of the AA pathway inhibitory natural products is a major problem for their clinical development as cancer chemopreventive and therapeutic agents. At the same time, several alternative strategies have been developed by several investigators to enhance the bioavailability of some of the natural products. In this context, discovery of new inhibitors of AA pathway from natural sources as well as a detailed investigations including clinical evaluation on existing AA pathway inhibitory natural products are needed for their development as effective and safe drugs for cancer prevention and therapy."

The referenced scientific work at PubMed:

Yarla NS, Bishayee A, Sethi G, Reddanna P, Kalle AM,
Dhananjaya BL, Dowluru KS, Chintala R, Duddukuri GR.
Targeting arachidonic acid pathway by natural products for
cancer prevention and therapy. Semin Cancer Biol.
2016 Oct;40-41:48-81. doi: 10.1016/j.semcancer.2016.02.001.

Full-text access:


Prof. Atanas G. Atanasov (Dr. habil., PhD)

Thursday, February 23, 2017

Ageing, neurodegeneration, and brain rejuvenation (NATURE INSIGHT REVIEW)

Abstract (as presented by the author of the scientific work):

"Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of the essence of being. Ageing, which is fundamental to neurodegeneration and dementia, affects every organ in the body and seems to be encoded partly in a blood-based signature. Indeed, factors in the circulation have been shown to modulate ageing and to rejuvenate numerous organs, including the brain. The discovery of such factors, the identification of their origins and a deeper understanding of their functions is ushering in a new era in ageing and dementia research."

Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Outlook (as presented by the author of the scientific work):

"In humans, the old brain shows the classic hallmarks of ageing and is particularly susceptible to abnormal protein accumulation and impairments in the phagolysosomal system, which leads to fluid boundaries between ageing and neurodegenerative diseases. Consequently, many old people have pathological abnormalities of the brain that do not necessarily correlate with their cognitive abilities. This has important implications for the treatment of those with clinical symptoms as well as for designing clinical trials to target protein abnormalities in a specific manner. Given the crucial functions that immune responses and inflammation have in brain ageing and neurodegeneration, it will be essential to discern beneficial attempts to maintain or repair damage from maladaptive ones. Clearly, the term neuroinflammation fails to capture the age- or disease-related changes in this sophisticated interplay between the surveillance, identification, targeting and execution functions of immunity and should probably be avoided. When studying age-related neurodegenerative diseases in animal models, it is important to consider ageing; those that have been genetically engineered to develop disease during adolescence and before midlife are unlikely to be influenced sufficiently by ageing and are therefore not very informative about age-related factors in sporadic neurodegeneration.

The increasing number of studies that show systemic effects on the brain, including those of young plasma or heterochronic parabiosis, as well as the effects of the microbiome, should remind neuroscientists that neurons do not function in isolation; instead, they are part of a sophisticated network that includes glial cells, vascular cells and peripheral cells.

So far, there is no published evidence that young blood or plasma has beneficial effects on an ageing human body, and the observation that young plasma can modulate brain ageing in mice presents more questions and opportunities than answers. Only a handful of proteins, which might represent factors involved in ageing or rejuvenation, have been shown to mimic the effects of plasma. However, many more proteins or other types of molecules are likely to exist, some of which might have direct therapeutic applications. Basic research will address the exciting questions that surround the origins of these factors, how they signal to the brain and why they change with age. Ultimately, it is hoped that by using such knowledge to alter basic processes involved in ageing, it will become feasible to counter the cellular abnormalities that lead to neurodegeneration."

The referenced scientific work at PubMed:

Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation. Nature. 2016
Nov 10;539(7628):180-186. doi: 10.1038/nature20411. Review. PubMed PMID:
27830812; PubMed Central PMCID: PMC5172605.

Full-text access:


Prof. Atanas G. Atanasov (Dr. habil., PhD)

Wednesday, February 22, 2017

Polyphenols 2017 Scientific Conference at Vienna, Austria


Polyphenols Applications 2017 World Congress (the 11th edition of this congress series) will take place on June 20-21, 2017. This event will be hosted by the University of Vienna, Austria. Covered topics include:

• Role of polyphenols in degenerative/chronic diseases
• Interactions between polyphenols and gut microbiota
• Bioavailability and metabolism of polyphenols
• The toxicological aspects of polyphenols
• Effects of conventional and novel processing technologies on polyphenol stability
• Novel approaches in polyphenol chemistry and analysis
• Applications of polyphenols in foods, beverages and cosmetics

Further information

List of the invited speakers who confirmed participation and further information about the conference can be viewed at the conference website.


Prof. Atanas G. Atanasov (Dr. habil., PhD)

Tuesday, February 21, 2017

Therapeutic properties of ferns: a 2017 comprehensive scientific review

Abstract (as presented by the authors of the scientific work)

"Ferns are an important phytogenetic bridge between lower and higher plants. Historically they have been used in many ways by humans, including as ornamental plants, domestic utensils, foods, and in handicrafts. In addition, they have found uses as medicinal herbs. Ferns produce a wide array of secondary metabolites endowed with different bioactivities that could potentially be useful in the treatment of many diseases. However, there is currently relatively little information in the literature on the phytochemicals present in ferns and their pharmacological applications, and the most recent review of the literature on the occurrence, chemotaxonomy and physiological activity of fern secondary metabolites was published over 20 years ago, by Soeder (Bot Rev 51:442–536, 1985). Here, we provide an updated review of this field, covering recent findings concerning the bioactive phytochemicals and pharmacology of fern species."

Covered topics (the letter size corresponds to the frequency of mentioning in the text)

Perspectives (as presented by the authors of the scientific work)

"Fern species are essential constituents of ecosystems and produce a wide array of bioactive components with diverse activities. Many of them are used in traditional medicines and could potentially be used to treat various diseases. However, wild fern plants around the world are subject to many severe threats due to environmental change, and significant losses of fern species and habitats have occurred, leading to a profound loss of biodiversity. At present, there is comparatively little data in the literature relating to the phytochemistry of ferns and their bioactivities, despite their potential as sources of novel bioactive compounds. Further analysis and testing of wild ferns to determine their biological properties and identify their active constituents could thus enable important improvements in human healthcare and help to valorize natural biodiversity. To this end, a survey will be performed to identify rare, traditional and wild fern species used in foods and medicines. High value products, pharmaceuticals and bioactive food ingredients from ferns will be harvested sustainably for analysis, and their nutritional and phytochemical profiles will be investigated to determine the bioactivity and toxicity of their extracts and components. In addition, the antioxidant and anti-inflammatory activity of selected fractions/purified compounds and ingredients will be examined in selected in vitro and cellular models. The ability of a diet enriched with fern foods and ingredients selected based on in vitro and ex vivo experiments to modulate clinically relevant parameters, oxidative and inflammatory stress, and cardiovascular function in overweight subjects will be assessed."

Full-text access for the referenced scientific work

Phytochemicals from fern species: potential for medicine applications. Cao, H., Chai, TT., Wang, X. et al. Phytochem Rev (2017). doi:10.1007/s11101-016-9488-7


Prof. Atanas G. Atanasov (Dr. habil., PhD)

Monday, February 20, 2017

Natural Products Utilization International Conference “From Plants to Pharmacy Shelf” (October 2017)


This is the third edition of a highly successful (ICNPU 2013 had 230 participants from 40 countries and ICNPU 2015 had 330 attendees from 50 countries) natural product-focused conference. Covered topics include:

Conservation and Sustainable Uses of Natural Resources
Herbal Medicine/Botanical Supplements
Medicinal Chemistry
Molecular Biology and Genetic Engineering (including functional genomics)
Natural Products Chemistry
Pharmacokinetics and Pharmacodynamics
Plant Biotechnology
Systems Biology

Time and Place

ICNPU 2017 will take place on 18-21 October 2017 at Bansko, Bulgaria. The conference will be held in Grand Hotel Bansko, a 4-star luxury hotel complex situated in the center of Bansko (a leading Bulgarian winter ski resort).

Further information

List of the invited speakers who confirmed participation and further information about the conference can be viewed at the conference website.


Prof. Atanas G. Atanasov (Dr. habil., PhD)

Sunday, February 19, 2017

Therapeutic properties of Russian medicinal plants

Abstract (as presented by the authors of the scientific work):

Due to the location of Russia between West and East, Russian phytotherapy has accumulated and adopted approaches that originated in European and Asian traditional medicine. Phytotherapy is an official and separate branch of medicine in Russia; thus, herbal medicinal preparations are considered official medicaments. The aim of the present review is to summarize and critically appraise data concerning plants used in Russian medicine. This review describes the history of herbal medicine in Russia, the current situation and the pharmacological effects of specific plants in the Russian Pharmacopoeia that are not included in the European Pharmacopoeia.
Based on the State Pharmacopoeia of the USSR (11(th) edition), we selected plant species that have not yet been adopted in Western and Central Europe (e.g., selected for inclusion in the European Pharmacopoeia) and systematically searched the scientific literature for data using library catalogs, the online service E-library.ru, and databases such as Medline/Pubmed, Scopus, and the Web of Science regarding species, effectiveness, pharmacological effects, and safety.
The Russian Federation follows the State Pharmacopoeia of the USSR (11(th) edition), which contains 83 individual plant monographs. Fifty-one of these plants are also found in the European Pharmacopoeia and have been well studied, but 32 plants are found only in the Pharmacopoeia of the USSR. Many articles about these medicinal plants were never translated in English, and much of the information collected by Russian scientists has never been made available to the international community. Such knowledge can be applied in future studies aimed at a safe, evidence-based use of traditional Russian medicinal plants in European and global phytopharmacotherapy as well as for the discovery of novel leads for drug development.
The review highlights the therapeutic potential of these Russian phytopharmaceuticals but also highlights cases where concern has been raised about product safety and tolerability, which would aid in supporting their safe use."

Covered topics (the letter size corresponds to the frequency of mentioning in the text):

The referenced scientific work at PubMed:

Shikov AN, Pozharitskaya ON, Makarov VG, Wagner H, Verpoorte R, Heinrich M.
Medicinal plants of the Russian Pharmacopoeia; their history and applications. J 
Ethnopharmacol. 2014 Jul 3;154(3):481-536. doi: 10.1016/j.jep.2014.04.007.
Review. PubMed PMID: 24742754.

Full-text access:


Prof. Atanas G. Atanasov (Dr. habil., PhD)

Open position for an experienced bioinformatician at Jastrzębiec (near Warsaw), Poland

A position for an experienced bioinformatician is available at the Institute of Genetics and Animal Breeding of the Polish Academy of Sciences (IGAB PAS) at Jastrzębiec, near Warsaw, Poland. The position is for two-years with a possibility of extension depending on results. with a possibility of extension depending on results.

This is primarily a 2-year project funded by NCN (Polish Science Center): "A cis-plus-trans predictive model of mammalian gene expression". This project was ranked first in Poland in biological sciences in the prestigious competition POLONEZ2 co-funded by Horyzont 2020 Marie Skłodowska-Curie COFUND. The post is also likely to involve collaborations with experimentalists (RNA-seq and microarray data). The post will be based in Jastrzebiec‚ IGHZ‚ in Poland. (This is an institute of the Polish Academy of Sciences close to Warsaw).

What you have:

1. A PhD degree in bioinformatics, computer science, software engineering, or a related discipline.

2. The knowledge and skills to implement: (a) R/Python pipeline for machine learning and statistical analysis, (b) next generation sequencing pipeline with the focus on RNA-seq.

3. Good publication track record.

4. Fluent English speaker.

5. Excellent English writing skills.

6. Excellent team player.

7. Expected future publication rate of more than two Q1 papers per year.

What can be offered:

1. Full-time 2-year employment with a possibility of extension.

2. Good salary.

3. Internal grants for preliminary studies.

4. Foreign research visits.

5. Inspiring scientific atmosphere and intellectual environment.

6. Excellent career development possibilities (option for Habilitation, and/or promotion to the level of Associate or Full Professor).

7. The possibility of accommodation at the hotel on the site if the Institute.

The candidates are asked to submit the following documents (combined into single PDF file):

1. Short motivation letter.

2. CV with a publication list (including impact factors and Q-ranking of the respective journals).

3. Scan of the MSc and the PhD degree.

4. Reference letters and/or contact details of previous supervisors.

5. List of relevant experiences in the areas crucial for this post:

(i) statistical programming in R;

(ii) pipeline development in Python;

(iii) RNA-seq NGS analysis;

(iv) machine learning: theory and implementation with R packages;

(v) shell scripting / UNIX / cluster computers.

Please send your application package simultaneously to:





Wished starting time: as soon as possible.


Lukasz Huminiecki (Adj. Prof., PhD)

Bioinformatics Team

Atanas G. Atanasov (Adj. Prof., Dr. habil., PhD)

Head of Molecular Biology Department,

Institute of Genetics and Animal Breeding of the Polish Academy of

Sciences, 05-552 Jastrzebiec, Poland



The project extends our published [1] integrative computational analyses of freely available human functional genomics data from ENCODE and FANTOM5. We continue to work with the concept of the experimentally-defined promoter architectures [1], but extend our modeling towards a cis-plus-trans strategy (to predict tissue-specificity of expression) and through the use of combinatorial approaches (to fish out strongly-determining promoter architectures). The project does not require any new data other then those precisely described by us in high-impact journals [1,2]. This makes our proposal affordable and highly feasible (the project was designed to be high-reward and low-risk by employing two complementary modeling approaches that together form a failsafe synergistic strategy).

Research objectives/hypothesis.

Within the proximal promoter, there are DNA cassettes which facilitate binding of transcription factors. These cassettes are cis-regulatory. The transcription factors are trans-regulatory. In the past, the cis-regulatory cassettes were identified by computer programs, but these programs have prohibitively high positive error rates. Now, there are massive / free databases of experimental data on the binding of transcription factors to databases of experimental data on the binding of transcription factors to proximal promoters (e.g., human ChIP-seq data from project ENCODE). We consistently argue that the ENCODE-derived experimentally-defined promoter architectures must revolutionize how we think about modeling gene expression in human. However, we previously modeled only cis- regulatory elements in the promoter architecture [1]. While the old model could predict the fraction of expressing tissues, it could not predict the identity of expressing tissues [1]. Now, we want to improve on the previous model by pursuing two cis-plus-trans modeling strategies. That is to say, as inputs, we will use not only (i) the architectures of proximal promoters computed as previously described [1], but also (ii) information on expression levels / presence / absence in the target tissue of transcription factors themselves.

Research methodology.

This project is timely because of the tsunami wave of data on gene expression and on protein-DNA interactions, e.g. FANTOM5 [3] and ENCODE [4]. We previously integrated these two databases and used the merged dataset to predict the breadth of expression [1] and demonstrate that haploid expression shaped biased gene content on X [2]. We will integrate ENCODE-derived experimentally-defined promoter architectures with FANTOM5 expression data [1]. Promoter architectures will be represented using sets / multisets (and their fuzzy counterparts that can model uncertainty about (and their fuzzy counterparts that can model uncertainty about promoter architectures due to variable quality scores of ENCODE peaks). To extend on the previously published work, we will create a mathematical and computational framework for representing / searching experimentally-defined the previously published work, we will create a mathematical and computational framework for representing / searching experimentally-defined promoter architectures and inferring expression from them in two cis-plus-trans strategies: (1) using support vector machines trained on data matrices integrating cis- and trans-regulatory inputs, and (2) with combinatorial workflows tailored, in face of data heterogeneity, to fish out promoter architectures strongly-determining expression.

Expected impact of planned research on development of science, civilization and society.

We can, now, identify experimentally-defined promoter architectures, and transcription factor combinations / permutations, which robustly support interesting expression characteristics, not just in one locus, but on the scale of the genome! In addition to basic knowledge, this work will facilitate technological progress in genome annotation and the construction of artificial promoters for gene therapy, transgenic farming or as research tools.


1. Hurst LD, Sachenkova O, Daub C, Forrest AR, Huminiecki L (2014) A simple metric of promoter architecture robustly predicts expression breadth of human genes suggesting that most transcription factors are positive regulators. Genome biology 15: 413.

2. Hurst LD, Ghanbarian AT, Forrest AR, Huminiecki L (2015) The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome. PLoS biology 13: e1002315.

3. Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, et al. (2014) A promoter-level mammalian expression atlas. Nature 507: 462-470.

4. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57-74.


Prof. Atanas G. Atanasov (Dr. habil., PhD)

Friday, February 17, 2017

What is the therapeutic potential of vitamin D in autoimmune disease?

Abstract (as presented by the authors of the scientific work):

"Over the last three decades, it has become clear that the role of vitamin D goes beyond the regulation of calcium homeostasis and bone health. An important extraskeletal effect of vitamin D is the modulation of the immune system. In the context of autoimmune diseases, this is illustrated by correlations of vitamin D status and genetic polymorphisms in the vitamin D receptor with the incidence and severity of the disease. These correlations warrant investigation into the potential use of vitamin D in the treatment of patients with autoimmune diseases. In recent years, several clinical trials have been performed to investigate the therapeutic value of vitamin D in multiple sclerosis, rheumatoid arthritis, Crohn's disease, type I diabetes, and systemic lupus erythematosus. Additionally, a second angle of investigation has focused on unraveling the molecular pathways used by vitamin D in order to find new potential therapeutic targets. This review will not only provide an overview of the clinical trials that have been performed but also discuss the current knowledge about the molecular mechanisms underlying the immunomodulatory effects of vitamin D and how these advances can be used in the treatment of autoimmune diseases."

Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Conclusion (as presented by the authors of the scientific work):

"Although various studies have shown a beneficial effect of cholecalciferol supplementation in autoimmune diseases, there are also studies that do not find any effect on disease parameters. This might be due to the supplementation strategy or the subjects included in the study, which are issues that should be addressed in properly designed multicenter clinical trials.

However, it is also possible that systemic cholecalciferol supplementation is not sufficient to establish effects in every patient. Therefore, another way to use the immunomodulatory effects of vitamin D to the advantage of patients with autoimmune diseases is to mimic the effects by targeting important pathways within immune cells. In order to do this, it is crucial to understand the working mechanisms of 1,25(OH)2D3. In the coming years, attention should be paid toward unraveling these molecular mechanisms to optimize the therapeutic potential of vitamin D."

The referenced scientific work at PubMed:

Dankers W, Colin EM, van Hamburg JP, Lubberts E. Vitamin D in Autoimmunity:
Molecular Mechanisms and Therapeutic Potential. Front Immunol. 2017 Jan 20;7:697.
doi: 10.3389/fimmu.2016.00697. Review. PubMed PMID: 28163705; PubMed Central
PMCID: PMC5247472.

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Prof. Atanas G. Atanasov (Dr. habil., PhD)

What are the therapeutic properties of the natural product cynaropicrin from artichoke?

Abstract (as presented by the authors of the scientific work):

"The different pharmacologic properties of plants-containing cynaropicrin, especially artichokes, have been known for many centuries. More recently, cynaropicrin exhibited a potential activity against all genotypes of hepatitis C virus (HCV). Cynaropicrin has also shown a wide range of other pharmacologic properties such as anti-hyperlipidemic, anti-trypanosomal, anti-malarial, antifeedant, antispasmodic, anti-photoaging, and anti-tumor action, as well as activation of bitter sensory receptors, and anti-inflammatory properties (e.g., associated with the suppression of the key pro-inflammatory NF-κB pathway). These pharmacological effects are very supportive factors to its outstanding activity against HCV. Structurally, cynaropicrin might be considered as a potential drug candidate, since it has no violations for the rule of five and its water-solubility could allow formulation as therapeutic injections. Moreover, cynaropicrin is a small molecule that can be easily synthesized and as the major constituent of the edible plant artichoke, which has a history of safe dietary use. In summary, cynaropicrin is a promising bioactive natural product that, with minor hit-to-lead optimization, might be developed as a drug for HCV."

Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Discussion and conclusions (as presented by the authors of the scientific work):

"Cynaropicrin has multi-medicinal potential therapeutics evidenced not just by the ample scientific literature describing it, but also by the plenty number of patent applications (http://www.thegoodscentscompany.com/data/rw1701261.html, accessed 28-2-2016). The most outstanding activity recently discovered for cynaropicrin is the activity against HCV where it presents a very attractive pan-genotypic anti-HCV natural product. It showed potent and broad spectrum potential against the major genotypes of HCV by inhibiting viral cell entry.

The discovery of novel anti-HCV entry inhibitors such as cynaropicrin could help to develop preventive therapies/measures against hepatitis C where immunization against HCV is at present unavailable due to the highly mutable nature of the virus. Important applications of entry inhibitors include the prevention of recurrence in the new liver in HCV-patients after liver transplantation. In patients with HCV-related end-stage liver diseases undergoing liver transplantation, re-infection of the graft is universal and characterized by accelerated progression of liver diseases. Entry inhibitors may be effective especially in these patients undergoing violent re-infection of HCV into hepatocytes (Nakajima et al., 2013).

From the histo-pharmacology of cynaropicrin action, it seems that most of its pharmacological effects are convergent to support the anti-HCV activity, as follows:

(1) Cynaropicrin was found to suppress hyperlipidaemia as mentioned above (Shimoda et al., 2003). The lipids are important factors for the life-cycle of HCV where the virus replication and assembly is dependent on host cell lipid metabolism. HCV attaches itself to lipids and very-low-density lipoproteins after its release from the infected cells. It will then circulate in the blood in the form of triglyceride-rich particles (Burlone and Budkowska, 2009). It was also demonstrated that HCV-core protein (C), and the non-structural proteins NS2 and NS5A of HCV induce lipid accumulation in the liver cells resulting in steatosis, fatty liver and potential progression of liver disease and associated with hepatic inflammation and fibrosis. Therefore, it is important to lower increased cholesterol and triglycerides concentrations in HCV-infected patients (Kim et al., 2009).

(2) Cynaropicrin is a potent antioxidant (Takei et al., 2015; Yamada et al., 2015) and hence it can play a supportive role for liver in different hepatic diseases. Oxidative stress plays an important role in the pathogenesis of chronic hepatitis C. Oxidative stress occurs early during HCV infection and increases with disease progression and severity and hence the infected patient with HCV is usually being advised to take antioxidants such as vitamins C, D, and E, which are the most investigated as antioxidant therapy in chronic liver diseases (Milliman et al., 2000).

(3) Cynaropicrin is a potent inhibitor of TNF-α action which is a major mediator of the inflammatory process in HCV patients. Serum levels of TNF-α have been correlated with elevated alanine aminotransferase (ALT) and increased severity of fibrosis in HCV patients. Patients receiving interferon showed decreased TNF-α concentration (Milliman et al., 2000). It is also suggested that the activation of the NF-κB and AKT pathways are involved in increased HCV replication (Brenndörfer et al., 2009).

(4) Since cancer is the result of a deregulation of multiple signaling pathways and cynaropicrin elicit multi-targeted activities, this natural product could hold a great potential for treating human tumors. Cynaropicrin having significant antitumor activity and it may be served as potential cancer chemopreventive lead drug for prevention or treatment of human cancers (Kang et al., 2007). Human infection with HCV is currently recognized as the leading cause of the severe complications such as HCC which demands liver transplantation (Ishida et al., 2014) since HCC is the major histological subtype of primary liver cancer (Hu et al., 2013). A total of ~27% of individuals that develop liver cirrhosis and HCC worldwide arise in HCV-infected people (Ishida et al., 2014). It appears to be the major causative factor responsible for the recent doubling of HCC which was estimated to result in ~10,000 deaths in the United States only in the year 2011 (Gonzalez et al., 2009; Ibrahim et al., 2013). Cynaropicrin has anti-inflammatory, anti-tumor, TNF-α inhibitory, and antioxidant activities and hence it can also prevent the progression of HCC. Indeed, most natural agents do not induce a high level of toxicity and target multiple signaling pathways involved in cell growth, invasion, apoptosis, angiogenesis and metastasis (Pulito et al., 2015).

Cynaropicrin as a potential therapeutic compound is having many other advantages:

(1) The cynaropicrin is one of the main active constituents of artichoke; the therapeutic effects of the latter have been observed in several clinical trials (Giacosa et al., 2015) and it has recently attracted attention because of its well-proven safety at concentrations currently employed in alcoholic beverages (Cravotto et al., 2005). Another clinical study recommended artichoke extract for treating hyperlipoproteinemia and, thus, prevention of atherosclerosis and coronary heart disease and showed that there were no drug-related adverse events indicating an excellent tolerability of artichoke extract (Englisch et al., 2000). Artichoke is a fundamental component of Mediterranean diet and is available globally in all markets (Pulito et al., 2015). (2) The compound is water-soluble and hence therapeutic injections can be formulated which will decrease the amount of dosage form and shorten the duration of therapy and thus reducing putative side effects.

(3) The compound has a simple structure and hence it can be synthesized and marketed with affordable prices.

The final conclusion is that cynaropicrin is a very effective and promising natural product for hepatitis C virus infection and a prospective new drug lead, since it has a direct action on HCV by cell entry inhibition and cell-cell coinfection inhibition and also it may exert inhibitory effects on HCV replication via suppression of one or more signaling pathways related to ROS, Akt, NF-κB, and STAT3. Further in-depth studies including clinical trials are needed to fully evaluate its value for HCV treatment. Thus, cynaropicrin represents a natural product with an excellent therapeutic potential that can be considered as one illustrative example in line with the re-emerging notion that medicinal plants are expected to be a continues magnificent source of molecules with therapeutic potential (Atanasov et al., 2015)."

The referenced scientific work at PubMed:

Elsebai MF, Mocan A, Atanasov AG. Cynaropicrin: A Comprehensive Research
Review and Therapeutic Potential As an Anti-Hepatitis C Virus Agent. Front
Pharmacol. 2016 Dec 8;7:472. doi: 10.3389/fphar.2016.00472. Review. PubMed PMID: 
28008316; PubMed Central PMCID: PMC5143615.

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Prof. Atanas G. Atanasov (Dr. habil., PhD)