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NRF2 - Dr. Albena Dinkova-Kostova — Transcript

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0:01[Music]
0:06dear listeners welcome to another
0:08episode of the podcast about enzymes and
0:11molecules I am Roberta foresty professor
0:15of biochemistry at the University of par
0:17ESR and researcher at The mondor
0:20Institute of biomedical research in
0:22France for our fourth episode we will
0:26talk about a special system that is very
0:28important for protecting the organism
0:31against stress the Nrf2 transcription
0:34Factor it is the master regulator of the
0:37stress response which is responsible for
0:40increasing the expression of a long list
0:43of genes that help to combat stress and
0:46restore cellular
0:48homeostasis interestingly Nrf2 is
0:52activated by stressful stimuli but also
0:55by plants deriv natural compounds
0:58showing how natur how Nature has evolved
1:01to harness the power of plants to
1:04provide benefits for our body in
1:07opposition to its fundamental role in
1:09protection Nrf2 also has a dark side in
1:13the context of cancer since its
1:16overactivation in cancerous cells
1:18renders them stronger and more resistant
1:21to the drugs that aim to kill them today
1:25we welcome a researcher that has greatly
1:28contributed to understanding in the
1:30detailed mechanisms underlying Nrf2
1:33activation by different stimuli and is
1:36actively engaged in examining the role
1:38of Nrf2 in metabolism and cancer I am
1:42delighted to host Dr Alina dinkova Cova
1:46originally from Bulgaria and currently
1:48professor of chemical biology at the
1:50University of dandi Scotland she
1:54obtained her PhD in Biochemistry from
1:56Washington State University in the USA
2:00and joined the laboratory of poter Ali
2:02at John Hopkins University where she
2:05became interested in chemo prevention by
2:08chemical and dietary induction of
2:10cytoprotective proteins after similar
2:13years in the USA in 2007 Dr dinkova
2:17kostova joined the medical research
2:19institute at the University of dandi as
2:23a research council's UK academic fellow
2:26her work is focused on the mechanism of
2:29induction of cytoprotective proteins
2:31through the keep one Nrf2 pathway and
2:34the chemistry of inducers she has an
2:37impressive record of Publications and
2:40has also been nominated on the global
2:42highly cited researcher list for five
2:45straight years from 2019 to
2:502023 hello ala thank you for your
2:54availability it is a pleasure to have
2:56you today as a guest for our podcast
3:00hello Roberta thank you very much for
3:02inviting me and giving me the
3:05opportunity to contribute to your
3:07podcast which I've uh enjoyed all of
3:09them so far thank you before we start
3:13with the questions I need to thank
3:15somebody who has been helping me a lot
3:18for the preparation of this podcast and
3:21I already told you before in our
3:23previous conversation is he is my son
3:26Mato mlini he is a data scientist
3:29working in a company he doesn't do any
3:31research or science but he helps me a
3:34lot with the editing and the preparation
3:37of the videos for this podcast so I
3:39think I will add a picture of him in the
3:42next H in our next episode and when it
3:45is published he's going to get some
3:47recognition for all the work that he
3:49does to help
3:51me that's great well deserved yes so to
3:56kick off Albina could you give us a
3:59definition of Nrf2 and how it is
4:03activated yes of course uh as you
4:07mentioned already Nrf2 is a
4:09transcription factor that regulates the
4:12expression of uh many genes uh probably
4:16more than 200 depending on the context
4:19the products of these genes are proteins
4:22with very diverse protective
4:25roles at homeostatic conditions Nrf2 is
4:29a very shortlived protein between 10 and
4:3220 minutes
4:34halflife because it is subjected to
4:36continuous
4:38degradation and one major contributor to
4:42this
4:43degradation is a protein called keep one
4:47keep one binds Nrf2 and brings it to a
4:51complex that promotes the ubiquitination
4:53of Nrf2 and its subsequent degradation
4:57via the
4:58protone when specific specific small
5:00molecules which we call inducers enter
5:03our cells they bind to keep one and
5:07prevent its ability to Target Nrf2 for
5:10degradation this leads to Nrf2
5:13accumulation translocation to the
5:15nucleus and up regulation of its
5:18Downstream Target genes the protein
5:21products of these genes have various
5:23protective functions they ensure as you
5:27already mentioned Roberta adaptation and
5:29survival under various conditions of
5:32stress that ourselves encounter and they
5:36act to restore uh the normal homostasis
5:43nf2 is continuously produced and is
5:46continuously
5:48degraded so this is a signal that the
5:51cell is trying to be ready right for a
5:55kind of possible potential stress that
5:58may be coming
6:00we don't know when it is coming and the
6:03cell is ready to react in case of
6:07whatever stressful Sim stimula it is
6:10coming this is how we can interpret the
6:12fact that Nrf2 is continuously produced
6:15and at the same time continuously
6:18degraded if it's not needed correct yes
6:21that is exactly correct in the beginning
6:24we were wondering why should a cell
6:27invest so much energy in making
6:29something only to destroy it as soon as
6:31it's made but uh as you precisely
6:36defined this is because we need its
6:39availability immediately under the
6:42conditions of
6:43stress if the cell has to rely on a
6:47different type of signaling for example
6:51uh which involves inovo gene expression
6:54of Nrf2 that will take many hours and if
6:58the insult is severe enough the cell may
7:02die in the process so this is why we
7:05think the cell under go through this
7:08um effort to make NF to continuously and
7:12destroy it yes but ensuring at the same
7:15time that it could be stabilized as soon
7:18as it is needed yes so it means that
7:22uh this energy spent for uh as you say
7:25the effort to make it it means it's
7:29let's say another way of recognizing the
7:34fundamental role of Nrf2 in the cell I
7:37think this is how I view it yes yes yes
7:41definitely so I wanted to continue by
7:43talking a little bit about a little bit
7:46more about keep one the repressor of
7:49Nrf2 I read that there is this assisting
7:52code which is very important for
7:55Activation of Nrf2 and that the systems
7:59on keep one have a particular role that
8:02you are going to describe to
8:05us yes sure um keep1 is indeed A protein
8:10that is rich in
8:12cyes and cine is a very special amino
8:15acid because it has the ability to
8:18undergo um oxidation to various
8:21oxidation States some of them reversible
8:24others
8:25irreversible in addition cine can form
8:29calent bonds with
8:32electrophiles electrophiles are
8:34molecules that can bind to nucleophiles
8:38and cine is one example of a
8:41nucleophile keep one is particularly
8:44special in that it has cyes that are
8:47highly reactive due to their local
8:50environment within the protein
8:53structure some of the cyes of Kon for
8:56example are surrounded by basic amino
8:58acids
8:59and that increases their reactivity so
9:02that they exist as state annion ready to
9:06bind electrophiles even at neutral
9:10pH when we say ctin
9:12coat we mean that inducers or these Eno
9:17activators preferentially bind to
9:19certain CES to keep one and not randomly
9:23to any
9:24Sy we also refer to these sys as sensor
9:28sys as they are the ones that recognize
9:31the electrophilic nfto
9:33activators and Trigger the induction of
9:36the cytoprotective
9:38proteins I think the idea and the pum
9:41cine cul uh was originally um invented
9:46in masayuki mamoto lab when they tried
9:50to classify different
9:53inducers uh the preference of each
9:56inducer to specific cyes that we know
9:59are particularly reactive in keep one
10:03what we still do not understand is
10:05whether modifications of any of the
10:07sensis in keep one leads to the same
10:10transcriptional response or whether the
10:13transcriptional response is more nuanced
10:16depending on the precise systems that
10:19have been modified so this is still an
10:22open area for potential Discovery in the
10:25by the younger
10:27scientists I see so I was thinking in a
10:31different way but you you tell me that
10:33it's a little bit more complex than what
10:35you than what I was thinking I was again
10:39referring to the thinking that certain
10:42systems are sensitive to certain
10:45inducers was a kind of specificity
10:49certain inducers that are produced
10:51during particular stess situations will
10:54act on some systems instead of others
10:59but you're saying that is more complex
11:01than that it's really also what inducers
11:05will attack with syain and which genes
11:08may
11:10be
11:12affected yes yes the action yes you're
11:16absolutely right this is the idea of the
11:18ctin con this specificity of specific
11:23cyes reacting with certain
11:26inducers but um so is relatively well
11:30understood based on U many masspec
11:34analysis and also uh crucially
11:37mutagenesis analysis in cells and even
11:40in
11:41animals uh but the reason that I mention
11:45that we don't what we don't understand
11:47this is the aspect the last aspect the
11:50more perhaps nuanced um possibility uh
11:55it may or may not exist but uh it's
11:58something that we can be open to whether
12:01the specific transcriptional responses
12:04may also depend on uh a certain um type
12:08of system that is modified we just not
12:11know that yet very interesting so
12:15different inducers although they
12:18might they will all induce nrs2
12:21accumulation in the nucleus may lead to
12:25different transcriptional regulations is
12:28that what you are
12:29saying I I wouldn't exclude that as a
12:33possibility interesting we don't know
12:36anything about it but uh it is not
12:39impossible and I think mainly some of
12:43this possibility could be because some
12:47system acting molecules they modify the
12:51systems of keep one
12:54reversibly and some may modify them
12:57irreversibly
12:59particularly we don't really understand
13:03very well how oxidants can do that for
13:06example hydrogen peroxide reacts with
13:10very specific cysteines which are
13:13completely different from uh let's say
13:16Balon or or oxyon the
13:20triterpenoids and we don't really
13:22understand they will be definitely
13:23overlapping targets but it is just
13:26possible that if the reversal of those
13:31sys to their normal state has different
13:35kinetics maybe that would also determine
13:37the duration of nf2 activation
13:40accumulation and that may um reflect be
13:45reflected in the downstream Target gene
13:47expression we just don't know we don't
13:50understand it yet I see I see so looking
13:53a little bit more into this chemical
13:56structures that of the inducers which
13:58seems to be very
13:59important we know that Nrf2
14:03inducers have to have some particular
14:07chemical features in their structure
14:09that are required for them to be able to
14:13induce Nrf2 and you have worked
14:16extensively on this what are these
14:19features and why is there presence so
14:23important for their nf2 activating
14:27properties
14:30yes um so far we can group The Nrf2
14:34inducers into large
14:37classes one class of
14:40compounds which is the younger class
14:43more uh recently discovered are
14:46compounds that bind to keep one
14:49non-covalently and by binding to keep
14:52one they are specifically designed to
14:54bind to the couch domain which is the
14:57domain of keep one weight in interacts
14:59with
14:59Nrf2 and that binding uh prevents the
15:03interaction between keep 1 and Nrf2 we
15:07call them protein protein interaction
15:10Inhibitors the class that we know much
15:13more about and which was discovered even
15:16before Nrf2 are the electrophiles that I
15:20already
15:21mentioned electrophiles bind coal to
15:25specific cyes in keep one as we l to in
15:29the previous question and they disa the
15:32function of keep one to Target Nrf2 for
15:36degradation in fact in the
15:391980s uh a decade before the discovery
15:42of Nrf2 and keep1 electrophilicity was
15:46recognized as the only common property
15:49among compounds that
15:52induce uh genes that we now know are
15:55regulated by the ref2 for example so
15:59these are um genes in coding quinon
16:03reductase one and q1 Oran
16:07transferases and this inducibility by
16:10many um electrophiles was found to
16:14protect against toxicity and
16:16carcinogenicity in U models rodent
16:19models using rats and
16:21mice and the recognition of the
16:24electrophilicity is the only common
16:26feature among diverse array of compounds
16:30that can uh induce the gene expression
16:33of these particular two um enzymes LED
16:37uh really Paul tal and his colleagues at
16:40Johns Hopkins University at the time to
16:42predict the existence of a sensor
16:45protein with reactive
16:47cines this idea was not welcomed very
16:51readily in the field at that time
16:53because it was a liant receptor
16:56interaction era and every one was
16:58looking for some common structural
17:01features among small molecules that
17:03affect the function of a protein but
17:06this was not the case from their study
17:08so because electrophilicity was the only
17:12common chemical signature they propos
17:15the existence of this sensor protein
17:17that has reactive
17:19systems and this protein was shown to be
17:21keep one uh by masayuki amamoto and his
17:25colleagues uh in sukua University in
17:28Japan
17:29and and uh most of the electrophiles
17:32that was studied both in the T lab uh as
17:36well as in theot lab at the time were
17:40exogenous they are present in our
17:42environment or our
17:44diet but more recently it's very
17:47interesting that um various
17:51investigators uh have observed that
17:53certain endogenous electrophilic
17:56molecules can also bind to keep one
17:58causing nf2
18:02activation interesting so this
18:04electrophilicity is a key feature which
18:08is found in exogenous substances that
18:10you basically started with these
18:13substances but now we are discovering
18:16that also there are many endogenous
18:18metabolites that do have possess the
18:22same property chemical property which is
18:24not structural but is chemical
18:29yes and they are produced in the cells
18:34under stress conditions okay and they
18:37will induce
18:38Nrf2 can you then give us some examples
18:41of these molecules and how they will
18:44connect metabolism to the stress
18:47response because they are metabolized
18:50they are produced during particular
18:52conditions and as a consequence they
18:55will activate the stress response
18:59yes exactly so electrophiles can be
19:02produced in our cells during uh certain
19:06physiological and pathological
19:08processes for example uh probably some
19:12of the earliest recognized electrophiles
19:14that were shown to activate
19:16Nrf2 are lipid peroxidation products
19:20such as F hydroxy Nal or the cyclop
19:23pentin
19:25prostaglandin and both of these uh are
19:28produced during inflammation for
19:31example uh
19:33and even more in immune cells
19:37specifically such as microphases for
19:40example one um electrophilic metabolite
19:44called
19:45itaconate can be produced in response to
19:48pathogen
19:49infections and this is because um it is
19:53derived from the crep cycle intermediate
19:56CIS a conate during the um
19:59transcriptional regulation of an enzyme
20:02C A
20:03conate DEC carboxilate which U produces
20:07itaconate itaconate in comparison to the
20:10lipid derived electrophiles for example
20:13such as for hydrin onal is much much
20:16weaker as an
20:18electrophile and even compared to most
20:20exogenous electrophiles it it's really
20:23very weak but it accumulates to Minima
20:27concentrations
20:28in activated microf phases both human
20:31and mouse itaconate is probably the most
20:34abundant metabolite when these cells are
20:38uh stimulated with a pro-inflammatory
20:41stimulus and the consequent activation
20:44of Nrf2 then plays a crucial role in the
20:47resolution of infection for example in
20:50Mouse models of
20:52sepsis enf to knockout mice do not
20:55survive unlike wild type mice because
20:58they lack this ability to adapt and
21:02counteract the stress that is imposed by
21:05inflammation this probably cyto kind
21:08storm that cannot be overcome in the
21:11absence of this role uh for resolution
21:14of
21:16inflammation another example is the CP
21:19cyc metabolite
21:21fumerate which uh can also induce Nrf2
21:25by binding to cyes in keep one
21:28and it's interesting that um there is a
21:31quite recent study showing that
21:34NAD increases the biosynthesis of
21:37fumerate which then activates Nrf2 and
21:41that in turn blunts
21:44inflammation and finally um there is
21:48also another um metabolite which is a
21:52derivative of
21:55tryptophan uh and derivative of curin
21:58and metabolite of
22:00tryptophan which uh is electrophilic
22:03form of curin called churin peroxy uh
22:08Ketone which also uh has been shown
22:11recently to um activate Nrf2 and promote
22:16the resolution of
22:17inflammation and maybe just to mention
22:20one more metabolite methyl gloal because
22:24it is
22:25important uh that it accumulate
22:29for example during
22:30diabetes uh also in cardiov vascular
22:34disease and some neurodegenerative
22:36diseases and meth glyoxal and that is
22:40one example how metabolism is linked to
22:44stress response meth glyoxal is a
22:48product of glycolysis
22:51byproduct which then activates
22:55Nrf2 and Nrf2 and it metal glyoxal can
22:59be damaging but the activation of
23:02Nrf2 um increases the transcription of
23:06glyoxalase one which is an enzyme that
23:09metabolizes meth glyoxal bringing the
23:12homeostatic state of the
23:16cell what what you're telling me is uh
23:19makes me think about also energy
23:22production because fumerate is part of
23:25crabs and we know that the full
23:28functional crab cycle is very important
23:30for producing fad H2 nadh and therefore
23:34you know the good functioning of the
23:37respiratory chain mitochondri
23:39respiratory chain so when you were
23:41talking and explaining about this I was
23:45thinking if fumerate is accumulated and
23:49the crab cycle is not continuing to
23:52function as we normally expect I imagine
23:55that here there is also an effect effect
23:58on energy levels in the cells which
24:01again is probably kind of regulation in
24:04relation maybe to infection we know that
24:06mitochondrial function usually during
24:09LPS activated macrofagos is decreased
24:12whereas glycolisis is
24:15increased and I am sure that these are
24:18again complex mechanisms but there must
24:21be some again
24:23connection you know disruption or
24:26alterations in important metabolic
24:29pathways that are there for energy
24:32production but they are also there for
24:34signaling and at the same time they will
24:37may have again a consequence for energy
24:41production in the short term and maybe
24:44in acute in you know in acute conditions
24:47which are exactly the conditions that we
24:49find when Nrf2 is
24:51activated very interesting yeah yeah
24:54exactly probably that's why we also uh
24:57find effects on
24:59Nrf2 for mitochondrial function it is
25:02important we don't know exactly yes why
25:05but uh it is definitely supporting
25:08mitochondrial function and adaptation to
25:11stress and adaptation yes this is the
25:13key word
25:16adaptation so the plant H derive
25:19compounds again going back to our
25:22exogenous and
25:24endogenous metabolized are important for
25:28to Activation so the plant derive
25:30compounds that induce Nrf2 are often
25:34molecules that are synthesized by plants
25:38during stress conditions again infection
25:41of plants lack of water so that these
25:45stress signaling molecules in Plants
25:49become effective activators of the
25:52stress response in Maman systems and I
25:55find this really really fascinating in
25:58this connection between plants
26:01metabolism and affecting mamian cells
26:05metabolism and stress response can you
26:08give us example of examples of some of
26:11these molecules and maybe you can also
26:15tell us how you see this plant H animal
26:19interaction in the context of evolution
26:22and adaptation to the environment not
26:26just what happens inside does but what
26:28we are surrounded
26:31by yes sure um so one example of a plant
26:36derived compound that activates
26:39activates
26:40mf2 is the isothiocyanate
26:44soran um we exposed to it when we
26:47consume cruciferous vegetables for
26:49example
26:51broccoli in fact sarhane is the most
26:54potent naturally occurring NF to
26:57activate that that we know what is
26:59particularly interesting in terms of
27:01evolution and environmental adaptation
27:05is the fact that the plant produces a
27:09precursor of sorane called glucoraphenin
27:14glucoraphanin is biologically completely
27:18inert however the same plant makes an
27:21enzyme called
27:22myosin which resides in specialized
27:25cells and it is not in contact with its
27:29glucosinolate substrate so it's
27:32only when the plant is injured for
27:35example when we chew it or when an
27:38insect bites it then the enzyme and
27:42substrate get in touch in contact
27:44because the tissue Integrity of the
27:47plant is
27:48compromised and this leads to the
27:50formation of sorane and also um other
27:54degradation
27:56products and
27:58it's
27:59interesting that some insects for
28:01example which we call
28:03Specialists have developed special
28:06proteins in their gut allowing them to
28:09divert this myrosinase reaction away
28:12from the formation of the isoy cyanates
28:17and we think that um it is very likely
28:21that in parallel to acting uh as
28:24deterrent presumably to the insect these
28:28isothiocyanates may help the plant
28:30tissue to heal by combating oxidative
28:33stress because plant also have quinon
28:36reductors they have gluathione or
28:40similar molecules so they and they need
28:43to heal their wounds when they wounded
28:46so like I think it's fascinating that
28:49some of these uh properties over up
28:51between plants and
28:53animals and it is disability probably to
28:57isothiocyanates nature is very economic
29:00so it uses the same molecule for
29:03different purposes on one side maybe to
29:06deter the insects because it some of
29:10Saran is not particularly pungent but
29:13some other isothiocyanates such as alil
29:17for example or you've experienced most
29:19of you Wasabi it's really pungent so
29:23that definitely the plant uses as
29:25deterrent for insect
29:28but uh they also use it for their own
29:31healing processes and when we consume it
29:34they'll help us heal as
29:38well interesting very interesting just a
29:41little question in addition to this the
29:44plants do they have their own Nrf2
29:47Master regulator oh that's a very good
29:50question and I don't think we know
29:53that um we do know that they have they
29:58produced uh some electrophilic molecules
30:01such as Mand di alide for example which
30:04activates very similar transcriptional
30:07program uh nq1 is activated some of the
30:11enzymes that are like Glo and transfer
30:14races but we don't know what is the
30:17transcription factor that mediates it so
30:19it is very likely that there is
30:21something like
30:24kf2 uh that does it but it's it's not
30:28known to my knowledge any yes well if
30:31you don't know I don't know who else
30:33could
30:35know so in relation to this planted
30:38derived Nrf2 activators you have me you
30:41have mentioned the ones present in
30:43broccoli and this is a very wellknown um
30:47information we hope that you know people
30:50are encouraged to eat broccoli because
30:52of this protective properties of the
30:55isoy cites that they
30:58contain um what are other plants that
31:04contain you know important levels of
31:06Nrf2 activators that you think we could
31:09include in the diet to increase our
31:12resistance to
31:14stress yeah um yeah there are many plant
31:18deriv phytochemicals that have been
31:21shown to activate
31:23nf2 and to to various extent some of
31:26them
31:28um probably uh better activators than
31:31others I already mentioned that sorane
31:33is the most potent naturally occurring
31:35andf to activator that we know but uh
31:39there are many others for example
31:42Resveratrol which is produced in the
31:44skin of red grapes during fungal
31:47infection it's known as phyto alexin
31:49because it's produced under this
31:50specific condition is one example we
31:55don't know exactly how our veratrol
31:58activates
31:59nf2 but it definitely has beneficial
32:02properties in terms of um and
32:05anti-inflammatory
32:07effects uh it's also present in red wine
32:10but I I must say the amounts are so tiny
32:14that um I don't think that we can get
32:17enough just by drinking wine we have to
32:20go to that plant to the
32:23fruit um yes uh it's funny that you say
32:26that because I used to write when I was
32:28in the UK I used to write for a little
32:32um a journal that was distributed to the
32:36Italian Community where we were living
32:38around London and the the editor of the
32:42journal used to ask me to write articles
32:44about nutrition and one article I wrote
32:47I Remember was on red veratrol and I
32:51made a calculation of how much red wine
32:55we should drink in order order to
32:57achieve the same amount of respirator
32:59that was used in studies and I remember
33:02I calculated there were they were they
33:05were
33:07332 glasses of red
33:11wine that we needed to drink in order to
33:15reproduce the concentration that were
33:17found in were used in the studies yeah
33:21so again as you say you know there is a
33:24little bit of difference between
33:26drinking and expecting that the ratron
33:29wine is going to give us this protection
33:33but there is a point that I think is
33:36important you know when you were saying
33:38that ratron and other naturally derived
33:42compounds are present in different foods
33:46obviously and they all have different
33:49potency of activating depending also on
33:52the concentration that is present in the
33:54food I was wondering again and if there
33:57isn't a similarity between the different
34:00activators that you talked about before
34:03that affect specific SE stains and
34:07therefore may have also different effect
34:09on the transcriptional
34:12regulation
34:13Downstream and whether also this fact
34:16that there are different potential Nrf2
34:20activators present in different foods
34:22but of course in our diet we can combine
34:24all these different foods we can eat
34:27grapes we can eat broccoli we can eat
34:31you know tomatoes and other things the
34:33kumin we were talking offline about
34:35Kumil we can eat these Foods in a mail a
34:40combination of Nrf2
34:43inducers that maybe you know will work
34:47together and will
34:48synergize to to induce do you agree with
34:52this concept do you agree with this
34:54possibility yeah yeah completely agree
34:56agree that there might be
34:59synergism uh and also they may not
35:02activate Nrf2 in the exactly same way we
35:06you already mentioned potentially they
35:08could affect uh different 16s of keep
35:11one but also um now that you mentioned
35:16circumin uh circumin um has been also
35:20shown to activate Nrf2 by inhibiting the
35:24interaction of Kean n
35:28p62 this is another way of up regulating
35:31U
35:32Nrf2 so it it is possible that if NF is
35:36activated by different mechanisms there
35:39might be some synergies in in the
35:42overall effect again even if the
35:46downstream Target genes are the same the
35:48duration of activation would be
35:51different if the mechanism of activation
35:53is
35:54different yes the so in a way we are uh
35:58coming back to the to the idea that it's
36:00very important to have this varied diet
36:03and if we think about the biome
36:05biomolecular mechanisms that could
36:08justify this approach of eating well
36:12there are actually real sound
36:15biochemical explanations for this kind
36:18of attitude in nutrition very
36:21interesting yeah yeah definitely one
36:24thing that I should point out though is
36:27that of course plant derived
36:29phytochemicals have multiple cellular
36:32targets so when we speak about keepon
36:35and nf2 the these are by no means they
36:38are only targets absolutely again Nature
36:41has evolved to have to be very
36:43economical and utilize the same molecule
36:46for multiple purposes so uh cumin
36:50specifically has also a very strong
36:53anti-inflammatory effects thata partly
36:56Med by nf2 but partly uh not through
37:00direct inhibition of NF Capa B for
37:03example uh so yeah they they do affect
37:06other signaling Pathways and ultimately
37:10that might be contributing also to their
37:12beneficial effects yes so we definitely
37:15need to eat a variety of in incorporate
37:20Variety in our diets for maximally
37:23beneficial effect yes and because Nrf2
37:26of of course I'm I'm happy pointing out
37:28we strongly believe in rnf2 but is not
37:31the only important uh biochemical
37:35mechanism that we have in
37:38ourselves you have worked for a long
37:40time and very productively in the
37:43laboratory of Dr portal laa we have
37:45already mentioned him in at the
37:47beginning of our interview and he was a
37:50Pioneer in the field of cancer chemo
37:53prevention who sadly he passed away a
37:56few years ago I I'm just curious I want
38:00to know if you can tell us how was your
38:03experience of working in with him in his
38:06lab and what are the major lessons that
38:08you learned from him as a
38:11mentor oh I had a wonderful experience I
38:15was really very fortunate to be able to
38:18work with him because Paul T was a
38:21remarkable person so charismatic very
38:25inspirational
38:27um he he is my scientific father um and
38:32my hero really so I I really miss him um
38:38but he did have a full life a wonderful
38:42life and I've learned a lot of things
38:45from him so I can spend the next hour
38:49talking about them but maybe if I can
38:53just say uh two or three uh things
38:57um what I learned from him is that um
39:02and I'm trying
39:03to
39:05to to convey that to my students as well
39:09is that um you can never be too careful
39:13with your experiments every detail
39:16really really matters and every detail
39:20should be carefully
39:22recorded and and then if you have made
39:26an
39:27observation or you have a result that is
39:31even the opposite of what you expected
39:34you shouldn't ignore that but you should
39:37view that as an opportunity to make a
39:40discovery because most discoveries come
39:43from the
39:45unanticipated results or the odd
39:49observation on the side of a another
39:53main question that's being asked and
39:57on this photo of Paul
40:00doy um I hope the viewers can see him uh
40:04first of all holding the molecule of
40:06sorane the space filling model which was
40:09his favorite molecule by far and also
40:13the inscription on the wall behind
40:16him this inscription I'm told um I don't
40:19know
40:20Chinese could be translated and that's
40:24very American style of translation
40:27Discovery is our
40:28business and he actually inherited that
40:33of his mentor Charles Huggins at the
40:36University of Chicago who is also a
40:38Nobel lawate uh for the treatment of
40:41prostate
40:43councel and um so yes Discovery um is
40:47really what our duty perhaps as
40:50researchers as human beings and helping
40:54others another thing that I have um
40:57probably learned is
40:59that we often we get
41:03overloaded and we have to really think
41:06carefully and
41:08prioritize um he used to
41:11say if something is not worth doing it's
41:15probably not worth doing it well so we
41:19should
41:21really uh keep our efforts and focus
41:24them where we think think um we have an
41:28opportunity to um make progress and make
41:31a
41:32difference so these are some of the
41:35things that um I've learned from him and
41:37I hope they will U be continued U by my
41:41students as well you know it's
41:45um it's very sweet to hear what you are
41:48saying about poine your experience and I
41:52think there is
41:54um so much Wis St in what you are saying
41:58and what he he was teaching you and I'm
42:02sure the rest of the people in his love
42:05and uh it is true that we are
42:08overwhelmed now about many things and uh
42:13perhaps we are um we have this
42:16perfectionist attitude that everything
42:19we do although it may not be so
42:22important we want to do it well I think
42:24there is a positive you know it's it's
42:27also a positive attitude but maybe we
42:30should also try to to prioritize and say
42:34no to some of the things that are not so
42:37important for us but uh you know it's
42:40really very interesting to but was he in
42:42the lab regularly was he yes he was yes
42:47supportive yes yeah he was in the lab he
42:50was very supportive and sometimes he
42:54really if we're introducing something
42:56knew a new technique he he always wanted
42:59to see and even try for
43:02himself and other times especially when
43:06it comes to working with
43:09animals we needed him on some occasions
43:13to come and Ian I remember once we were
43:18tagging the animals with e attacks with
43:21numbers to for identification and one
43:24Mouse had stuck
43:26her H limb into that
43:30earring and the poor thing
43:32was really not well
43:35so but yet she didn't let us
43:40disentangle
43:42this it was her nail that was very long
43:46so it was only when Dr T came and held
43:49the mouth she just Cal down completely
43:53it had this power of it had this
43:58some quiet energy
44:01and even the my thought now everything
44:05is fine I
44:07relax excellent so interesting well I
44:11think the messages that you you said
44:13were transmitted to you by Paul are
44:16definitely something very important for
44:18the Young Generation of scientist you
44:21know there are many other things that we
44:24we and they have to learn but this
44:26definitely are you know fundamental
44:29messages I think we are getting to the
44:31end of this conversation which was
44:34really really interesting for me and uh
44:38I knew it would be you would give us
44:40wonderful insights but as usual with my
44:43conversations I get even more than what
44:46I'm hoping for from these interviews so
44:50I need to thank you Alina for your time
44:53and for your excellent explan Nations I
44:57really need to thank you and um I I hope
45:00the listeners will have the same
45:03enjoyable time as I did listening to the
45:07podcast and um thank you again and I'll
45:10see you the next time thank you very
45:12much Roberta it was a pleasure and an
45:15honor to get this opportunity thank you
45:18thank you
45:20[Music]
45:24Alina

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