Podcasts about trpa1

Piezo touch and pressure-sensing ion channels are showing up everywhere as the explanation for physiologic phenomena, both at the macro and micro levels. Ardem Patapoutian, my friend and colleague at Scripps Research, discovered these receptors back in 2010 and was awarded the Nobel Prize in 2021 for his work. As you'll see/hear from our conversation, the field has exploded. And you'll get to know Ardem, who is such a fun, charismatic, and down-to-earth person. He also recently got a unique tattoo (videos below) and I wonder (unlikely) if any other Nobel laureates have one related to their discovery?!Below is a video clip from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The current one is here. If you like the YouTube format, please subscribe! The audios are also available on Apple and Spotify.Transcript with links to audioEric Topol (00:07):Well, hello. It's Eric Topol with Ground Truths, and I've really got a special guest today. The first time for the podcast, I've been able to interview a colleague and faculty at Scripps Research, Ardem Patapoutian, who just by the way happens to be the 2021 Nobel Laureate in Physiology or Medicine. So welcome, Ardem. It's so wonderful to have you.Ardem Patapoutian (00:30):Thanks so much, Eric. Looking forward to chatting with you.Eric Topol (00:34):Well, this has been interesting because although I've known you for several years, I didn't research you. I mean, I had to learn about more than I even do. And of course, one of the great sources of that is on the Nobel Prize website where you tell your whole story. It is quite a story and not to review all of it, but I wanted to go back just before you made the call to move to Los Angeles from Beirut, Lebanon and with the scare that you went through at that time, it seemed like that was just extraordinary that you had to live through that.Ardem Patapoutian (01:11):Yeah, so I am of Armenian origin, but I was born in Lebanon and born in 1967, so I was eight years old when the civil war started. So it's a kind of bizarre childhood in the sense that with all the bombs and fighting in Lebanon. So it was tough childhood to have, but it was never personal. It was bombs and such. And so, the event you're talking about is, I happened to be kidnapped while crossing East to West Beirut. They only held me for four or five hours at first asking me questions to see who I am, but I think they pretty soon figured out that I was not a dangerous guy and they ended up letting me go. But before that, that incident really had a huge impact on me so that by the time I got home, I literally said, I'm out of here. I'm going to find a way to leave the country. And so, that's what, very quickly within a few months I packed and came to United States.Eric Topol (02:19):And how did you pick LA to be your destination?Ardem Patapoutian (02:22):Being from the Armenian community, there's a lot of Armenians in Los Angeles. My cousins already had moved there. They also grew up in Lebanon. And my brother, who's a few years older than me, got admitted to USC graduate school in engineering. So he was going to be there. So it made a lot of sense.Eric Topol (02:44):Oh yeah.Ardem Patapoutian (02:45):Unlike him, I came with no school or job prospects because it happened so fast that I kind of just left. One year I was at American University of Beirut for one year, but then just left and came here. So worked for a year in various jobs and then started going back to school to UCLA.Eric Topol (03:07):Yeah, I saw how there was about a year where you were delivering pizzas and before you got into UCLA, and that must have been an interesting off year, if you will. Well, the story of course, just to fast forward, you did your baccalaureate at UCLA, your PhD at Caltech, postdoc at UCSF, and then you came to Scripps Research 24 years ago along with Pete Schultz, and it's been quite an amazing run that you've had. Now, before we get into PIEZO receptors, the background, maybe you could help me understand, the precursor work seems to be all related to the transient receptor potential (TRP) series, also ion channels. They were of course related to whether it was heat and temperature or somatosensory. How do these channels compare to the ones that you discovered years later?Background on these Ion ChannelsArdem Patapoutian (04:09):Yeah, so the somatosensory neurons that innervate your fingertips and everywhere else in your body, their main job is to sense temperature and pressure. And this is very different than any other neuron or any other cell. So when you touch a hot stove that's burning hot, you need to know about that immediately within milliseconds or something cold. So the opposite side of it is pressure sensing, and it also comes in light touch, which is pleasant or a hammer hitting your finger, which is unpleasant. But all of these have the same characteristic anyway, that is your body has learned at the molecular level to translate a physical stimulus such as temperature and pressure into an electrical signal that neurons use to communicate with each other. But this idea of how you translate physical stimuli into chemical or electrical signal has been a long open question because as you know, most of our cells communicate by chemicals, whether that's hormones or small molecules, we know how that works, receptor bind to ligand, confirmational change and you get a kinase activation and that's enough. But here, how do you sense pressure? How do you sense temperature? It was just, there wasn't much known about that. And that's why our earlier work on TRP channels, which were temperature sensors came before the pressure. And so, they're very related in that sense.Eric Topol (05:52):The structure of these, if you were to look at them, do they look pretty similar? What the TRP as you say, and what you did back in the 2010 Science paper, which we'll link to, of course the classic paper where you describe PIEZO1 and PIEZO2, but if you were to look at this structures, would they look pretty similar?Ardem Patapoutian (06:14):No, that's a good question. And they absolutely don't. That's why finding these receptors were so hard. So if you go back to other sensory receptors, vision rhodopsin G-protein coupled receptor (GPCRs), larger G-protein coupled receptor look the same. So for example, when it was identified by chemically, that smell also works through G-protein coupled receptor. Richard Axel and Linda Buck, who also won the Nobel Prize, found those receptors by homology to visual GPCRs. The ion channels other than the fact that they crossed the membrane a few times or more, they have nothing else in common. If you looked at their structure, you can't even immediately tell they're ion channels. So you couldn't find these by structural homology or sequence homology. So you had to do something else. And usually that means functional screens and et cetera.Eric Topol (07:09):Well, yeah, and I'm in touch with the screening. We'll get to that and how you dig these up and find them. But the somatosensory ones are really interesting because I don't think a lot of people realize that when you have wasabi or you have Listerine mouthwash and feel the burn and that these are all mediated through these channels, right?Ardem Patapoutian (07:35):Yeah. So there's this whole field of chemesthesis, which means senses in your mouth, for example, that are not explained by taste transduction and olfactory. And these are actually by the same somatosensory neurons that help you sense temperature and pressure. And some of these receptors are the same. Their evolution has taken over and used them for many different things. The prime example of this is the capsaicin receptor that David Julius my co-laureate identified, which is also heat receptors. So all languages describe chili peppers as hot, and that's not a coincidence. It actually activates heat activated channel, and that's why we think of it as hot. And so, the same goes to another one of these TRP channels that you mentioned, which is TRPA1, and this one is also activated, but a lot of spicy foods other than the chili pepper active ingredient includes what's in garlic and onions and everything that has this burning sensation and chemicals of this and wasabi and chemicals of this are used in over the counter products like Listerine that cause that burning sensation.Eric Topol (08:54):So when you're chopping onions and it makes you cry, is that all part of it as well?Ardem Patapoutian (08:59):That's all TRPA1, yeah.The Discovery, A Test of PerseveranceEric Topol (09:01):It's wild. Now, this was the groundwork. There were these heat temperature and somatic sensory, and then you were starting to wonder what about touch, what about out pressure and proprioception. And so, you went on a hunt, and it's actually kind of an incredible story about how you were able to find out of these cells that you had, screening hundreds or I guess you got to 72 different small interfering RNA blocking that you finally found the one. Is that right?Ardem Patapoutian (09:37):That's right. So in retrospect, looking back at it, I think there's such an interesting scientific message there. And so, many of us were looking for this touch pressure sensors and we were all looking in the DRG sensory neurons that are complicated heterogeneous, they don't divide. It's not easy to do a screen on them. And ultimately after a lot of failures, what worked for us is to take a step back and ask a much more simpler question. And that was, can we find one of these cell lines that you could easily homogeneously grow in a culture dish, if they respond to mechanical force, can we find our channel there? And then go back and look if it's relevant in vivo for what process. So I think the message is ask the simplest question to answer the question you're after. And finding what that is, is actually the challenge lots of times.Ardem Patapoutian (10:36):But yeah, that's what Bertrand Coste in my lab did is found a simple cell line that neuroscientists had been using for a hundred years and somehow found that they over overexpressed this channel because you can record from them, you can push them and record the currents from them. And then it became a simpler question of finding it. It still took a whole year. He made a list and one by one knocking them out and looking at it. And finally, as you say, number 72 was the hit. When he knocked that out, the current was gone. And that's where we started believing that we have what we were looking for.Eric Topol (11:12):Were you all ever about ready to give up at that point?Ardem Patapoutian (11:16):Oh yeah. I mean that's another lesson. These are postdocs doing the work, right? And they're here three, four years and this was coming close to end of two years, and he didn't have anything yet. So we started talking about having a backup project and he started that and we said, okay, we were ordering this oligos 30 at a time because they're expensive. And so, the first 30 nothing, the second 30 nothing. And how many more are we going to do before we potentially give up? And we said, well, let's do at least a third and then decide, thank goodness it was in that last set.Eric Topol (11:54):Wow, that is so wild. Now what's happened since this discovery, which I guess when you published it in 2010, so it means 14 years ago, but we're on this exponential growth of learning that these piezo receptors are everywhere. They're doing everything. In fact, I recently put on Bluesky, PIEZO ion channels are to human physiology as GLP-1 drugs are to treating many diseases because it's just blowing up. And you've published on some of these of course, on itch and bladder function and vascular function. We'll get to maybe malaria, I mean, but even the cover of Science recently was about wet dog shakes and how animals shake because of water. These receptors are so fundamental to our function. So maybe you could comment, 15 years ago when you were doing the work and you're making this discovery, did you ever envision it was going to blow up like this?Ardem Patapoutian (12:57):Not to this level, but I should have. I think that this idea, again, that most of cell communication is through chemicals is of course a lot of it is true.Ardem Patapoutian (13:12):But it would be ridiculous for evolution to ignore all the physical forces, the pressures that cells experience. And once they do, you would think you would put an instructive way of sensing this pressure signal and using it beneficially to the system or the cell. And so, when we used to talk about pressure sensing at the beginning, there were a couple of touch, pain, maybe proprioception, hearing are like the poster children of pressure sensing. But I think what these molecules, as you say is enabling us is finding out the much more wider role that pressure sensing is playing in physiology and in disease that no one had thought seriously about. And this is, I compare sometimes the finding the PIEZO molecules. You're going in a dark room, and you need to find a door to get into there. And PIEZO is kind of that finding the door once you get in, now you use that molecule now to find physiology instead of the opposite way around. So by pursuing PIEZO expression and function, we're finding all these new roles that they play in physiology and in disease that we didn't think about. And because they're so specialized to sense tension, membrane tension, they don't do anything else. So if you see them expressed somewhere or if you see a function for them, you can bet that they are playing a role in sensing pressure. A lot of biology has kind of come from this hypothesis.Eric Topol (15:00):Well, I mean it is so striking to see the pervasiveness, and I do want to go back just for a second because when you name them PIEZO, you named it after the Greek word. How did you come to that name?Ardem Patapoutian (15:13):So Bertrand and I were actually sitting on Google Translate and we were typing pressure and trying to see what it's like in Greek or in Latin or different languages. His native French and my Armenian and píesi in Greek is pressure. And of course, what's really cool is that the word that more people know about this is piezoelectric device.Eric Topol (15:41):Oh, right.Ardem Patapoutian (15:41):Actually, translates physical force into electricity and vice versa. And in a way, this is a little molecular machine that does the same thing, and he uses this piezoelectric device to actually push on the cell. That's his assay. So it all came together as a very appropriate name for this gene and protein.Call from the Nobel CommitteeEric Topol (16:04):Oh really, it's perfect. And you get to name it, even that's fun too, right? Now we're going to go to getting the call at 2:00 AM, but it didn't come to you because your phone from the Nobel Committee was on ‘do not disturb' and your 94-year-old father, Sarkis. How did the Nobel Committee know to get ahold of him? How did they reach him in the middle of the night?Ardem Patapoutian (16:37):Yeah, so I mean, since receiving it, I've had conversations with various committee members, and they are very resourceful folks, and they have assistants who throughout the year collect information on all potential people who might win. They're also doing last minute searches. So they looked for other Patapoutian's in California. So they just called my dad who initially yelled at them for disturbing him at 2:00 AM.Eric Topol (17:17):And he could get through to you because he was not on your list of ‘do not disturb' or something like that.Ardem Patapoutian (17:22):I didn't even know this. And I don't know if the policy has changed, but in some phones the ‘do not disturb' if it's called by someone who's in your contacts or favorites.Ardem Patapoutian (17:34):After I think they called twice and they get through, and that's how.Getting a Tattoo!Eric Topol (17:39):That's amazing. Wow. Well, that's quite a way to find out that you're getting recognized like this. Now recently you got a tattoo, which I thought was really remarkable, but we're going to put that of course in the post. Tell us about your decision to get the PIEZO channel on your arm.Ardem Patapoutian (18:02):So as you can tell, I'm obsessed about PIEZO and it's been good to me. And I had the idea a while ago, and my very wise wife, Nancy Hong, said that you might be going through midlife crisis. Why don't you wait a year? If you still believe in it, you should do it. And that's what I did. I waited a year, and I was like, I still want to do it. And I guess I could show it. Here it is.Eric Topol (18:32):Oh yeah, there it is. Oh wow.Ardem Patapoutian (18:33):What's cool is that I can pretty much flex to show the activation mechanism because the channel is like bent like this in the plasma membrane. When it's stretched, it opens and it actually flattens like this. So I feel like other than being a tattoo, this is both performance art and instructional device. When I'm giving talks without PowerPoint slides, I could give a demonstration how this ion channel works.[Below is from a presentation that Ardem recently gave, the Harvey Lecture, at Rockefeller University.]Eric Topol (19:04):It's wild. Now how did you find a tattoo artist that could, I mean, it's pretty intricate. I mean, that's not your typical tattoo.Ardem Patapoutian (19:14):Yeah, I put it up on social media that I was thinking of doing this, and many scientists are into tattoos, so I actually got so many recommendations. And one of them was a local here in San Diego, and she is very popular. I waited six months to get this, I was on a waiting list. The appointment was six months off when we made it. So she's very popular and she's very good.Eric Topol (19:45):Was it painful to get that done?Ardem Patapoutian (19:47):Well, that's actually really cool, right? Because PIEZO2 is involved in pain sensation, and I felt it while it was being tattooed on my arm. The whole day, I was there like six and a half hours.New Prospect for Pain MedicationEric Topol (20:00):Oh my gosh. Wow. Now that gets me to pain because, I'd like you to talk a bit about the people that don't have mutations or loss of function PIEZO receptors and also what your thoughts are in the future as to maybe we could develop a lot better pain medications.Ardem Patapoutian (20:22):Yeah, we're working on it. So you're right. One of the great parts of the science story, and this is mainly the work of Alex Chesler and Carsten Bönnemann at the NIH, where they identified people who came to the clinic for undiagnosed conditions, and they were uncoordinated and had difficulty walking. And when they did whole-exome sequencing, they found that they had mutations in PIEZO2, there were loss of function, as you say. So complete loss on both chromosomes. And when they started testing them, they realized that just like we had described them in animal models, humans without PIEZO2 as well, didn't sense touch, don't have proprioception. This sense of where your limbs are, that's so important for balance and most other daily functions that we take it for granted. So they were completely lacking all of those sensations. They also do not feel their bladder filling.Ardem Patapoutian (21:26):And so, they have learned to go on a schedule to make sure they don't have accidents. And many of these projects that we've done in the lab collaboration with Alex Chesler, et cetera, have come from the observations of what else these individuals experience. And so, it's been a great kind of collaboration communication between mechanistic animal model studies and the clinic. And so, one of the things that these individuals don't sense in addition to touch, is something called tactile allodynia, which is simply when touch becomes painful. You and I experienced this after small injury or sunburn where just touching your shoulder becomes painful, but for peripheral neuropathy and other neuropathic pain conditions, this is one of the major complaints that individuals have. And we know from the NIH studies that these individuals don't have this tactile allodynia. So touch becomes painful and doesn't apply to them, which tells us that if we block PIEZO2, we can actually get interesting relief from various aspects relative to neuropathic pain on other pain related neuropathies. But given everything we talked about, Eric, about how this is important for touch and proprioception, you don't want to make a pill that blocks PIEZO2 and you take it because this will have some serious on target side effects. But we are developing new compounds that block PIEZO2 and hope that it might be useful, at least as a topical medication pain and other indications. And we're actively working on this, as I said.Eric Topol (23:15):Yeah, I mean the topical one sounds like a winner because of peripheral neuropathy, but also I wonder if you could somehow target it to sick cells rather than if giving it in a systemic targeted way. I mean it has tremendous potential because we are on a serious hunt for much better relief of pain than exists today.Ardem Patapoutian (23:41):Absolutely.Eric Topol (23:42):Yeah. So that's exciting. I mean, that's another potential outgrowth of all this. Just going back, I mean the one that prompted me in November to write that about the human physiology in PIEZO, it was about intestinal stem cell fate decision and maintenance. I mean, it's just everywhere. But the work you've done certainly now has spurred on so many other groups to go after these different and many unanticipated functions. Were there any ones, of course, you've been pretty systematically addressing these that actually surprised you? You said, oh, are you kidding me when you read this? I never would've guessed this, or pretty much they followed suit as things were moving along.Ardem Patapoutian (24:33):So one of them is this role in macrophages that I found fascinating that we found a few years ago. So again, this came from human studies where PIEZO1 gain-of-function mutations. So in relation to loss of function, their gain-of-function where there's more activity given a certain amount of pressure. They have dehydrated red blood cells, which I'm not going to talk about right now. But they also have shown that in these patients, individuals, it's not really that pathological. They also have age-onset iron overload. What does that have to do with pressure sensing? And we brought that information into animal models, and we found that macrophages, their rate of phagocytosis depends on PIEZO, so that if you have too little PIEZO, they don't phagocytosis as much. If you have too much PIEZO, the phagocytosis too much. And this increased rate of phagocytosis in the long term because it's constantly eating red blood cells and the iron is circulating more causes long-term effects in iron overload. And again, as you kind of set that up, who would've thought that mechanical sensation is important for this basic hematology type?Eric Topol (25:52):Yeah, I mean, because we've been talking about the macro things, and here it is at the cellular level. I mean, it's just wild.Ardem Patapoutian (25:59):If you go back and look at a video of a macrophage eating up red blood cells, then you go, oh, I see how this has to do with pressure sensing because it is like extending little arms, feeling things letting go, going somewhere else. So again, I want to bring it back by this simple cell biological function of a cell type, like macrophage, exploring its environment is not just chemical, but very mechanical as well. And so, in retrospect, it is maybe not that surprising, that pressure sensing is important for its physiology.Career Changing?Eric Topol (26:33):Yeah, that's extraordinary. Well, that gets me to how your life has changed since 2021, because obviously this a big effect, big impact sort of thing. And I know that you're the first Armenian, first person from Lebanon to get this recognition. You recognized by the Lebanese Order of Merit. There's even a stamp of you, your picture characterized in 2022.Eric Topol (27:04):So if you were to sum up how it's changed because I see no change in you. You're the same person that has a great sense of humor. Often the tries to humor relaxed, calming. You haven't changed any to me, but how has it affected you?Ardem Patapoutian (27:26):Thank you, Eric. That's very kind of you. I try very hard for it not to change me. I do get a little bit more attention, a ton more invites, which unfortunately I have to say no to a lot of them because, and I'm sure you're very familiar with that concept and a lot of things are offered to you that I feel like it's so tempting to say yes because they're wonderful opportunities and an honor to be asked. But the end of the day, I'm trying to be very disciplined and not taking things on that I can do as an opportunity. But things that I really want to do. I think that's so hard to do sometimes is to separate those two. Why am I doing this? Is this really important for the goals that I have? So in one way, the answer for that is that I just want to stay in the lab and do my research with my students and postdoc, which is what I enjoy the most. But on the other hand, as you said, being the first Armenian who's received this, literally after the Nobel, I got this whole elementary school, all Armenian kids write to me multiple letters.Ardem Patapoutian (28:39):And they said, you look like me. I didn't think I could do this, but maybe I can. So in a sense, to ignore that and say, no, I just want to do my science, I don't want to be involved in any of that is also wrong. So I'm trying to balance being engaged in science outreach and helping to make science understood by the general public, realize that we're just regular people and at the same time how awesome science is. I love science and I like to project that, but leave plenty of time for me to just be a scientist and be in my lab and interact with my colleagues at Scripps, including you.Immigrant ScientistsEric Topol (29:21):Well, we're so lucky to have that chance. And I do want to mention, because you're prototyping in this regard about great immigrant scientists and other domains of course, but every year the Carnegie Foundation names these great immigrants and one year you were of course recognized. And in recent years, there have been more difficulties in people wanting to come to the US to get into science, and they wind up going to other places. It seems like that's a big loss for us. I mean, what if we weren't able to have had you come and so many hundreds, thousands of others that have contributed to this life science community? Maybe you could comment about that.Ardem Patapoutian (30:10):Yeah, I think it is tragic, as you say. I think in some circles, immigrants have this negative image or idea of what they bring, but at every level, immigrants have contributed so much to this country. It's a country of immigrants, of course, to start with. And I think it is important to put up a positive image of immigration and science is the ultimate example of that, right? I mean, I think when you go into any laboratory, you probably find if there's a lab of 16 people, you probably find people from 10 different countries. And we all work together. And the idea of also immigrant and especially about science is that I'm a big believer of changing field, changing things because just like that, immigrants have changed their whole life. So they come to a new culture, they bring with them their own way of thinking and their way of seeing things. And then you come into a new environment, and you see it a little bit differently. So that kind of change, whether it's because of physical immigration or immigrating from one field to another in science is really beneficial for science and society. And I think positive examples of this are an important part of highlighting this.Eric Topol (31:40):I couldn't agree with you more really.Bluesky vs Twitter/XEric Topol (31:41):Now, speaking of migration, there's been recently a big migration out of X, formerly Twitter to Bluesky, which I like the metaphor you liken to the Serengeti. Can you tell us about, now I know you're posting on Bluesky and of course so many others that you and I are mutual contacts, and our different networks are. What do you think about this migration outside of what was the platform where a lot of this, we shared things on X or before Musk took over known as Twitter? Thoughts about Bluesky?Ardem Patapoutian (32:27):Yeah, I think I use social media for a few reasons. The number one reason should be is to see new science by colleagues. My main point is that, but also, again, having fun in science is a big part of my draw to this. And as you can see from my posts, it's a bit lighthearted, and that's really me.Eric Topol (32:52):Right. Yeah.Ardem Patapoutian (32:52):I think on Twitter, things start getting a little bit dark and too many negative comments, and it was just not productive. And I just felt like after the elections, I felt like it was time to migrate. And I find Bluesky a great scientific community, and it's remarkable how quickly people have migrated from Twitter to Bluesky. But the counter argument for this is that you should stay in a place where majority of people are, because being in a bubble surrounding yourself by people like you doesn't help society. And so, I get that perspective as well. It just depends on what you're using the platform for and it's a difficult issue. But yeah, I've taken a break probably long-term break from Twitter. I'm on Bluesky now.Eric Topol (33:48):Yeah, no, the point you're bringing up about the echo chamber and is there going to be one for people that are leaning one way and they're thinking, and another with a whole different, often politically charged and even extreme views? It's really unfortunate if it does wind up that way. But right now, it seems like that migration is ongoing and it's substantial. And I guess we'll see how it settles out. I share your concern, and so far, I've been trying to keep a foot in both areas because I think if we all were to leave, then we're just kind of caving into a, it's tricky though. It really is because the noxious toxic type of comments, even when you try to avoid comments, you say, only followers can make a comment, they'll of course, quote your thing and then try to ding you and whatever. It's just crazy stuff, really.Ardem Patapoutian (34:53):I mean, what I think is that, that's why I said depends on why. I mean, your presence on social media is such an important part of science education. And I could almost say you can't afford to do what I do, which is I'm just putting my goofy posts and having fun. So we have different purposes in a way, and yeah, that affects what you use and how you use it.Eric Topol (35:17):Yeah, no, it's tricky it really is. We covered a lot of ground. Is there anything I missed that you want to get out there? Any part of this, your story and the PIEZO story, science and everything else that I didn't bring up?The Essentiality of Basic ScienceArdem Patapoutian (35:42):I just think that the basic science community is really suffering from decreasing amounts of funding and appreciation of doing basic science. And one of my goals, in addition to this immigrant scientist thing, is to remind people that all medicines start with basic science work. And funding this has mainly been through NIH and it's getting harder and harder for basic scientists to secure funding and I'm really worried about this. And we need to find ways to be okay for people to do basic science. And I'll give you one example. Whenever we make a publication and there's a journalist talking to us or some kind of press coverage, they ask, how is this directly affecting patients? And my work actually is very much related to patients, and I answer that question, but I also say, but it's also important to do science for the science sake because you don't know where the applications are going to come from. And we need to, as a society, encourage and fund and support basic science as the seeds of all these translational work. And I think doing that just kind of highlights that this is important too. We should support it, not just things that right now seem very related to translational that directly helps patients.Eric Topol (37:16):Well, I'm so glad you emphasized that because I mean, the PIEZO story is the exemplar. Look what's come of it, what might still come of it. In many respects here you are maybe 15 years into the story and there's still many parts of this that are untold, but if it wasn't for the basic science, we wouldn't have these remarkable and diverse insights. And recently you cited, and I think so many people read about the ‘crown jewel' NIH, front page New York Times, and how it's under threat because the new NIH director doesn't have a regard for basic science. He's actually, he's confirmed, which is likely, he's an economist, physician economist, never practiced medicine, but he doesn't really have a lot of regard for basic science. But as you point out, almost every drug that we have today came out of NIH basic work. And I mean, not just that, but all the disease insights and treatments and so much.Eric Topol (38:25):So this is really unfortunate if we have not just an NIH and other supporting foundations that don't see the priority, the fundamental aspect of basic science to then lead to, as we call translational, and then ultimately the way to promote human health, which is I think what we're all very much focused on ultimately. But you can't do it without getting to first base, and that's what you have done. You served it up and it's a great example. Well, Ardem, it's always a pleasure. This is a first time talking through a podcast. I hope we'll have many, many visits informally that will complement the ones we've already had, and we will follow the PIEZO work. Obviously, you have had just an exceptional impact, but you're still young and who knows what's next, right? I mean, look what happened to Barry Sharpless. He won here. He won two Nobel prizes, so you never know where things are headed.Ardem Patapoutian (39:36):Thank you, Eric, and I really appreciate what you do for the biomedical community. I think it's wonderful through your social media and this podcast, we all appreciate it.***********************************************************************************Please take a moment to complete the poll above.Thank you for reading, listening and subscribing to Ground Truths.If you found this informative please share it!All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.Paid subscriptions are voluntary and of course appreciated. All proceeds from them go to support Scripps Research. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. I welcome all comments from paid subscribers and will do my best to respond to each of them and any questions.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio and video support at Scripps Research.And Happy New Year! Get full access to Ground Truths at erictopol.substack.com/subscribe

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.30.547260v1?rss=1 Authors: Tian, J., Bavencoffe, A. G., Zhu, M. X., Walters, E. T. Abstract: Nociceptor cell bodies generate spontaneous discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia (DRGs) have shown that prior pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Here we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. Input resistance and both the amplitude and frequency of DSFs were increased in neurons exhibiting spontaneous activity. Ion substitution experiments indicated that the depolarizing phase of DSFs is generated by spontaneous opening of channels permeable to Na+ and/or Ca2+, and that Ca2+-permeable channels are especially important for larger DSFs. Partial reduction of the amplitude and/or frequency of DSFs by perfusion of pharmacological inhibitors indicated small but significant contributions from Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, and N-type Ca2+ channels. Less specific blockers suggested a contribution from NALCN channels, and global knockout suggested a role for Nav1.9. The combination of high somal input resistance plus background activity of diverse ion channels permeable to Na+ and/or Ca2+ produces DSFs that are poised to reach AP threshold if resting membrane potential (RMP) depolarizes, AP threshold decreases, and/or DSFs become enhanced -- all of which have been reported under painful neuropathic and inflammatory conditions. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Discover the fascinating connections between diet, pollutants, probiotic therapy, as we explore the it's impact on eczema rates. ​ In this episode, Dr. Ian Myles helps us: - Unravel the link between chemicals like diisocyanates and eczema triggers, often lurking in fabrics, foam mattresses, nylon, and carpet underlay - Dive deep into the skin's receptor, TRPA1, in itch, pain, and rash reactions in eczema - Explore the intriguing connection between bacteria on the skin and eczema - Find out how pollution, automotive exhaust, and wildfires can be contributing to eczema - Discover the sibling theory and how siblings can have different effects of eczema ​ Don't miss this enlightening episode packed with life-changing discoveries! ​ Book a free eczema breakthrough call to help you conquer eczema: https://www.conqueryoureczema.com/client-results ​ Visit www.eczemaconquerors.com for more support. ​ ​ *Research papers mentioned:  ​ Assessing the effects of common topical exposures on skin bacteria associated with atopic dermatitis - https://onlinelibrary.wiley.com/doi/full/10.1002/ski2.41 ​ https://www.niaid.nih.gov/news-events/probiotic-skin-therapy-improves-eczema-children-nih-study-suggests ​ Exposure to isocyanates predicts atopic dermatitis prevalence and disrupts therapeutic pathways in commensal bacteria - https://www.science.org/doi/10.1126/sciadv.ade8898 ​ Association of frequent moisturizer use in early infancy with the development of food allergy - https://pubmed.ncbi.nlm.nih.gov/33678253/ ​ Assessing the effects of common topical exposures on skin bacteria associated with atopic dermatitis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555759/ ​ First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis https://pubmed.ncbi.nlm.nih.gov/29720571/

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.13.532477v1?rss=1 Authors: Genovese, F., Xu, J., Tizzano, M., Reisert, J. Abstract: In the mammalian nose, two chemosensory systems, the trigeminal and the olfactory mediate the detection of volatile chemicals. Most odorants in fact are able to activate the trigeminal system, and vice versa, most trigeminal agonists activate the olfactory system as well. Although these two systems constitute two separate sensory modalities, trigeminal activation modulates the neural representation of an odor. The mechanisms behind the modulation of olfactory response by trigeminal activation are still poorly understood. In this study, we addressed this question by looking at the olfactory epithelium, where olfactory sensory neurons and trigeminal sensory fibers co-localize and where the olfactory signal is generated. We characterize the trigeminal activation in response to five different odorants by measuring intracellular Ca2+ changes from primary cultures of trigeminal neurons (TGNs). We also measured responses from mice lacking TRPA1 and TRPV1 channels known to mediate some trigeminal responses. Next, we tested how trigeminal activation affects the olfactory response in the olfactory epithelium using electro-olfactogram (EOG) recordings from WT and TRPA1/V1-KO mice. The trigeminal modulation of the olfactory response was determined by measuring responses to the odorant, 2-phenylethanol (PEA), an odorant with little trigeminal potency after stimulation with a trigeminal agonist. Trigeminal agonists induced a decrease in the EOG response to PEA, which depended on the level of TRPA1 and TRPV1 activation induced by the trigeminal agonist. This suggests that trigeminal activation can alter odorant responses even at the earliest stage of the olfactory sensory transduction. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.23.525238v1?rss=1 Authors: Yang, C., Yamaki, S., Jung, T., Kim, B., Huynh, R., McKemy, D. D. Abstract: The detection of environmental temperatures is critical for survival, yet inappropriate responses to thermal stimuli can have a negative impact on overall health. The physiological effect of cold is distinct among somatosensory modalities in that it is soothing and analgesic, but also agonizing in the context of tissue damage. Inflammatory mediators produced during injury activate nociceptors to release neuropeptides, such as CGRP and substance P, inducing neurogenic inflammation which further exasperates pain. Many inflammatory mediators induce sensitization to heat and mechanical stimuli but, conversely, inhibit cold responsiveness, and the identity of molecules inducing cold pain peripherally is enigmatic, as are the cellular and molecular mechanisms altering cold sensitivity. Here, we asked if inflammatory mediators that induce neurogenic inflammation via the nociceptive ion channels TRPV1 and TRPA1 lead to cold pain in mice. Specifically, we tested cold sensitivity in mice after intraplantar injection of lysophosphatidic acid (LPA) or 4-hydroxy-2-nonenal (4HNE), finding each induces cold pain that is dependent on the cold-gated channel TRPM8. Inhibition of either CGRP, substance P, or toll-like receptor 4 (TLR4) signaling attenuates this phenotype, and each neuropeptide produces TRPM8-dependent cold pain directly. Further, the inhibition of CGRP or TLR4 signaling alleviates cold allodynia differentially by sex. Lastly, we find that cold pain induced by inflammatory mediators and neuropeptides requires the neurotrophin artemin and its receptor GFRalpha3. These results demonstrate that tissue damage alters cold sensitivity via neurogenic inflammation, likely leading to localized artemin release that induces cold pain via GFRalpha3 and TRPM8. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.13.523766v1?rss=1 Authors: Trotier, A. F., Bagnoli, E., Walski, T., Evers, J., Pugliese, E., Lowery, M. M., Kilcoyne, M., Fitzgerald, U., Biggs, M. Abstract: Clinical applications for neural implant technologies are steadily advancing. Yet, despite clinical successes, neuroelectrode-based therapies require invasive neurosurgery and can subject local soft-tissues to micro-motion induced mechanical shear, leading to the development of peri-implant scaring. This reactive glial tissue creates a physical barrier to electrical signal propagation, leading to loss of device function. Although peri-electrode gliosis is a well described contributor to neuroelectrode failure, the mechanistic basis behind the initiation and progression of glial scarring remains poorly understood. Here, we develop an in silico model of electrode-induced shear stress to evaluate the evolution of the peri-electrode fluid-filled void, encompassing a solid and viscoelastic liquid/solid interface. This model was subsequently used to inform an in vitro parallel-plate flow model of micromotion mediated peri-electrode fluid shear stress. Ventral mesencephalic E14 rat embryonic in vitro cultures exposed to physiologically relevant fluid shear exhibited upregulation of gliosis-associated proteins and the overexpression of two mechanosensitive ion channel receptors, PIEZO1 and TRPA1, confirmed in vivo in a neural probe induced rat glial scar model. Finally, it was shown in vitro that chemical inhibition/activation of PIEZO1 could exacerbate or attenuate astrocyte reactivity as induced by fluid shear stress and that this was mitochondrial dependant. Together, our results suggests that mechanosensitive ion channels play a major role in the development of the neuroelectrode micromotion induced glial scar and that the modulation of PIEZO1 and TRPA1 through chemical agonist/antagonist may promote chronic electrode stability in vivo. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.30.514409v1?rss=1 Authors: Velez-Ortega, A. C., Stepanyan, R., Edelmann, S. E., Torres-Gallego, S., Park, C., Marinkova, D. A., Nowacki, J. S., Sinha, G. P., Frolenkov, G. I. Abstract: TRPA1 channels are expressed in nociceptive neurons, where they detect noxious stimuli, and in the mammalian cochlea, where their function is unknown. Here we show that TRPA1 activation in the supporting non-sensory Hensen's cells causes prolonged Ca2+ responses, which propagate across the organ of Corti and cause long-lasting contractions of pillar and Deiters' cells. Caged Ca2+ experiments demonstrated that, similar to Deiters' cells, pillar cells also possess Ca2+-dependent contractile machinery. TRPA1 channels are activated by endogenous products of oxidative stress and by extracellular ATP. Since both these stimuli are present in vivo after acoustic trauma, TRPA1 activation after noise may affect cochlear sensitivity through supporting cell contractions. Consistently, TRPA1 deficiency results in larger but less prolonged noise-induced temporary shift of hearing thresholds, accompanied by permanent changes of latency and shape of the auditory brainstem responses. We conclude that TRPA1 contributes to the regulation of cochlear sensitivity after acoustic trauma. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.01.506151v1?rss=1 Authors: Semizoglou, E., Gentry, C., Vastani, N., Stucky, C. L., Andersson, D. A., Bevan, S. Abstract: TRPA1 expressed in peripheral sensory neurons is important for nociception. Pharmacological inhibition or genetic ablation of TRPA1 profoundly reduces normal behavioural sensitivity to noxious cold and mechanical stimulation, as well as sensory neuron responses to mechanical stimulation. TRPA1 inhibition also reverses cold and mechanical hypersensitivities in chronic pain models in vivo. Here we demonstrate that these striking effects of TRPA1 inactivation result from an increased constitutive activity of kappa opioid receptors (KOR) co-expressed with TRPA1 in sensory neurons. Inhibition of KOR in Trpa1-/- mice restores nociception and neuronal activity to the levels observed in wild-type mice and reverses the analgesic effects of TRPA1 antagonism in naive mice and in neuropathic and inflammatory pain conditions. TRPA1 regulation of KOR activity in sensory neurons provides a novel mechanism to produce peripherally mediated analgesia. Our findings suggest that TRP channel regulation of constitutive GPCR activity, may be a process of general physiological importance. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Often used as an additive for cat toys and treats due to its euphoric and hallucinogenic effects on cats, catnip has also long been known for its powerful repellent action on insects, mosquitoes in particular. Recent research shows catnip compounds to be at least as effective as synthetic insect repellents such as DEET. #catnip​ #mosquito​ #insectrepellent​ N. Melo et al. The irritant receptor TRPA1 mediates the mosquito repellent effect of catnip. Current Biology. Published online March 4, 2021. doi: 10.1016/j.cub.2021.02.010. --- Support this podcast: https://anchor.fm/ralph-turchiano/support

In this episode, we discuss the mechanisms of burning with propofol infusion and explore the evidence behind strategies like mixing lidocaine with propofol.  Our guest today is Dr. Stu Forman, Professor of Anesthesiology at Massachusetts General Hospital. He is an investigator on several NIH-sponsored basic research grants and co-director of the Harvard Anesthesia Research Training Fellowship. Connect with us @DepthAnesthesia on Twitter or email us at depthofanesthesia@gmail.com. Thanks for listening! Please rate us on iTunes and share with your colleagues.  Music by Stephen Campbell, MD.  -- References Bengalorkar GM, Bhuvana K, Sarala N, Kumar T. Fospropofol: clinical pharmacology. J Anaesthesiol Clin Pharmacol. 2011 Jan;27(1):79-83. PMID: 21804712; PMCID: PMC3146164. Dajun Song, Mohamed A. Hamza, Paul F. White, Stephanie I. Byerly, Stephanie B. Jones, Amy D. Macaluso; Comparison of a Lower-lipid Propofol Emulsion with the Standard Emulsion for Sedation during Monitored Anesthesia Care. Anesthesiology 2004; 100:1072–1075 doi: https://doi.org/10.1097/00000542-200405000-00007 Euasobhon P, Dej-Arkom S, Siriussawakul A, Muangman S, Sriraj W, Pattanittum P, Lumbiganon P. Lidocaine for reducing propofol-induced pain on induction of anaesthesia in adults. Cochrane Database Syst Rev. 2016 Feb 18;2(2):CD007874. doi: 10.1002/14651858.CD007874.pub2. PMID: 26888026; PMCID: PMC6463799. Fischer MJ, Leffler A, Niedermirtl F, Kistner K, Eberhardt M, Reeh PW, Nau C. The general anesthetic propofol excites nociceptors by activating TRPV1 and TRPA1 rather than GABAA receptors. J Biol Chem. 2010 Nov 5;285(45):34781-92. doi: 10.1074/jbc.M110.143958. Epub 2010 Sep 7. PMID: 20826794; PMCID: PMC2966094. Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O, Pace NL, Apfel CC; Perioperative Clinical Research Core. Prevention of pain on injection of propofol: systematic review and meta-analysis. BMJ. 2011 Mar 15;342:d1110. doi: 10.1136/bmj.d1110. PMID: 21406529. Klement W, Arndt JO. Pain on i.v. injection of some anaesthetic agents is evoked by the unphysiological osmolality or pH of their formulations. Br J Anaesth. 1991 Feb;66(2):189-95. doi: 10.1093/bja/66.2.189. PMID: 1817619. Sahinovic MM, Struys MMRF, Absalom AR. Clinical Pharmacokinetics and Pharmacodynamics of Propofol. Clin Pharmacokinet. 2018;57(12):1539-1558. doi:10.1007/s40262-018-0672-3 Scott RP, Saunders DA, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia. 1988 Jun;43(6):492-4. doi: 10.1111/j.1365-2044.1988.tb06641.x. PMID: 3261547.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.04.325118v1?rss=1 Authors: Madasu, M. K., Thang, L. V., Chilukuri, P., Palanisamy, S., Arackal, J. S., Sheahan, T. D., Foshage, A. M., Houghten, R. A., McLaughlin, J. P., McCall, J. G., Al-Hasani, R. Abstract: Noxious cold sensation is commonly associated with peripheral neuropathies, however, there has been limited progress in understanding the mechanism of cold pain. Transient receptor potential (TRP) A1 channels facilitate the perception of noxious cold at the level of dorsal root ganglia (DRG), where kappa opioid receptors (KOR) are also expressed but have not previously been implicated in cold sensation. Here we identify a new role for KOR in enhancing cold hypersensitivity. First, we show that systemic KOR agonism (U50,488, KOR agonist), significantly potentiates the latency to jump and the number of jumps on the cold plate compared controls at 3oC. Importantly, NorBNI (KOR antagonist) attenuates U50,488-induced cold hypersensitivity. However, the central administration of NorBNI does not block U50,488-induced cold hypersensitivity suggesting that peripheral KOR likely modulate this effect. Furthermore, the peripherally-restricted KOR agonist, ff(nle)r-NH2 also induces cold hypersensitivity. Using fluorescent in situ hybridization, we show that KOR mRNA colocalizes with the transcripts for the cold-activated TRPA1 and TRPM8 channels in DRG. Finally, using calcium imaging in DRG, we show that intracellular calcium release is potentiated during the simultaneous application of a TRPA1 agonist, mustard oil (MO), and a KOR agonist (U50,488), when compared to MO alone. This potentiated calcium response is absent in TRPA1 KO mice. Together our data suggest that KOR-induces cold hypersensitivity through modulation of peripheral TRPA1 channels. These findings indicate that whether activation of peripheral KOR is protective or not may be dependent on the pain modality. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.14.295600v1?rss=1 Authors: Thakore, P., Alvarado, M. G., Ali, S., Mughal, A., Pires, P. W., Yamasaki, E., Pritchard, H. A. T., Isakson, B. E., Tran, C. H. T., Earley, S. Abstract: Blood flow regulation in the brain is dynamically regulated to meet the metabolic demands of active neuronal populations. Recent evidence has demonstrated that capillary endothelial cells are essential mediators of neurovascular coupling that sense neuronal activity and generate a retrograde, propagating, hyperpolarizing signal that dilates upstream arterioles. Here, we tested the hypothesis that transient receptor potential ankyrin 1 (TRPA1) channels in capillary endothelial cells are significant contributors to functional hyperemic responses that underlie neurovascular coupling in the brain. Using an integrative ex vivo and in vivo approach, we demonstrate the functional presence of TRPA1 channels in brain capillary endothelial cells, and show that activation of these channels within the capillary bed, including the post-arteriole transitional region covered by ensheathing mural cells, initiates a retrograde signal that dilates upstream parenchymal arterioles. Notably, this signaling exhibits a unique biphasic mode of propagation that begins within the capillary network as a short-range, Ca2+ signal dependent on endothelial pannexin-1 channel/purinergic P2X receptor communication pathway and then is converted to a rapid, inward-rectifying K+ channel-mediated electrical signal in the post-arteriole transitional region that propagates upstream to parenchymal arterioles. Two-photon laser-scanning microscopy further demonstrated that conductive vasodilation occurs in vivo, and that TRPA1 is necessary for functional hyperemia within the somatosensory cortex of mice. Together, these data establish a role for endothelial TRPA1 channels as sensors of neuronal activity and show that they respond accordingly by initiating a vasodilatory response that redirects blood to regions of metabolic demand. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.30.069849v1?rss=1 Authors: Mulier, M., Van Ranst, N., Corthout, N., Munck, S., Vanden Berghe, P., Vriens, J., Voets, T., Moilanen, L. Abstract: Genetic ablation or pharmacological inhibition of the heat-activated cation channel TRPM3 alleviates heat hyperhyperalgesia in animal models of inflammation, but the mechanisms whereby the channel contributes to inflammatory pain are unknown. Here, we induced unilateral inflammation of the hind paw in mice, and directly compared expression and function of TRPM3 and two other heat-activated TRP channels (TRPV1 and TRPA1) in sensory neurons innervating the ipsilateral and contralateral paw. We detected increased Trpm3 mRNA levels in dorsal root ganglion neurons innervating the inflamed paw, as well as augmented TRP channel-mediated calcium responses, both in the cell bodies and the intact peripheral endings of nociceptors. Notably, inflammation provoked a pronounced increase in nociceptors co-expressing functional TRPM3 with TRPV1 and TRPA1, and pharmacological inhibition of TRPM3 caused normalization of TRPV1- and TRPA1-mediated responses. These new insights into the mechanisms underlying inflammatory heat hypersensitivity provide a rationale for developing TRPM3 antagonists to treat pathological pain. Copy rights belong to original authors. Visit the link for more info

Heute geht es um um die Frage “Wie gefährlich oder sicher sind eigentlich e-Zigaretten”, ein sehr aktuelles Thema mit dramatischen Entwicklungen in den letzten Wochen. SONG / INTRO -  Was sind e-ZigarettenEigentlich ein Sammelbegriff, elektronisch, batterie betrieben, erhitzen entweder Flüssigkeiten oder Tabak VerdampferVerdampfen Flüssigkeiten mit Nikotin und anderen Substanzen.  Gelten als „sichere“ und „saubere“ Methode zur Inhalation von Nikotin, da angeblich frei von den krebserregenden Substanzen, die beim Verbrennen von Ta­bak entstehen. ABER! Krebs in Mäusen (Tang 2019)  Weiterhin suchterzeugende Wirkung von Nikotin, fördert die regelmäßige Nut­zung von E-Zigaretten,  Abstinenz vom Rauchen bei 18% versus 10 % bei Standard-Nikotinersatz (Kaugummi, Pflaster) → 82% Rauchen weiterhin, Zigaretten plus eZigaretten TabakerhitzerIQOS = I Quit Ordinary Smoking HEET Sticks statt Zigaretten  Heat-Not-Burn Lifestyle-Produkt, teuer, Flagstores, wie ein Apple-Laden, stylish: Nichts mit Zigaretten zu tun Erhitzer Sieht aus wie ein Schwangerschaftstest oder USB-Stick Verbrennt nicht, sonder erhitzt auf 300°C  20 Zig/HEETS 6€: Zigaretten 3,26€ Steuer;  HEETS nur 0,88€ Steuer, da rechtlich keine Zig, sondern Pfeifentabak in D seit 2017, 100.000 Nutzer, Pro Monat 30 Mio. sticks verkauft, 10 / Tag!! stark steigend in den USA erst 2019 und nur vorläufig zugelassen Schädlich oder nicht? Risiko-LebensV für Raucher teurer Egal ob Zigarette oder eZigarette Man sollte da nicht lügen: Verstößt der Versicherte dagegen, führt dies – bei Vorsatz oder grober Fahrlässigkeit – zu einem Rücktrittsrecht des Versicherers und im Todesfall durch Lungenkrebs keine Zahlung an die Hinterbliebenen, Philip Morris-LebensV Geschäft ein, Rabatte für Zigarette-IQOS-Umsteiger; für e-Zigaretten nur 1/10 Rabatt (2 vs. 25%) https://www.aerzteblatt.de/nachrichten/102752/Philip-Morris-gruendet-Lebensversicherung-mit-Praemienrabatten-fuer-eigene-Produkte  ErhitzerMan atmet keinen Rauch sondern Tabakdampf ein Bundesinstitut für Risikobewertung (BfR):  Weniger Schadstoffe (Formaldehyd, Benzol) als Zigaretten,  Lungenkrebsrisiko nicht verzehnfacht sonder nur 2-3x erhöht Herz-Kreislauf 20x → ? Verdampfer (Vaping) Alle Zigarettenfirmen haben auch in e-Zigaretten/Verdampfer investiert Altria, Tochterfirma von Philip Morris, hat 35% von Juul gekauft Akut, v.a. USA (Centers for Disease Control and Prevention) Bis Ende August 2019 : mindestens 215 akute, schwerwiegende Atemnotanfälle, Sichtbar mit bildgebenden Verfahren (Henry) in 25 Staaten (Layden)(Maddock) mindestens 2 Todesfälle  Bis Ende September, 1 Monat später:  800 Fälle,  46 Staten,  12 Todesfälle Eindeutig eine Epidemie, die eine dringende Reaktion erfordert. Ursachen: Keine aktive Infektion (einschl. lebende bakterielle Kontamination) Akute toxische Lungenverletzung  bis hin zu akutem Lungenversagen ARDS (acute respiratory distress syndrome) z. B. Metalle, Lösungsmitteln, Säuren, Basen, Ozon, Phosgen oder Chlor, bei Bränden oder Unfällen Symptome: geringfügigen Atemwegsbeschwerden bis zu akuten Atemwegs Verletzungen und Schädigungen des Gewebes mit Pneumonitis, Ödem, Atemstillstand und Tod (Matthay) 7 potenziell toxischer Verbindungsgruppen enthalten (Lee; Lee): Nikotin, der eigentliche Grund für die Benutzung von E-Zigaretten, hemmt den mukoziliären Transport, wichtiger Selbstreinigungsmechanismus, nicht über den normalen Nikotinrezeptor, sondern Ionenkanal TRPA1(Chung) Aromastoff Zimtaldehyd bindet ebenfalls an TRPA1 verstärkt die schädliche Wirkung; Blutgefäß Schäden, wieder Zimt und Menthol; Diacetyl und 2,3-Pentandiol, hemmen ebenfalls Zilien. Lösungsmittel (Benzol und Toluol), organische-chemische Verbindungen (Carbonyle)  Partikel  Spuren von Metallen Zwar keine Bakterien und Pilzen, aber Toxine von Bakterien und Pilzen ...

This is the March episode of 3-Minute 3Rs, brought to you by the North American 3Rs Collaborative (www.na3rsc.org, the NC3Rs (www.nc3rs.org.uk), and Lab Animal (www.nature.com/laban) The papers behind the pod: 1. Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS. https://bit.ly/2uiF64X 2. A critical evaluation of TRPA1-mediated locomotor behavior in zebrafish as a screening tool for novel anti-nociceptive drug discovery. https://go.nature.com/2Cu7u8C 3. No-touch measurements of vital signs in small conscious animals. https://bit.ly/2WdN5Mw [NC3Rs] A team led by Dr Rickie Patani has developed a human-derived model of ALS that could bring us a step closer to treating the disease effectively while avoiding the use of animals altogether. Animal models are widely used to study ALS, also known as motor neurone disease, but current therapies can only slow its progression – and even then, the effect is modest. Instead, Dr Patani's team, based at UCL and the Francis Crick Institute, used human induced pluripotent stem cells to study how ALS causes motor neurones to degenerate. They investigated the molecular processes that lead to the death of motor neurones, which are kickstarted by the loss of a protein called TDP-43 from the cell nucleus. They also discovered that ALS makes astrocytes degenerate too, so they can't play their usual role in helping motor neurones survive, compounding the effects of the disease. For this work, Dr Patani was awarded the NC3Rs' International 3Rs Prize earlier this month. The prize is sponsored by GSK and celebrates outstanding 3Rs science every year. Read the paper in Cell Reports or visit the NC3Rs website to learn more about the 3Rs Prize. [LA] Rodents remain popular for in vivo validation of novel drugs. But screening candidates is costly to do in rodents, which has researchers looking for alternatives to evaluate compounds in a higher throughput manner. Zebrafish are increasingly used for such screening purposes. A new paper from Richard van Rijn's lab at Purdue published in the journal Scientific Reports evaluates a zebrafish screen for drugs that Transient Receptor Potential A1, or TRPA1. TRPA1 encodes a calcium ion channel and has been shown to be involved in pain perception in rodent models. In zebrafish, activating TRPA1 causes hyperlocomotion, which the researchers hypothesized could be a useful phenotypic readout of drug efficacy. They tested compounds known to activate and inactivate TRPA1 in human cells, mice, and zebrafish larvae and found that the compounds affect all three models in a dose-dependent manner. Evaluation can be somewhat tricky in the zebrafish because they have a second copy of TRPA1 to contend with, but the fish could still help screen initial compounds before researchers take them onward. [LA] What if you could measure the vital signs of your animals without having to prep or handle them? Engineers at Cornell recently described the use of radio frequency near-field coherent sensing to do just that in a paper published in Science Advances. They developed the technology first for humans, but have now shown its potential for use with small animals in real-time. The technology uses radio waves. These penetrate the body and can be used to detect the motion of internal organs. When the signal is processed, parameters like heart rate and respiration rate can be captured. The system can be wired or wireless, and was shown to work with an anesthetized rat and freely moving hamster, Russian tortoise, and betta fish. There was some variability and further comparisons with existing methods would help clarify the accuracy and robustness of the new system, but near-field coherent sensing could be a promising new way to keep an eye on animal vital signs. See acast.com/privacy for privacy and opt-out information.

Scott Earley explains how reactive oxygen species activate TRPA1 ion channels to trigger dilation of cerebral arteries.

TRPA1 ist ein Kationenkanal aus der Familie der "transient receptor potential" (TRP)-Kanäle. Die Expression und Funktion dieses Ionenkanals wurde bisher hauptsächlich in neuronalen Zellen, insbesondere in Schmerzneuronen, untersucht. Dort übt TRPA1 eine Warnfunktion aus und fungiert als Sensormolekül für Reizstoffe. Dementsprechend wird TRPA1 durch eine Reihe von irritativen oder toxischen Substanzen direkt aktiviert, z. B. durch Allylisothiocyanat (AITC), Formalin, Zigarettenrauch, Tränengas oder Ozon. Im Einklang mit dieser Funktion wurde eine neuronale Expression von TRPA1 in vielen Grenzflächen des Körpers, z. B. in der Haut, im Gastrointestinaltrakt oder in der Lunge gefunden. Im Respirationstrakt konnte TRPA1 in sensorischen Nervenendigungen in den luftleitenden Atemwegen nachgewiesen werden, wo seine Aktivierung durch inhalative Schadstoffe mit entzündlichen und asthmatoiden Reaktionen in Verbindung gebracht wird. Im Gegensatz zur gut charakterisierten Rolle von TRPA1 in Neuronen ist bisher noch relativ wenig über die Expression von TRPA1 in non-neuronalen Zellen bekannt. Auch eine Funktion von TRPA1 in Tumoren ist bisher weitgehend unerforscht. In dieser Arbeit wurde eine Reihe von Zelllinien des Kleinzelligen Bronchialkarzinoms (engl.: "small cell lung cancer", SCLC) im Hinblick auf die Expression von TRP-Kanälen und im Speziellen von TRPA1 untersucht. Dabei zeigte sich, dass TRPA1 in SCLC-Zelllinien exprimiert wird und seine Aktivierung zur Stimulierung von Tumor-relevanten Signalkaskaden führt. Die Aktivierung von TRPA1 durch AITC oder durch ein wässriges Extrakt aus Zigarettenrauch führte in diesen Zellen zu einer Erhöhung der intrazellulären Calciumionenkonzentration ([Ca2+]i). Diese Ca2+-Erhöhung erwies sich als transmembranärer Ca2+-Einstrom und konnte von TRPA1-Inhibitoren blockiert werden. Darüber hinaus führte die TRPA1-abhängige Erhöhung der [Ca2+]i zu einer Aktivierung der extrazellulär signalregulierten Kinase ERK1/2 über einen Src-abhängigen Mechanismus. Des Weiteren wirkte eine TRPA1-Aktivierung in SCLC-Zellen anti-apoptotisch und förderte das Überleben der Zellen in serumfreiem Medium. Umgekehrt hatte die siRNA-vermittelte Herunterregulierung von TRPA1 eine schwere Wachstumsreduzierung von SCLC-Zellen in semisolidem Medium zur Folge. Die potentielle tumorbiologische Relevanz dieser Befunde wird durch die Tatsache unterstrichen, dass in humanen Tumorproben von Patienten mit SCLC eine gegenüber non-SCLC-Proben und normalem Lungengewebe deutlich erhöhte TRPA1-Expression zu verzeichnen war. Interessanterweise fand sich eine funktionelle Expression von TRPA1 außerdem auch in zwei Pankreaskarzinom-Zelllinien sowie einer Lungenzelllinie mit Alveolarzell-Typ-II-Charakteristika. Die Tatsache, dass eine Aktivierung von TRPA1 das Überleben von SCLC-Zellen förderte, weist auf potentielle Tumor-promovierende Wirkungen von TRPA1-Aktivatoren hin. Bekanntermaßen stimulieren zahlreiche Inhaltsstoffe des Tabakrauchs den TRPA1-Kanal und Nikotinabusus ist einer der Hauptfaktoren bei der Entstehung des SCLC. Insofern weist die vorliegende Untersuchung auf einen möglichen neuen Signalweg hin, der neben den etablierten genotoxischen Effekten von Tabakrauch für die Entstehung von Lungentumoren wichtig ist. Weiterhin sind die hier vorgestellten Befunde ein Anknüpfungspunkt für weitere Studien zur Rolle von TRPA1 im Pankreaskarzinom und in epithelialen Zellen in der Lunge.

Some anesthetics activate TRPA1 channels to trigger pain and nerve-mediated inflammation.