Podcasts about ctgf

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.14.520376v1?rss=1 Authors: Zhao, H., Chen, J., Qi, C., Wang, T., Liang, T., Hao, X., Li, X., Yin, X., Yu, T., Zhang, Y. Abstract: Restoring the normal structure and function of injured tendons is one of the biggest challenges faced by the Department of Orthopedics and Sports Medicine. Tendon-derived stem cells (TDSCs), a new type of pluripotent stem cells with multidirectional differentiation potential, are expected to be promising cell seeds for the treatment of tendon injury and tendon-bone healing in the future. In this study, tendon stem cells were successfully isolated from human tissues, which were positive for markers CD44, CD90, and CD105, and exhibited clonality and multilineage differentiation ability. Analysis of single-cell sequencing results and mass spectrometry identification results showed that there were differences in protein expression during CTGF-induced TDSC tendon differentiation. Reverse Co-IP, qPCR, WB, and immunofluorescence detection all confirmed that CTGF directly interacts with KIT, thereby mediating the transcription factor HES1 to regulate the Wnt/{beta}-catenin signaling pathway (GSK3{beta}, {beta}-catenin, TCF4). ChIP-qPCR and dual-luciferase reporter gene assays indicated that HES1 regulates stem cell differentiation by directly regulating the expression of GSK3{beta} in the Wnt/{beta}-catenin pathway. Rats were treated with TDSCs overexpressing the KIT gene after repair surgery. This method had a more ideal recovery effect than other methods through animal behavioral scores, mechanical properties testing, and HE staining tissue observation. This study found that the use of modified human tendon stem cells (hTDSC) could promote graft ligamentization and tendon-bone healing after ACL reconstruction, which could provide an effective way for faster and better recovery from tendon injury. 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/2022.10.20.513009v1?rss=1 Authors: Zhao, Z., Hong, L., Huang, G., He, Y., Zuo, X., Han, W. Abstract: Cells sense physical cues, such as changes in extracellular matrix (ECM) stiffness, and translate these stimuli into biochemical signals that control various aspects of cellular behavior, thereby facilitating physiological and pathological processes in various organs. Evidence from multiple studies suggests that the anterior vaginal wall stiffness is higher in POP patients than in non-POP patients. Our experiments found that the expression of -smooth muscle actin (-SMA) in the anterior vaginal wall of patients with POP was increased, and the expression of DNMT1 was decreased. We used polyacrylamide gel to simulate matrix stiffening in vitro, and substrate stiffening induced the high expression of myofibroblast markers -SMA and CTGF in L929 cells. Inhibition of DNMT1 promotes fibroblast differentiation into myofibroblasts in vitro. The results of bioinformatics analysis showed that the expression of DNMT1 was significantly correlated with microtubule polymerization-related proteins. The experiment showed that the microtubule polymerization inhibitor nocodazole could eliminate the decrease of DNMT1 expression in fibroblasts induced by high stiffness. We conclude that fibroblasts sense an increase in the stiffness of the surrounding matrix and regulate fibroblast differentiation by regulating the expression of DNA methyltransferase 1 (DNMT1) through the regulation of microtubule polymerization. This study may help to elucidate the complex crosstalk between vaginal fibroblasts and their surrounding matrix in both healthy and pathological conditions, and provide new insights into the implications of potentially targeted phenotypic regulation mechanisms in material-related therapeutic applications. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Recogelocos - f. vulg. 1 Colectivo no muy visiblemente agradable2 Transporte de los barrios bordean el cerro de La Popa

Manolo Duque fue elegido alcalde de Cartagena por su fama y carisma como periodista radial en 2015. Casi dos años después fue enviado a la cárcel por un escándalo de corrupción, y Sebastián, su hijo, también periodista, explora desde Cartagena Federal las consecuencias emocionales que este descalabro político desató en sus vidas y en su hogar. Relato de un Periodista que no sabía que lo tenía todo hasta que lo perdió es un podcast de CTGF y el diario El Espectador.

This week’s episode of Circulation on the Run features author Ami Aronheim and Associate Editor Thomas Eschenhagen as they discuss early cardiac remodeling that promotes tumor growth and metastasis. Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor of the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Greg, today we're taking a look at the cardio-oncology world in our feature discussion, but in a very interesting reverse way. Cardio-oncology, what would you think of? I suppose the effects on the heart of cardiotoxic drugs that we use in oncology, right? But this feature paper looks at it the other way around and says does the heart and its remodeling promote tumor growth and cancer? Terribly interesting data coming right up after we discuss a couple of papers, well, all the papers in today's issue. So I want to start. Greg, do you remember what parasites are and why they're important? Dr Greg Hundley: Well, Carolyn, this is actually one of the things that I do remember because we study the parasites when we're looking at microcirculatory dysfunction after the administration of potentially cardiotoxic agents for treatment of cancer. But how about you tell us a little bit more. Dr Carolyn Lam: This is going to be very basic just for all of us. Now, the blood vessels are composed of endothelial cells and mural cells. Endothelial cells line the vascular lumen. Whereas the mural cells, which include faster smooth muscle cells and parasites adhere to the abluminal surface of the endothelium. Parasites regulate vessels stabilization and function, and their loss has been associated in diseases such as diabetic retinopathy, vascular malformation, stroke, and cancer. Just like you said, Greg. Now here we have a series of elegant experiments by Dr Mariona Graupera from IDIBELL in Barcelona and colleagues who use genetic mouse models to identify the specific molecular signature of mural cells at early and late stages of the energetic process and unveil their biological relevance. Their results show that phosphatidyl inositol 3-kinase or PI3K-beta is the main regulator of parasite, proliferation and maturation in vessel growth. PI3K-beta deletion in parasites triggered early parasite maturation, whereas exacerbated PI3K signaling delayed parasite maturation, and thus vessel maturation during angiogenesis. Dr Greg Hundley: So clinically what's the take home message here. Dr Carolyn Lam: The proposed model of mural cell maturation together with the tools developed would be instrumental for the characterization of mural cells in pathologies associated with deregulated vessel growth, such as ischemia stroke, vascular malformation, diabetic retinopathy, and cancer. The therapeutic potential of modulating parasite biology through PI3K signaling provides a new window of clinical intervention for vascular related diseases in which parasite dysfunction contributes to their onset and or progression. Dr Greg Hundley: Very nice, a very important cell type Carolyn. Well, my paper comes from Professor Xiang Qian Lao from The Chinese University of Hong Kong. In this paper, the authors investigated in 140,072 adults all greater than the age of 18, without hypertension who joined a standard medical screening program with 360,905 medical exams that occurred between the years of 2001 and 2016. They assess the joint associations of habitual physical activity and long-term exposure to find particulate matter with the development of hypertension in Taiwan. Dr Carolyn Lam: Wow. A huge study. So what did they find Greg? Dr Greg Hundley: After adjusting for a wide range of co-variants including a mutual adjustment for physical activity or particulate matter, a higher physical activity level was associated with a lower risk of hypertension. Whereas a higher level of particulate matter was associated with a higher risk of hypertension. No significant interaction was observed between physical activity and particulate matter. So Carolyn in conclusion, a high physical activity and a low particulate matter exposure were associated with a lower risk of hypertension. What we would expect the negative association between physical activity and hypertension remain stable in people exposed to various levels of particulate matter. The positive association between particulate matter and hypertension was not modified by physical activity. Thus, Carolyn the authors believed their results indicate that physical activity is a suitable hypertension prevention strategy for people residing in relatively polluted regions. Dr Carolyn Lam: Oh, thanks for summarizing that. So well, Greg, Hey, I've got a question for you. Do you measure a high density, lipoprotein cholesterol or HDL cholesterol? Do you measure the levels or do you measure the particle concentration in your clinical practice? Dr Greg Hundley: I think just the levels Carolyn. Dr Carolyn Lam: Yeah. Same, but there's a lot of data coming out about the particle concentration. Let's review a little bit about that. So the HDL cholesterol is an established athero-protective marker, particularly for coronary artery disease, but HDL particle concentration may better predict the risk. However, the associations of HDL cholesterol and HDL particle concentration with ischemic stroke and with myocardial infarction among women and blacks has not been well defined. And so Dr Rohatgi from UT Southwestern and colleagues analyzed individual level participant data in a pool cohort of four large population studies without baseline atherosclerotic cardiovascular disease. These were the Dallas Heart Study, the ERIC study and the MISA study, as well as the PREVENT study. Dr Greg Hundley: What did they find? Were there any unique pieces of data related to either sex or those of black race? Dr Carolyn Lam: They found that HDL particle concentration is inversely associated with the specific endpoint of ischemic stroke overall and among women. Whereas HDL cholesterol was not associated with ischemic stroke. Neither HDL particle concentration nor HDL cholesterol levels were associated with myocardial infarction in blacks. Thus HDL particle concentration, but not HDL cholesterol may be a useful risk marker for ischemic stroke. HDL particle concentration may be a useful risk marker for both myocardial infarction and ischemic stroke among women. There is likely minimal utility of HDL markers for risk prediction of myocardial infarction in the black population. Dr Greg Hundley: Thanks Carolyn. That was such a great introduction and overview and then the results was so clear. Carolyn, my next paper comes from Dr Peter Willeit from the Medical University of Innsbrook. In this paper, the author systematically collated carotid intima-medial thickness data from randomized controlled trials. The primary outcome was a combined cardiovascular disease endpoint defined as myocardial infarction, stroke, revascularization procedures, or a fatal cardiovascular event. The authors estimated intervention effects on carotid intima-medial thickness progression and incident CVD for each trial before relating the two using a Bayesian eta- regression approach. Dr Carolyn Lam: Oh, this is important. So what did they find? Dr Greg Hundley: Carolyn, they're going to have 10 micrometer per year evaluations. So across all intervention, each 10 micrometer per year reduction of carotid intima-medial thickness progression resulted in a relative risk for cardiovascular disease of 0.91 with an additional relative risk for cardiovascular disease of 0.92 being achieved independent of carotid intima-medial thickness progression. So combining these results, the authors estimate that interventions reducing carotid intima-medial thickness progression by 10, 20, 30 or 40 micrometers per year would yield relative risks of 0.84, 0.76, 0.69 or 0.63 each incrementing with the magnitude of reduction in micrometers per year. Results were similar when grouping trials by type of intervention. Time of conduct, time to ultrasound follow-up, availability of individual participant data, primary versus secondary prevention trials, the type of carotid intima-medial thickness measurement, and the proportion of women in the studies. Dr Carolyn Lam: So could you summarize that Greg? Dr Greg Hundley: You bet, Carolyn. So the extent of intervention effects on carotid intimal-medial thickness progression predicted the degree of cardiovascular disease risk reduction. This provides a missing link supporting the usefulness of carotid intimal-medial thickness progression as a surrogate marker for cardiovascular disease risk prediction in clinical trials. Dr Carolyn Lam: Indeed. Thanks, Greg. It's important because it also quantifies that risk reduction. Very nice. Now let's just round up with some other papers in the issue. There is a perspective paper by Dr Bunch on Dementia and atrial fibrillation, a research letter by Dr Ellinor on myocyte specific upregulation of ACE two in cardiovascular disease, the implications for our SARS-coronavirus to mediated myocarditis. There are letters to the editor regarding the article small extra cellular macrovesicles mediated, pathological communications between dysfunctional adipocytes and cardiomyocytes as a novel mechanism, exacerbating ischemia reperfusion injury in diabetic mice. These letters were by Dr Li with response by Dr Ma. There's a research letter by Dr Natarajan on genetic variation and cardiometabolic traits and medication targets and the risk of hypertensive disorders of pregnancy. Dr Greg Hundley: Carolyn, I've got a couple other features to describe. Aaron Baggish and Ben Levine provide an On My Mind piece, related to sports after COVID-19. Jeffrey Smietana has an ECG challenge regarding an ELVAD artifact. Then finally, Bridget Kuhn has cardiology news related to an announcement from the Association of Black Cardiologists calling for an urgent effort to address health inequality and diversity in cardiology. Can't wait to get to that feature discussion and that really unique twist in cardio-oncology. Dr Carolyn Lam: Here we go. Greg. Based feature discussion. We are diving into the world of cardio-oncology. Now, usually that refers to the intersection between cancer and cardiovascular disease, where we usually talk about cancer and cancer treatment effects on the cardiovascular system. But emerging data now suggests the concept of reverse cardio-oncology, whereby heart disease potentiates cancer. Today's feature paper really provides very important and significant preclinical data to support this. I'm so pleased to have with us, the corresponding author, Dr Ami Aronheim from Israel Institute of Technology, as well as our associate editor, Dr Thomas Eschenhagen from University Hospital Hamburg Eppendorf in Germany. Ami, thank you very much for joining us today. Please. Could you walk us through your very elegance study and the results? Prof Ami Aronheim: We used a model, which is called the transfers, all the constriction, which promotes pressure overload on the heart. Actually following this procedure, we implanted cancer cells into mice and we followed the growth of these tumors. Actually we found out that the tumors of a tuck operated mice is growing much faster. Also when we used a metastatic model, namely, when we injected cells into the tail vein, we obtained more metastatic lesions in the lungs. Actually we found out that the serum from these mice is able to promote the variation of cancer cells in vitro. Then we also identified a protein, which is potentially promoting these cell proliferation in vitro. Dr Carolyn Lam: That is really significant. I mean, am I right that this is the first study to show that cardiac remodeling actually promotes tumor growth and metastasis and this is probably via secreted factor. Prof Ami Aronheim: This is the first paper showing that early events of cardiac remodeling promote cancer cell proliferation. It is known that heart failure by the work of De Boer’s group, that heart failure is promoting cancer load in mice. This paper was also published in Circulation 2018. Dr Carolyn Lam: Indeed. Thank you for reminding me about that. And I am a huge fan of Rudolph de Boer and his work. Indeed. Could I ask though, in your study, did you identify a particular secreted factor? Prof Ami Aronheim: We looked at the RNA seq from conduct remodeled heart, and we looked for secreted factors in the heart and we focused on two secreted factors CTGF and periostin, which are known to promote cancer growth. And indeed we found in our mice models that reduced in level is increased in the serum of mice of tuck operated mice. Once we deplete the serum from periostin, we ambulated this increase in cell proliferation. Dr Carolyn Lam: Wow. So periostin appears a culprit, but I'm sure the listeners are dying to know. Was there any human data that you had that supported the animal findings? Prof Ami Aronheim: The model in mice, the tack operation, it's hard to find the right model in human because the operation is really rapid. When the mice wake up, they have this pressure overload, the only disease which in human correlates or is mimicked by the tag is Altucher's stenosis, which is the restriction of the outtake evolve, the right aortic valve]. And we looked in these patients and what we found out, we looked at the echo cardiography data of a lot of patients. We actually found out that for young basically patients 40 to 60 years old, if they have moderate to severe aortic stenosis, they have higher risk to develop cancer about 1.6-fold higher than our external these patients. Although I must say with caution that this size group is quite small and it should be repeated with much higher number of patients. Dr Carolyn Lam: Wow. Thank you so much, Ami. Thomas, I have to bring you in here. Thank you for managing this very remarkable paper. Could you share some thoughts on what you think this means for the field? Thomas Eschenhagen: We all immediately as editorial team like this paper. When it came in on the background of the different paper, it really provides significant additional evidence that this interaction between cancer and the heart is two sided. And that's, as you said in the intro, that's really very important. And it's all very interesting that apparently these two different models used by Rudolf de Boer, which wasn't ischemia myocardial injury model. And here it's a hypertrophy model with early remodeling. They both do similar things, but apparently by different mechanisms. Because the number of the factors identified in the de Boer paper do not match with, with these two factors, CTGF and periostin. And for both, I think we have now convincing evidence that they may play a role, but it also shows that this is probably a quite complex interaction between the heart and the cancer. That makes it extremely interesting. Of course it's important because it's such a common comorbidity, I mean, cancer, cardiovascular diseases, are the most prevalent and the second most prevalent diseases is cancer. So this interaction must be very, very important. And it's very good that these two papers now focus of you on the reverse side and not only on the classic cardiac toxicity side, which me as pharmacologists, of course, we, I was always interested in. Dr Carolyn Lam: Yeah, indeed. I mean, Thomas me too. As a heart failure clinical trial list and epidemiologists, if I may, I always thought it was just shared risk factors, you know, age being particularly one of them. Thomas Eschenhagen:   Obviously, as you said, shared risk factors do play a role must, must their role. So it's certainly not only this direct interaction, but this new paper shows that there is in addition to this risk factor model, something specific. And that of course could be, I mean, at least theoretically be addressed. Dr Carolyn Lam: For both Thomas and Ami, what do you think are the implications now? I mean, should we be screening all patients with aortic stenosis more closely for cancers? What do you think are the clinical implications? Maybe Ami first? Prof Ami Aronheim: I think cardiovascular disease patients are already watched very carefully beforehand. But certainly I think that they should be also observed for cancer specifically. So yes I believe it should be. Also I this cardiovascular treatment should consider to make them early as possible to avoid any interaction with cancer. Dr Carolyn Lam: Yeah, that completely opens the field to, for example. Early aortic valve replacement, reducing subsequent cancer risk, like you mentioned in your paper, I mean, that's just mind blowing. Thomas, what do you think? Thomas Eschenhagen: I agree, 10 years ago, we said that more cancer patients, particularly those under treatment should be sent to the cardiologist to look for the heart. Now we will say the other way around as well. We really need to look more carefully for cancer. So I think this paper and the other one have the consequences we should do more here. There's also obviously a number of very interesting questions because one of the findings I found fascinating in this paper by Ami and this group was that this mouse strain, which finally did not show the classical science of remodeling after transverse aortic striction. So no BNP, no NP, no BDMEC increase in this small strain. There was no increase in cancer growth. Very interesting, because normally you would think somehow that these mice, which were kind of normal in the cardiac response would be worse, but in this respect they were better. So that's a very interesting aspect. The second aspect I found really fascinating is the human data suggest, I guess it's quite preliminary data, but there's a suggestion here that this interaction is mainly seen in younger patients. And I'm not quite sure what that means, but it's something to look at. Dr Carolyn Lam: Wow. Thanks for highlighting those Thomas. So Ami maybe the last word from you. Given all of this remaining questions and so on, what are your next steps? Prof Ami Aronheim: First, I wanted to comment something more wide view for this interaction that we find with cancer. I think all the organs actually communicate with one another. The fact that we are looking on a heart and cancer, this is due to the fact that it's easy. We have the models working in the lab and it's easy. But I'm sure if we're going to look to other diseases and other organs, there will be other connections of the heart with other organs and other diseases and maladies, which by conducting modeling, they will promote or maybe even reverse other maladies. So I'm sure that there is a communication between all organs, many organs altogether, and they will affect one another. Our directions currently are to look more precisely for the periostin story because we follow this mainly in vitro and would like to follow it in vivo. Also I think this mice model are nice, but to look also in human, where the periostin in aortic stenosis patients, where then, we can find out earliest in, in the serum before intervention, and to look after whether this secreted factor goes down or reduced. Also we are looking in other transgenic model that we generated along the years, which are known to result in cardiac modeling. We want to see whether these mechanisms are similar or different and whether they can promote also cancer progression. The use of these transgenic mice is very nice because we can induce them and we can shut down them so we can learn more about the kinetic, which influence one another, and exactly whether they can be reversed or not. Dr Carolyn Lam: Thank you so much Ami for sharing your thoughts on those future actions, a lot of work and such worthwhile areas to explore. Thank you too, Thomas for sharing your thoughts. Listeners. Thank you for joining us today on circulation on the run. Dr Greg Hundley: This program is copyright the American Heart Association, 2020.  

The Gary Null Show is here to inform you on the best news in health, healing, the environment.   How adding green tea extract to prepared foods may reduce the risk for norovirus In study, edible coating made with tea extract killed the virus and bacteria Ohio State University, July 22, 2020   Infusing prepared foods with an edible coating that contains green tea extract may lower consumers' chances of catching the highly contagious norovirus by eating contaminated food, new research suggests. Norovirus, which causes vomiting and diarrhea, sickens an estimated 48 million people in the United States every year and causes about 3,000 deaths. It's transmitted from person to person and through consumption of contaminated water and food. Lots of things we consume contain what are known in the industry as edible films: They can enhance appearance, like wax that makes apples shiny; hold contents together, like plastic drug capsules; and prevent contents from seeping together by, for example, being placed between a prepared pie crust and the filling. "In many cases, an edible film is in a product, but you are not aware of it," said Melvin Pascall, professor of food science and technology at The Ohio State University and senior study author. "We don't have to put that on the label since the material is edible. That's another way in which we use packaging - and the consumer doesn't have to know." Some edible films are also enriched with antimicrobial agents that can kill or slow the growth of organisms that cause illness, such as E. coli and mold. In this new study led by Pascall, adding green tea extract to a film-forming substance created a safe-to-eat barrier that killed norovirus as well as two types of bacteria. While most antimicrobial packaging advances to date have emphasized fighting bacteria, this finding holds promise for a newer area of research into the concept of using edible film to kill a virus, Pascall said. "Norovirus is a tough virus to work with - it is a non-enveloped virus, which is the type more resistant to sanitizers and antimicrobial agents," he said. "However, because it has public health concerns and has been implicated in a number of foodborne outbreaks, we wanted to look at the effects of green tea extract on norovirus." The study is published in the International Journal of Food Science. Pascall and his team created the films with a base substance called chitosan, a sugar found in the exoskeleton of shellfish. Chitosan is marketed as a weight-loss supplement and used in agricultural and medicinal applications, and has been studied extensively as a safe and readily available compound for edible film development. Previous studies have suggested that chitosan has antimicrobial properties. But norovirus might exceed its bug-fighting abilities: In this study, the researchers found that chitosan by itself did not kill the virus. To test the effects of green tea extract, the researchers dissolved it alone in water and added it to a chitosan-based liquid solution and dried film. Several different concentrations of the extract showed effectiveness against norovirus cells, with the highest level tested in this study killing them all in a day. "We had tested the chitosan by itself and it didn't show much antimicrobial activity against the virus," Pascall said. "But when we added the green tea extract to chitosan, we saw that the film had antiviral properties - so we concluded the antiviral properties were coming from the green tea extract." The scientists introduced at least 1 million virus cells to the solution and dried films. Those containing green tea extract lowered the presence of virus cells within three hours. The films with the highest concentration of green tea extract reduced norovirus to undetectable levels by 24 hours after the exposure. Though norovirus was the focus of this work, the researchers also found that green tea extract lowered E. coli K12 and listeria innocua, surrogates for bacteria that also cause foodborne illness, to undetectable levels within 24 hours. This study didn't identify how the killing happens - typically an antimicrobial agent disables organisms in ways that cause them to die or render them unable to reproduce. The researchers used mouse norovirus cells because human norovirus cells don't grow well in a lab setting. There is still a lot of work to do before green tea extract-infused films are ready to enter the market. A tricky part of adding natural substances to edible packaging is ensuring that enough is used to deliver the microbe-killing effect without changing the taste or smell of the food. "A higher concentration of a natural antimicrobial might cause a large drop in the target organism, but at the same time it defeats the purpose of the food by adding an objectionable taste or odor," Pascall said. "There is also the impact of the natural compound on the material itself - it may cause the film to become too brittle or sticky. These are things food scientists have to consider when using antimicrobial agents, especially those from natural sources." It's also too soon to tell which kinds of food would be the best candidates for antiviral edible films made with green tea extract. It depends on whether the food would be exposed to heat, moisture or acidic conditions, for example. There is also a chance another natural substance could do an even better job - Pascall is conducting similar studies with other extracts.       The brain-boosting potential of tart cherry juice University of Delaware, July 21, 2020   A recent study by scientists from the University of Delaware (UD) has found that drinking cherry juice has beneficial effects on memory. Published in the journal Food & Nutrition, it demonstrated that drinking Montmorency tart cherry juice every day for 12 weeks improved cognitive function in adults aged 65 to 80. Tart cherry juice supplementation can improve cognitive performance in older adults Lead author Chai Sheau Ching and colleagues had previously observed the beneficial effects of tart cherry antioxidants, such as melanin, melatonin and anthocyanin, on high blood pressure and cholesterol. In particular, the team found that drinking juice made from Montmorency tart cherries, the most common cherries in the U.S., helped reduce systolic blood pressure, fight inflammation and neutralize the harmful effects of oxidative stress. Based on these earlier findings, the team speculated that the antioxidants in tart cherries could also exert neuroprotective effects on the brain and improve cognitive abilities in older adults. To test their hypothesis, the team asked 37 adults, aged between 65 and 80, to drink either 16 ounces of Montmorency tart cherry juice or a placebo drink of the same amount every day – one in the morning and one in the evening – for 12 weeks. The team also asked the participants to maintain their diet and record their food consumption for the duration of the trial. None of the participants had prior diagnoses of medical conditions like diabetes, heart disease, stroke, cancer and neurological disorders at the time of the trial. Neither were they taking medications that might affect their cognitive abilities. To see whether or not the cherry juice had any effect on the participant's cognitive abilities, the team had each participant answer a series of questionnaires and tests before and after the trial period. At the end of the experiment, the researchers found that the participants in the tart cherry group scored higher in the tests that measured subjective memory, episodic visual memory and spatial memory than the participants in the placebo group. Compared with their pre-trial test results, the tart cherry group also experienced a four percent reduction in their movement time – the time it takes to complete a task – in the post-trial cognitive tests. In addition, the tart cherry group had a 23 percent reduction in errors in episodic visual memory. In both the pre- and post-trial cognitive tests, the participants in the tart cherry group scored significantly higher than those in the placebo group. These findings suggest that the antioxidants in tart cherries are behind the juice's beneficial effects on cognition. Chai hopes that future studies can shed more light on the molecular mechanisms underlying the cognitive-enhancing effects of Montmorency tart cherries. Cognitive health and aging Commenting on their findings, Chai noted that cognitive health plays a key role in determining the quality of life of older adults. According to recent reports by the World Health Organization, about 50 million people around the globe suffer from some form of dementia. And every year, 10 million cases are added to this figure. (Related: Adding more dietary choline can cut back the risk of dementia.) Dementia is a major cause of disability and dependency among older adults. Despite the fact that dementia is not a natural part of aging, its symptoms, including forgetfulness and difficulty communicating, are usually felt later in life. Fortunately, an emerging body of evidence suggests that proper diet and nutrition can reduce the risk of dementia and neurodegenerative diseases in old age. For instance, people can incorporate Montmorency tart cherry juice into a well-balanced diet to enhance their brain performance.     Study suggests benefit for vitamin C in endometriosis Zhejiang University (China), July 20, 2020   According to news reporting originating in Hangzhou, People's Republic of China, research stated, “Endometriosis is a common disease in females that seriously affects quality of life. The principal pathological process of endometriosis is pelvic inflammation, and local and peripheral fibrosis.” The news reporters obtained a quote from the research from Zhejiang University, “Treatment of endometriosis requires both pharmacological and surgical approaches. Vitamin C can scavenge oxygen free radicals and thus accelerate repair of damaged endometrium. This aim of this study was to investigate whether vitamin C can reduce fibrosis in endometriotic lesions. After establishing a rat model of endometriosis, vitamin C solution (vitamin C group) or physiological saline solution (control group) was injected into the abdominal cavity. We compared the indices of fibrotic endometriotic lesions between the two groups. The volume of endometriotic lesions and degree of fibrosis observed in rats within the vitamin C group was significantly reduced compared with those observed in the control group. Immunohistochemistry showed that transforming growth factor-beta 1 (TGF-beta 1), connective tissue growth factor (CTGF), alpha-SMA, and collagen type I staining in lesions of the vitamin C group was significantly less than that observed in lesions from the control group (P < 0.05). Quantitative, real-time PCR (RT-PCR) determined that relative mRNA expression levels of TGF-beta 1, CTGF, alpha-SMA, and collagen type I in lesions obtained from the vitamin C group were significantly lower than levels measured in lesions obtained from animals in the control group. Vitamin C can reduce the volume of endometriotic lesions and inhibit fibrosis of lesions in rats.” According to the news reporters, the research concluded: “This study supports the use of vitamin C in the treatment of endometriosis.”     Cannabis Appears Safe And Effective At Treating Chronic Pain, New Clinical Trial Shows University of California Irvine, July 21, 2020   Cannabis appears to be a safe and potentially effective treatment for the chronic pain that afflicts people with sickle cell disease, according to a new clinical trial co-led by University of California, Irvine researcher Kalpna Gupta and Dr. Donald Abrams of UC San Francisco. The findings appear in JAMA Network Open. “These trial results show that vaporized cannabis appears to be generally safe,” said Gupta, a professor of medicine on the faculty of UCI's Center for the Study of Cannabis. “They also suggest that sickle cell patients may be able to mitigate their pain with cannabis – and that cannabis might help society address the public health crisis related to opioids. Of course, we still need larger studies with more participants to give us a better picture of how cannabis could benefit people with chronic pain.” Opioids are currently the primary treatment for the chronic and acute pain caused by sickle cell disease. But the rise in opioid-associated deaths has prompted physicians to prescribe them less frequently, leaving sickle cell patients with fewer options. The double-blind, placebo-controlled, randomized trial was the first to employ such gold-standard methods to assess cannabis's potential for pain alleviation in people with sickle cell disease. The cannabis used in the trial was obtained from the National Institute on Drug Abuse – part of the National Institutes of Health – and contained equal parts of THC and CBD. “Pain causes many people to turn to cannabis and is, in fact, the top reason that people cite for seeking cannabis from dispensaries,” Gupta said. “We don't know if all forms of cannabis products will have a similar effect on chronic pain. Vaporized cannabis, which we employed, may be safer than other forms because lower amounts reach the body's circulation. This trial opens the door for testing different forms of medical cannabis to treat chronic pain.”   Twenty-three patients with sickle cell disease-related pain completed the trial, inhaling vaporized cannabis or a vaporized placebo during two five-day inpatient sessions that were separated by at least 30 days. This allowed them to act as their own control group. Researchers assessed participants' pain levels throughout the treatment period and found that the effectiveness of cannabis appeared to increase over time. As the five-day study period progressed, subjects reported that pain interfered less and less with activities, including walking and sleeping, and there was a statistically significant drop in how much pain affected their mood. Although pain levels were generally lower in patients given cannabis than in those given the placebo, the difference was not statistically significant.     Bad eating habits may cause blindness, warn researchers University of Bristol (UK), July 20, 2020   There's no denying that eating junk food is bad for your health, as it's linked to obesity and an increased risk of various health problems. A report in the Annals of Internal Medicine even found that a diet full of junk food could eventually cause vision loss. Researchers from the University of Bristol in the U.K. looked at a particular case involving a teenager who was a “fussy eater” and didn't eat anything except junk food. Several years of following an unhealthy diet eventually made him lose his eyesight. This unusual and shocking case highlights the dangers of an unhealthy diet. It can cause obesity and increase your risk of developing heart disease and cancer. The report also found that consuming junk food may “permanently damage the nervous system, particularly vision.” The adverse effects of poor eating habits The teen first experienced problems when he was 14, and he consulted a doctor due to symptoms like tiredness. His blood tests then revealed that he had anemia. Since the teenager had B12 deficiency, he was also treated with injections of the vitamin. His physician then told him to improve his eating habits. When the teenager turned 15, he reported more issues like hearing loss and vision problems. His physicians were baffled because the results from an MRI and eye exam were all normal. (Related: Cut the junk: Eating junk food can give you food allergies.) After two years, the teenager's vision worsened. At 17, an eye test revealed that his vision was 20/200 in both eyes: The threshold for being considered “legally blind” in America. Results from other tests revealed that the teenager also suffered damage to his optic nerve, the bundle of nerve fibers that connects the back of the eye to the brain. Despite being told to improve his eating habits when he was 14, the teenager still had a vitamin B12 deficiency. Worse, he also had low levels of copper, selenium and vitamin D. The physicians were alarmed at these deficiencies. After questioning the teenager, they found out that he didn't like eating “certain textures of food.” Since elementary school, the patient followed a limited diet that consisted only of foods such as: Chips Fries Processed ham slices Sausage White bread Once the doctors ruled out other possible causes for his vision loss, the patient was diagnosed with nutritional optic neuropathy or damage to the optic nerve because of nutritional deficiencies. The researchers noted that “[purely] dietary causes are rare in developed countries.” Most of the time, nutritional optic neuropathy is caused by alcohol abuse, drugs, poor diet or the malabsorption of food. Early detection can potentially reverse vision loss due to nutritional optic neuropathy. But unfortunately for the teenager, by the time his condition was diagnosed, his vision loss was permanent. Dr. Denize Atan, a senior lecturer in ophthalmology at Bristol Medical School and a co-author of the study, explained that eyeglasses wouldn't help the patient's vision since any damage to the optic nerve can't be addressed with lenses. To prevent his vision loss from worsening, physicians prescribed the teenager nutritional supplements. Avoidant-restrictive food intake disorder and mental health The doctors involved in the patient's case also referred him to mental health services for an eating disorder because there seemed to be more to his unusual diet. Unlike kids who were simply picky eaters, the teenager's diet “was very restrictive and caused multiple nutritional deficiencies.” They believe that the teenager might have a condition called “avoidant-restrictive food intake disorder” (ARFID). This relatively new diagnosis, previously called “selective eating disorder,” may cause a lack of interest in food or avoidance of foods with certain colors, textures or other factors without links to the patient's body weight or shape. Other symptoms of ARFID include: Abdominal pain, cold intolerance, constipation, lethargy or excess energy Dramatic restriction in amount or types of food eaten Dramatic weight loss Eating only certain textures of food Eating a limited range of preferred foods that becomes narrower over time or picky eating that worsens with time Fears of choking or vomiting Inconsistent and vague gastrointestinal issues, like an upset stomach, around mealtimes with no known cause No body image disturbance or fear of weight gain ARFID often manifests in childhood, and patients tend to have a normal body mass index (BMI) like the teenaged boy, concluded the study authors.   Chronic inflammation alters the evolution of cells in the colon, study finds Researchers have compared diseased colon with healthy tissue to better understand how inflammatory bowel disease (IBD) is linked to an increased risk of colorectal cancers Cambridge University and Wellcome Sanger Institute, July 21, 2020   In a new study, researchers have compared diseased colon with healthy tissue to better understand how inflammatory bowel disease (IBD) is linked to an increased risk of colorectal cancers, at a molecular level. Researchers from the Wellcome Sanger Institute and Cambridge University Hospitals found that the rate of DNA change within colon cells affected by IBD was more than double that in healthy colon, increasing the likelihood of these cells gaining DNA changes that could lead to cancer. The study, published today (21 July) in Cell, also found that chronic inflammation associated with IBD disrupts the tissue structure of the colon, allowing cells to expand over an abnormally wide area. The results provide valuable insights into evolution within the body, and the development of IBD and colorectal cancers. IBD primarily refers to ulcerative colitis and Crohn's disease, chronic illnesses characterised by inflammation of the digestive system that can be highly disruptive to a patient's quality of life. Between 1990 and 2017, the number of IBD cases worldwide rose from 3.7 million to 6.8 million*. The causes of the disease remain unknown, though it is thought that inflammation occurs as a result of an inappropriate immune response to gut microbes. People suffering from IBD are at an increased risk of developing gastrointestinal cancers compared to the general population. Patients will undergo regular surveillance for this and may, in some cases, opt to undergo surgery to remove their entire colon in order to mitigate this risk. In this new study, clinicians at Addenbrooke's Hospital, Cambridge provided colon tissue samples donated by 46 IBD patients, along with anonymised information about their medical history and treatment. Researchers at the Wellcome Sanger Institute then used laser-capture microdissection to cut out 446 individual crypts, the tiny cavities that make up colon tissue, so they could be whole-genome sequenced. These sequences were analysed to discover the mutation rate in the tissue, the genetic relationship between crypts and any genes that were more mutated than normal. They were then compared to sequences from 412 crypts from 41 individuals without IBD, so that the effects of chronic inflammation on the DNA sequence could be observed. The team found that there were more than twice as many DNA changes in the diseased tissue than in normal, and the longer the duration of the disease, the greater this excess. The study also uncovered evidence of an evolutionary process whereby mutations in particular genes are under positive selection. Some of these positively-selected mutations were enriched in genes associated with colorectal cancers, shedding light on the link between IBD and certain cancers. The researchers also detected evidence of positive selection of mutations in genes associated with immune system regulation in the gut and the ability of the cells to fend off the bacteria resident in the colon. Sigurgeir Olafsson, first author of the study from the Wellcome Sanger Institute, said: "How our bodies continue to evolve during our lifetime is a fundamental part of our biology. It has been fascinating to study the effect of a chronic disease on this process and uncover evidence that changes in the genetic sequence of gut cells could have a direct role in the onset of inflammatory bowel disease." Dr Tim Raine, clinical lead for the inflammatory bowel disease (IBD) service at Addenbrooke's Hospital, Cambridge and Honorary Faculty member at the Wellcome Sanger Institute, said: "Colorectal cancer is one of the main clinical concerns when treating patients with IBD. In this study, we found that normal mutational processes that are operative in us all are accelerated in the IBD affected gut, leading to a more than two-fold increase in the rate at which some gut cells acquire mutations, and this underpins the increased cancer risk in IBD." Dr Peter Campbell, an author on the study from the Wellcome Sanger Institute, said: "The role of somatic mutations in cancer susceptibility has long been appreciated. It is exciting to see the methods that we and others have used to understand cancers now being applied to other common diseases. These approaches have given us unique insights into the effects of inflammatory bowel disease on the DNA sequence of the inflamed tissue." A previously unexplained observation in IBD is that repeated flares of inflammation tend to affect the same patch of tissue, suggesting some permanent alterations to the colon. These findings highlight genetic mutations as a possible explanation, with some positively-selected mutations in immune regulation genes occurring in the same regions of the bowel affected by chronic inflammation. Dr Carl Anderson, lead author of the study from the Wellcome Sanger Institute, said: "We know that DNA changes contribute to the development of cancer, but their role in common non-cancerous diseases like inflammatory bowel disease (IBD) has not been extensively studied. Our study revealed that somatic changes in the DNA sequence of the cells that line our gut may contribute to the development of IBD. I strongly believe that studying somatic mutations in all common diseases, not just IBD and cancers, has the potential to provide novel insights into disease biology and highlight potential drug targets."   Studies suggest a fasting diet could boost breast cancer therapy A USC-led team of international scientists found that a one-two punch of a fasting diet with hormone therapy may enhance the effects of breast cancer treatment  University of Southern California, July 22, 2020   A USC-led team of scientists has found that a fasting-mimicking diet combined with hormone therapy has the potential to help treat breast cancer, according to newly published animal studies and small clinical trials in humans. In studies on mice and in two small breast cancer clinical trials, researchers at USC and the IFOM Cancer Institute in Milan -- in collaboration with the University of Genova -- found that the fasting-mimicking diet reduces blood insulin, insulin-like growth factor 1 (IGF1) and leptin. In mice, these effects appear to increase the power of the cancer hormone drugs tamoxifen and fulvestrant and delay any resistance to them. The results from 36 women treated with the hormone therapy and fasting-mimicking diet are promising, but researchers say it is still too early to determine whether the effects will be confirmed in large-scale clinical trials. The research was published in the journal Nature. "Our new study suggests that a fasting-mimicking diet together with endocrine therapy for breast cancer has the potential to not only shrink tumors but also reverse resistant tumors in mice," said Valter Longo, the study's co-senior author and the director of the Longevity Institute at the USC Leonard Davis School of Gerontology and professor of biological sciences at the USC Dornsife College of Letters, Arts and Sciences. "We have data that for the first time suggests that a fasting-mimicking diet works by changing at least three different factors: IGF1, leptin and insulin." The researchers say the two small clinical trials are feasibility studies that showed promising results, but they are in no way conclusive. They believe the results support further clinical studies of a fasting-mimicking diet used in combination with endocrine therapy in hormone-receptor-positive breast cancer. The scientists also contributed to a recent clinical study of 129 breast cancer patients conducted with the University of Leiden. The results, published last month in Nature Communications, appeared to show increased efficacy of chemotherapy in patients receiving a combination of chemotherapy and a fasting-mimicking diet. In the two new small clinical trials -- one of which was directed by the study co-corresponding author Alessio Nencioni -- patients with hormone-receptor-positive breast cancer receiving estrogen therapy along with cycles of a fasting-mimicking diet seemed to experience metabolic changes similar to those observed in mice. These changes included a reduction in insulin, leptin and IGF1 levels, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity, so further studies in humans is needed. "Some patients followed monthly cycles of the fasting-mimicking diet for almost two years without any problems, suggesting that it is a well-tolerated intervention," Nencioni said. "We hope this means that this nutritional program that mimics fasting could one day represent a weapon to better fight cancer in patients receiving hormone therapy without serious side effects." "The results in mice are very promising. And the early clinical results show potential as well, but now we need to see it work in a 300- to 400-patient trial," Longo explained. The data also suggest that in mice, the fasting-mimicking diet appears to prevent tamoxifen-induced endometrial hyperplasia, a condition in which the endometrium (or the lining of the uterus) becomes abnormally thick. The study authors believe this potential use of the fasting diet should be explored further, given the prevalence of this side effect of tamoxifen and the limited options for preventing it. Approximately 80% of all breast cancers express estrogen and/or progesterone receptors. The most common forms of hormone therapy for these breast cancers work by blocking hormones from attaching to receptors on cancer cells or by decreasing the body's hormone production. Endocrine therapy is frequently effective in these hormone-receptor-positive tumors, but the long-term benefits are often hindered by treatment resistance. Several clinical trials, including one at USC on breast cancer and prostate patients, are now investigating the effects of the fasting-mimicking diets in combination with different cancer-fighting drugs. "I like to call it the nontoxic wildcard for cancer treatment," Longo said. "These clinical studies we have just published -- together with the many animal studies published in the past 12 years -- suggest that cycles of the fasting-mimicking diet has the potential to make standard therapy more effective against different cancers, each time by changing a different factor or nutrient important for cancer cell survival."   Scientists identify 10 risk factors for Alzheimer disease Fudan University (China), July 17, 2020   Alzheimer's disease may be preventable by keeping an eye on key factors including weight gain, blood pressure and avoiding stress, experts say. Researchers said many risk factors are modifiable in the fight to prevent dementia, which affects around 850,000 people in the UK, two-thirds of whom have Alzheimer's. Their review of existing studies found 10 risk factors had strong evidence of a link with Alzheimer's, and people could take action to avoid them. These included ensuring good education in early life, keeping the brain active through activities such as reading, and not being overweight or obese in later life. People should also avoid depression, stress, high blood pressure, head trauma and diabetes to reduce their risk, they said. Other factors had weaker links that could be adjusted, including not being obese in midlife, taking exercise, getting enough sleep, including vitamin C in the diet and not smoking. The study, published in the Journal of Neurology, Neurosurgery & Psychiatry, was led by Professor Jin-Tai Yu at Fudan University in China. The researchers gathered 395 studies and came up with a list of factors that could be used by doctors to try to prevent Alzheimer's disease. They said research into preventing dementia should continue but their report offered “clinicians and stakeholders an evidence-based guideline for Alzheimer's disease prevention”. Fiona Carragher, director of research and influencing at the Alzheimer's Society, said: “In recent years, research has suggested that nearly a third of dementia cases may be preventable and this review builds on this idea, specifically in relation to Alzheimer's disease and how certain risk factors, many of which are associated with cardiovascular health, may be within our control. “We need a deeper dive into each of these risk factors to understand how they work together on an individual level and how best to support people to manage them. “This review demonstrates that, while observational studies are useful to help identify potential risk factors, we need to see many more interventional trials to understand what the best approaches are to preventing Alzheimer's disease developing in the first place. “We don't have all the answers yet, but we do know that small steps to improving your physical and mental health can make a big difference, like walking to your local shop for milk instead of jumping in the car.”

This month on Episode 5 of the Discover CircRes podcast, host Cindy St. Hilaire highlights five featured articles from the September 27 and October 11, 2019 issues of Circulation Research and talks with Sarvesh Chelvanambi and Matthias Clauss  about their article HIV-Nef Protein Transfer to Endothelial Cells Requires Rac1 Activation and Leads to Endothelial Dysfunction: Implications for Statin Treatment in HIV Patients.   Article highlights:   Stamatelopoulos, et al. Reactive Vasodilation in AL Amyloidosis   Cao, et al. Miro2-Mediated Cardiac Mitochondrial Communication   Georgakis, et al. Circulating MCP-1 Levels and Incident Stroke   Sun, et al. Body Mass Index and DNA Methylation   Tan, et al. Yy1 Suppresses DCM Through Bmp7 and Ctgf Transcript Cindy St. H:                       Hi. Welcome to Discover CircRes, the monthly podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, and I'm an assistant professor at the University of Pittsburgh. My goal as host of this podcast is to share with you highlights from recent articles published in the September 27th and October 11th issues of Circulation Research.                                            We'll also have an in-depth conversation with Drs Matthias Clauss and Sarvesh Chelvanambi, who are the lead authors in one of the exciting discoveries from our October 11th issue.                                            The first article I want to share with you is titled, Reactive Vasodilation Predicts Mortality in Primary Systemic Light Chain Amyloidosis. The first authors are Drs Kimon Stamatelopoulos, Georgios Georgiopoulos, and the corresponding author is Dr Efstathios Kastritis. And the studies were conducted at the National Kapodistrian University of Athens School of Medicine in Athens, Greece.                                            So we hear about amyloids a lot in things like Alzheimer's, but amyloids are really just aggregates of protein that fold into shapes. And the nature of these shapes allows these individual protein molecules to bind and form many copies that form these fibers that are rather sticky. And the fibers then aggregate into larger and larger globules. And light chain amyloidosis is the most common type of amyloidosis. It's a rare but deadly disease, and it's caused by antibody-producing cells that are aberrantly churning out parts of antibodies called light chains. And it's these light chains that will aggregate and form sticky fibers.                                            So these fibers aggregate and form amyloid deposits, and these deposits build up and damage the organs and the tissue in which they're accumulating. And because it's dependent on where the aggregates are accumulating, AL amyloidosis can present with a wide variety of symptoms. However, symptoms of heart dysfunction and low blood pressure correlate with poor prognosis.                                            And because vascular dysfunction can contribute to hypotension or low blood pressure, this group decided to examine the vascular health of patients by conducting a measurement called flow-mediated vasodilation. And so this is a measurement where the diameter of the brachial artery, which is located in your arm, is measured before and then after a brief period of lower arm ischemia. And they formed a cohort of 115 newly diagnosed AL patients and another cohort of 115 matched controls. This study found that in AL patients, flow-mediated vasodilation was higher than in aged, sex, and cardiovascular risk factor-matched controls. The mean follow-up time for this study was 54 months, and in that time, the authors went on to find that high values of FMD in the amyloidosis patients was strongly predictive of mortality. In fact, high FMD values were more predictive of death than some measures of cardiovascular health. These results suggest that flow-mediated vasodilation may be a superior means of identifying AL patients most at risk and for assessing potential benefits of therapeutic interventions.                                            The next article I'd like to highlight is titled, Miro2 Regulates Inter-Mitochondrial Communication in the Heart and Protects Against TAC-Induced Cardiac Dysfunction. The first author is Yangpo Cao, and the corresponding author is Ming Zheng. And the work was conducted at Peking University, Beijing, China, Key Laboratory of Molecular Cardiovascular Science at the Ministry of Education, also in Beijing, China.                                            Beating heart cells have very high energy requirements, and thus they need lots of fully functioning mitochondria. And as we all know from our good old high school biology days, mitochondria are the powerhouse of the cell. Mitochondrial health and performance is directly dependent on the ability of individual mitochondria to be able to communicate with each other. In many cells, this mitochondrial communication occurs via the fusion of mitochondria into a giant network. However, in cardiomyocytes, the mitochondrial movement is much more constrained. In cardiomyocytes, mitochondria communicate by briefly connecting with neighboring mitochondria, which is often called kissing, mitochondrial kissing, or by nanotunneling, which is when the mitochondria create a sustained connection by means of long nanometer-sized tubular protrusions called nanotubes. And it's thought that the proper health of the cell is dependent on proper mitochondrial communication.                                            Miro2 is a Rho GTPase on the outer mitochondrial membrane and it harbors a calcium sensing domain. Miro2 can interact with transport proteins to promote mitochondrial transport along microtubules in a calcium-dependent manner. This group wanted to investigate whether Miro2 regulates cardiac inter- mitochondrial communication. To do this, they used transverse aortic constriction or TAC or they used an Ang II infusion model to induce hypertrophy in murine hearts. Using these two models, they found Miro2 expression was decreased via Parkin-mediated ubiquitination, and they also found that inter-mitochondrial communication was disrupted.                                            By contrast, transgenic mice over-expressing Miro2 were more resistant to hypertrophy, and they were able to do this by maintaining proper cardiac function than their wild type counterparts. Together these results reveal a novel role for Miro2 in mitochondrial communication and show that maintaining such communication may mitigate effects of hypertrophy.                                            The next paper I want to highlight is titled, Circulating Monocyte Chemoattractant Protein-1 or MCP-1 and the Risk of Stroke: A Meta-Analysis of Population-Based Studies Involving 17,180 individuals. That is a huge study. The first author is Marios Georgakis, and the corresponding author is Martin Dichgans. And they are from the University of Munich in Munich, Germany.                                            A major component of atherosclerosis is chronic inflammation and inhibiting the activity of proinflammatory cytokines has been identified as a potential therapeutic strategy to help slow the disease progression. One such cytokine under study is monocyte chemoattractant protein-1 or MCP-1, and animal studies have shown that blocking MCP-1 limits, or boosting MCP-1, accelerates atherosclerosis. However, large scale observational studies of MCP-1 in humans are lacking. To address this gap in knowledge, this group performed a meta-analysis of previously unpublished data from six population cohorts, which totaled over 17,000 individuals.                                            These individuals were followed for an average of 16 years, which when you think about it, this is an absolutely huge study. So in looking at this cohort of patients, the team identified a significant association between high baseline MCP-1 levels and the likelihood of suffering a future ischemic stroke. Interestingly, this effect was not seen with hemorrhagic stroke, which is typically not associated with atherosclerosis. These findings not only support the previous animal studies, but also support a recent study in humans in which a genetic predisposition for high levels of MCP-1 was associated with an increased risk of coronary artery disease and stroke. This study also suggests that future studies should explore the potential of lowering MCP-1 levels as a possible prevention strategy. Perhaps there could be another CANTOS-like trial where we use something to block MCP-1 signaling. Maybe that would have much broader effects. I guess we'll have to wait and see what the data says.                                            The next paper I want to highlight is titled, Body Mass Index Drives Changes in DNA Methylation, a Longitudinal Study. The first authors are Dianjianyi Sun, Tao Zhong and Shaoyong Su, and the corresponding authors are Shengxu Li and Wei Chen. And they're from the Children's Minnesota Research Institute, Children's Hospitals and Clinics of Minnesota in Minneapolis, Minnesota and The Peking University Health Science Center in Beijing, China, respectively.                                            So it's well appreciated that obesity is increasing worldwide. And obesity contributes to a whole host of cardiovascular morbidity, and ultimately contributes to mortality. It's also well known that environmental factors such as the food we eat and the air we breathe, as well as genetic factors, can influence a person's risk of obesity. And recently there have been studies that suggest that perhaps epigenetic factors also contribute to obesity. And just to remind you what epigenetics is, DNA is the genetic code, and mutations can happen on DNA that can alter either gene expression or maybe protein folding or whether a protein is made at all. But epigenetic factors are not as permanent as DNA mutations.                                            Epigenetic factors are alterable modifications that can happen to DNA itself or that can happen to the proteins on which the DNA is wrapped around. And epigenome-wide association studies have shown that DNA methylation at certain loci is linked to an increase in body mass index, or BMI. However, it's unknown whether these methylations are a cause or consequence of obesity.                                            So to get to the bottom of this, this group performed a large-scale longitudinal study. They examined thousands of DNA methylation sites in 995 white individuals and 490 black individuals. And they also determined the subjects' BMIs. They did this at a baseline measurement and then approximately six years later, they collected the same data in the same patient cohort. What they found was that only a handful of methylation sites were shared between the two ethnicities. And in both groups, however, there was a similar unidirectional link between BMI and methylation. Very interestingly, baseline BMI could predict methylation at a number of genetic loci. However, the team found that none of those baseline methylation sites could predict future BMI. From this data, the authors are able to conclude that it's obesity driving the methylation at certain genetic loci as opposed to certain genetic loci driving obesity, which I think is just extremely interesting. Really nice study.                                            The last article I want to highlight for you is a paper titled, Yin Yang 1 Suppresses Dilated Cardiomyopathy and Cardiac Fibrosis Through Regulation of Bmp7 and Ctgf. The first author is Chia Yee Tan, and the corresponding author is Jianming Jiang, and they're from the National University of Singapore.                                            Dilated cardiomyopathy or DCM is characterized by left ventricle enlargement and associated contractile dysfunction and fibrosis. Patients with DCM are at risk of arrhythmia and also of sudden death. And there's actually a huge number of genetic variants that have been linked to DCM, but the most common one or the most well-studied are mutations that affect the nuclear lamin gene or LMNA. So LMNA knockout mice are used to study the role of this gene in DCM, and these animals exhibit not only cardiac defects but also systemic defects. And those systemic defects include things like shorter lifespan, growth retardation, muscular dystrophy, neuropathy, and lipodystrophy.                                            Recently, LMNA-related dilated cardiomyopathy was linked to the deregulation of cardiac cell cycle. Meaning there was issues in how these cardiac cells are proliferating. So in this study, Tan and colleagues showed that boosting expression of a protein involved in cell cycle regulation, this protein is called Yin Yang 1, so boosting this gene's expression actually reversed the dilated cardiomyopathy symptoms in mice with heart-specific LMNA deficiency. Compared with untreated mice, mice receiving Yy1 via an adenoviral vector exhibited improved cardiac function and also reduced fibrosis after four weeks. The team then went on to show that Yy1 treatment prompted suppression of the extracellular matrix factor, Ctgf, and the upregulation of the growth factor, Bmp7.                                            Now, neither of these factors alone could rescue the symptoms of LMNA lacking mice. However, when both of these factors were manipulated together, they mimicked Yy1 treatment. These results highlight that Yin Yang 1 and its downstream targets Bmp7 and Ctgf are key players and potential therapeutic targets that can be harnessed for tackling LMNA-driven dilated cardiomyopathy.                                            Okay, so now we're going to have our interview with Drs Matthias Clauss and Sarvesh Chelvanambi. And they are from Indiana University School of Medicine in Indianapolis, Indiana. And their title of their paper is, HIV-Nef Protein Transfer to Endothelial Cells Requires Rac1 Activation and Leads to Endothelial Dysfunction: Implications for Statin Treatment in HIV Patients. So thank you both very much for joining me. Sarvesh C:                         Thank you so much, Cindy. Matthias C:                       Thanks for having us here. Cindy St. H:                       Could you both introduce yourselves and tell us a little bit about your background? Sarvesh C:                         My name is Sarvesh Chelvanambi. I grew up in Chennai, India. I did my undergraduate degree at Miami University in Oxford, Ohio. I got a Bachelor of Arts in Zoology with a minor in Finance. I then went to the Pennsylvania State University where I got my Masters in Biotechnology before coming over to Indiana University in 2014 to do my PhD work. And then I joined the lab of Dr Matthias Clauss, and in 2016, I got an American Heart Association predoctoral fellowship to study this project specifically. Cindy St. H:                       Wow! Congratulations. That's wonderful. Sarvesh C:                         Thank you so much. Cindy St. H:                       And now you completed the circle by publishing your AHA grant in Circulation Research. Sarvesh C:                         Exactly. Cindy St. H:                       And Matthias, how about you? Matthias C:                       I'm a Research Professor at IU School of Medicine, and my research interests focus in understanding how stressors connected with endothelium in this way contribute to vascular disease. These stressors include cigarette smoke and viral infections. Regarding viral agents, we are studying both acute infections and chronic infections and that is HIV. This HIV interest started actually 12 years ago in collaboration with Dr Samir Gupta who is also of course on this paper. We started off with a simple question, why are there so many cardiovascular events in patients, in HIV patients, with interrupted antiretroviral therapy? Cindy St. H:                       So it's not just the fact that they're HIV positive, it's that they were on therapy and then went off it? Matthias C:                       Yes. And this was part of this SMART study and this study was then actually halted because of the safety issues. Cindy St. H:                       So you're starting with the idea that patients with HIV who go off this antiviral therapy are more prone or get more cardiovascular events. So what did you start with, with this particular study? Matthias C:                       Well, our overarching idea was that the HIV virus could also do damage in the era of the combined antiretroviral therapy. And we started up with two questions, one was, is there an HIV protein which is persistent? And the other question, how is this HIV protein, if there's any one which is persistent, performing this? And this may be then leading over to your specific way to address these questions. Sarvesh C:                         That's kind of where we are starting with this project. Because back in 2016, the START trial came out saying, "We need to change the way we treat HIV patients," because initially the previous regimen of our drugs had a lot of metabolic side effects, but the current regimen of integrase inhibitors is actually really good and has very low metabolic effects. So there was a New England Journal Of Medicine paper that said, "Well, if a patient walks into the clinic, they're diagnosed as being HIV positive, put them on antiretroviral therapy right away."                                            But even in this era when everybody is on ART and there's almost no viral replication, you still see the persistence of a lot of comorbidities. And especially those associated with vascular events, whether it's peripheral arterial disease, coronary arterial disease, and a lot of other vascular diseases in the lung, or the kidney or the brain. So that kind of is what set us up, is there an element in the blood of these patients that is contributing towards vascular dysfunction? Cindy St. H:                       And so the protein that you are talking about in this paper is a protein called Nef, and is that where you come in,  Sarvash? Sarvesh C:                         Yes, because the project before I joined the lab, that's kind of where it led off, saying that Nef can get to the endothelium and it's very good at killing endothelial cells, but the mechanism through which it transfers into endothelial cells and the signaling pathways that Nef hijacks to induce this apoptosis was not clearly elucidated. A lot of work is done in Nef in monocytes and macrophages because as an HIV protein, it was studied in CD40 cells and the whole immune system as a whole, but we were the first to leverage all of those findings within an endothelial context and answer the questions, so what does Nef do and how does it get there? Cindy St. H:                       All right, so tell us a little bit what does it do and how does it get there? Sarvesh C:                         So we started doing some experiments with starting with HIV patient blood. So we took two fragments, we took the PBMC fraction, that Dr Clauss was talking about, which we knew had Nef within many of those cells. We also took the extracellular vesicle fraction, and we chose to look at this because there's a lot of literature out there saying that this fraction could not only disseminate particles throughout the body but also help signal through that. So in both of these fractions we added to the endothelial cells, we found increased apoptosis in HIV patients when compared to HIV negative patients.                                            And we were excited, but then we went and asked which of these patients had HIV Nef positivity in their blood, and then using that information when we stratified our apoptosis results, we made the surprising observation that the HIV positive, Nef positive patients were more prone to endothelial cell apoptosis. And this sparked a lot of conversation, so how do we target this and what is the signaling pathway it gets into? And that is kind of what led to most of the work in this paper, where you're showing that the transfer is mediated by extracellular, because this is such a nice tool, for HIV I guess, to spread itself into literally every cell type. Because while the HIV virus can only infect very few cell types, extracellular vesicles can be taken up by anything.                                            And the second observation we made was within endothelial cells, we found the signaling pathways that Nef was able to hijack to induce cell death. And that became the focus of this paper. Cindy St. H:                       That was one thing I wanted you to clarify, because I think what a really interesting aspect of this study is that it's the immune cells that are infected. The endothelial cells themselves are healthy and really they're getting this damage from the vesicles. That is,…wow! I don't know. It's just a really, really neat study. So can you tell us a little bit about the techniques you used in this paper? Sarvesh C:                         Yes, so we did a lot of assays to evaluate endothelial cell stress. So we started by looking at apoptosis, and a lot of those studies were done by looking at caspase-3 activity, which is a classic marker for cell death. We also did a lot of microscopy work where we took out extracellular vesicles out of those vesicles on the endothelial cells to show the uptake of Nef protein and thereby hammer that extracellular vesicles are indeed a mechanism of transfer for this protein in particular.                                            Now, one of the interesting experiments that we actually ended up doing, which was not a part of this paper really, was we wanted to see if chemotaxis was being affected by this. So we took an endothelial monolayer and separated T-cells that are expressing Nef using a Transwell membrane. And I had this huge problem where I couldn't read for a week because instead of using the 4-micron filters that allow T-cells to transfer, I was using 0.4 micron filters that T-cells cannot transfer through. But I still went about it and did my whole experiment because I didn't make that realization until a week later, because when I looked at the bottom of these chambers, there were no T-cells at all. But when I looked at the endothelial cells, I observed cytoplasmic transfer and Nef transfer, and we had a couple of conversations going, why is this happening? Did the T-cells all die or did they disappear?                                            And that's when we went back and looked in literature and found that Nef is very good at making virion particles. And those are the similar pathways that extracellular vesicle trafficking comes from. And so that was a huge shift in the way this project was designed and where we then started looking into the modes of transfer, the protein and the subsequent apoptosis that that transfer can cause. Cindy St. H:                       I love this story. So essentially your mistaken filter created this paper and this finding of the vesicles affecting the endothelial cells. Matthias C:                       Yeah, that's a typical finding for practitioner Chelvanambi, because he has this gift to turn negative things into positive things. So we have a lot of fun, and this mistake was really the beginning of a great study. Cindy St. H:                       That's wonderful. Really beautiful images, as well. So a little bit digging into, I guess, the next step. So first off, how were the endothelial cells getting damaged? They're getting damaged from these extracellular vesicles, but then what's Nef doing in the endothelial cell? What's happening there? Sarvesh C:                         So that was a very big question because if you look at it, Nef is a very small protein with almost no known enzymatic function. And yet it is able to interact with a lot of host proteins, which I guess makes it a very good viral protein. So when I went back and looked at literature, there were a host of studies in the 90s to show that Nef interacts with this kinase and that small GTPases, and there was a giant list for us to go after. And we were kind of left a bit fuddled, because we were like, which signaling pathway do we start with? Cindy St. H:                       Right. It's almost like there's too many. Sarvesh C:                         Exactly. And so what we ended up doing was we started looking into one of the various mutants of Nef that we had access to. And one of these mutants was a mutant that was incapable of PAK2 activation, and we showed that that doesn't have a lot of these stress damages. So we asked, "What is directly upstream of PAK2?" And that is where Rac1 came into the picture. And the small GTPase Rac1 is a nice candidate because it is also a master of many, many trades. Cindy St. H:                       I love this because it's such an interesting multidisciplinary approach to addressing the question, why are patients with HIV getting more cardiovascular events? What do you think evolutionarily is going on? Why would this be beneficial? Why would damaging the endothelium be beneficial? What are your thoughts on that? Sarvesh C:                         Personally, I think this is a side effect because HIV is never meant to exist in the era of ART. One of the analogies I always like to use is from Harry Potter, where HIV is Voldemort, which is the big bad villain. And what we have done is a really good job of banishing Voldemort. But what we have failed to do as a field is target its Death Eater, Nef. And I think with what we are suggesting, this paper with additional statins and other strategies that focus this, we can get to that point where we not only block HIV expansion but also the expansion of its minions, Nef. Cindy St. H:                       I love this analogy. I think you should redo your graphical abstract in a Harry Potter theme. Matthias C:                       Yeah, but I like your question. But also in this regard, I think it may be an example of a novel mechanism, how viral infections work in a different way than just infecting cells. And there's evidence from lots of viruses that they make toxic proteins, and why they are doing this, we don't know. But we noticed that the systemic effect of Nef may have some advantage for the infectious agent, because it makes T-cells more sticky, it makes them stick and transmigrate through the endothelium, and that is also shown in our paper. Cindy St. H:                       You have evidence that perhaps statins would be beneficial to give to these HIV patients on ART therapy. Can you tell us a little bit about that and how that would work? Sarvesh C:                         So based on what we did on our mouse studies that was a part of this paper, even after there is endothelial dysfunction, treatment with statins was able to restore endothelial function. Currently, there is a study going on called The Reprieve Trial where they're giving a statin called pitavastatin to HIV patients. The interesting part here is that these are HIV patients who don't have dyslipidemia. And the long-term goal is that statin treatment can help prevent the development of cardiovascular events. We're eagerly awaiting the results of this trial. Cindy St. H:                       Well done. Well thank you so much for speaking with me today. It was a pleasure to speak with you, Dr Chelvanambi and Dr Clauss. And congratulations again on this beautiful project, this beautiful story. And really, the implications for helping patients with HIV is really profound. HIV used to always be in the news and now that we have the ART therapy it's not talked about as much, but these patients are still in danger and I think your study is really doing a lot to highlight that and maybe even help them. So thank you very much and congratulations. Matthias C:                       Thank you. Sarvesh C:                         Thank you so much for the opportunity. Cindy St. H:                       So that's it for highlights from the September 27th and October 11th issues of Circulation Research. Thank you so much for listening. This podcast is produced by Rebecca McTavish, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams.                                            I'm your host, Dr Sidney St. Hilaire, and this is Discover CircRes, your source for the most up-to-date and exciting discoveries in basic cardiovascular research.  

The goal of the present study was to determine whether treatment with cigarette smoke extract (CSE) induces cell loss, cellular senescence, and extracellular matrix (ECM) synthesis in primary human retinal pigment epithelial (RPE) cells. Primary cultured human RPE cells were exposed to 2, 4, 8, and 12% of CSE concentration for 24 hours. Cell loss was detected by cell viability assay. Lipid peroxidation was assessed by loss of cis-parinaric acid (PNA) fluorescence. Senescence-associated ß-galactosidase (SA-ß-Gal) activity was detected by histochemical staining. Expression of apolipoprotein J (Apo J), connective tissue growth factor (CTGF), fibronectin, and laminin were examined by real-time PCR, western blot, or ELISA experiments. The results showed that exposure of cells to 12% of CSE concentration induced cell death, while treatment of cells with 2, 4, and 8% CSE increased lipid peroxidation. Exposure to 8% of CSE markedly increased the number of SA-ß-Gal positive cells to up to 82%, and the mRNA expression of Apo J, CTGF, and fibronectin by approximately 3-4 fold. Treatment with 8% of CSE also increased the protein expression of Apo J and CTGF and the secretion of fibronectin and laminin. Thus, treatment with CSE can induce cell loss, senescent changes, and ECM synthesis in primary human RPE cells. It may be speculated that cigarette smoke could be involved in cellular events in RPE cells as seen in age-related macular degeneration.

Connective tissue growth factor (CTGF/CCN2) is an angiogenetic and profibrotic factor, acting downstream of TGF-β, involved in both airway- and vascular remodeling. While the T-helper 1 (Th1) cytokine interferon-gamma (IFN-γ) is well characterized as immune-modulatory and anti-fibrotic cytokine, the role of IFN-γ in lung endothelial cells (LEC) is less defined. Tumour necrosis factor alpha (TNF-α) is another mediator that drives vascular remodeling in inflammation by influencing CTGF expression. In the present study we investigated the influence of IFN-γ and TNF-α on CTGF expression in human LEC (HPMEC-ST1.6R) and the effect of CTGF knock down on human LEC. IFN-γ and TNF-α down-regulated CTGF in human LEC at the promoter-, transcriptional- and translational-level in a dose- and time-dependent manner. The inhibitory effect of IFN-γ on CTGF-expression could be almost completely compensated by the Jak inhibitor AG-490, showing the involvement of the Jak-Stat signaling pathway. Besides the inhibitory effect of IFN-γ and TNF-α alone on CTGF expression and LEC proliferation, these cytokines had an additive inhibitory effect on proliferation as well as on CTGF expression when administered together. To study the functional role of CTGF in LEC, endogenous CTGF expression was down-regulated by a lentiviral system. CTGF silencing in LEC by transduction of CTGF shRNA reduced cell proliferation, but did not influence the anti-proliferative effect of IFN-γ and TNF-α. In conclusion, our data demonstrated that CTGF was negatively regulated by IFN-γ in LEC in a Jak/Stat signaling pathway-dependent manner. In addition, an additive effect of IFN-γ and TNF-α on inhibition of CTGF expression and cell proliferation could be found. The inverse correlation between IFN-γ and CTGF expression in LEC could mean that screwing the Th2 response to a Th1 response with an additional IFN-γ production might be beneficial to avoid airway remodeling in asthma.

Background/Aims: The goal of the present study was to determine whether transforming growth factor-beta(2) (TGF-beta(2))- and oxidative stress-induced cellular changes in cultured human optic nerve head (ONH) astrocytes could be reduced by pretreatment with the antioxidant alpha-lipoic acid (LA). Methods: Cultured ONH astrocytes were treated with 1.0 ng/ml TGF-beta(2) for 24 h or 200 mu M hydrogen peroxide (H2O2) for 1 h. Lipid peroxidation was measured by a decrease in cis-pari-naric acid fluorescence. Additionally, cells were pretreated with different concentrations of LA before TGF-beta 2 or H2O2 exposure. Expressions of the heat shock protein (Hsp) alpha B-crystallin and Hsp27, the extracellular matrix (ECM) component fibronectin and the ECM-modulating protein connective tissue growth factor (CTGF) were examined with immunohistochemistry and real-time PCR analysis. Results: Both TGF-beta(2) and H2O2 increased lipid peroxidation. Treatment of astrocytes with TGF-beta(2) and H2O2 upregulated the expression of alpha B-crystallin, Hsp27, fibronectin and CTGF. Pretreatment with different concentrations of LA reduced the TGF-beta(2)- and H2O2-stimulated gene expressions. Conclusion: We showed that TGF-beta(2)- and H2O2-stimulated gene expressions could be prevented by pretreatment with the antioxidant LA in cultured human ONH astrocytes. Therefore, it is tempting to speculate that the use of antioxidants could have protective effects in glaucomatous optic neuropathy. Copyright (C) 2012 S. Karger AG, Basel

A major cause of blindness in the Western world is degeneration of photoreceptors as a result of point mutations in genes coding for either phototransduction-related proteins or other proteins important for retinal function. Despite the diversity of mutated genes and proteins involved in this heterogeneous group of progressive retinal dystrophies with homologous phenotypes, the final event leading to blindness is apoptosis of photoreceptors. This has led to intensive studies of the effects of neuroprotective agents on the survival of photoreceptors in animal models of retinitis pigmentosa. One such effective molecule discovered to date to exert substantial rescue of retinal photoreceptors is glial cell line-derived neurotrophic factor (GDNF). However, the molecular mechanism of action underlying GDNF-mediated neuroprotection remains unresolved. This dissertation and the herein described studies were carried out with the goal of elucidating neuroprotective mechanisms using the porcine retina as a model. This species was selected due to its morphological and anatomical similarities to human retina. In order to clarify possible cellular mechanisms involved in neuroprotection, the initial studies involved analysis of GDNF action in porcine retina. It soon became evident that the GDNF-receptive cell in retina was not the photoreceptor itself but rather retinal Mueller glial cells (RMG), which are the major retinal glial cells. Thus, primary RMG cell cultures prepared from porcine retina were established and characterised to analyse this cell type without extraneous effects from the retinal environment. Proteomic profiling revealed profound changes in expression of RMG-specific marker proteins as an effect of in vitro conditions. Thus, the in vitro experiments for studying GDNF-induced signalling were performed with primary RMG cultures in an early state (two weeks in vitro) in order to study cells resembling the in vivo phenotype. GDNF was found to induce the ERK, SAPK and PKB/AKT pathways, as well as upregulating basic fibroblast growth factor (bFGF). Application of bFGF to primary porcine photoreceptors in vitro promoted a concentration-dependent rescue. Therefore a model of RMG-mediated indirect survival promoting mechanism induced by GDNF could be proposed. The finding that RMG are mediators of photoreceptor survival prompted further screenings for RMG-specific, secreted molecules promoting photoreceptor survival. A large-scale primary photoreceptor survival assay (96well format) was developed, in which RMG-conditioned medium (RMG-CM) was tested for survival activity. Conditioned medium was observed as having specific photoreceptor survival-promoting activity stemming from previously unidentified protein/s. Reducing the complexity of RMG-CM by anionic chromatography revealed that the activity does not bind to anionic resins. Mass spectrometric identifications of the mono-Q flow-through identified 23 different proteins from the active fraction, among them three potential new candidates for neuroprotective activity in the context of photoreceptor survival: connective tissue growth factor (CTGF), insulin-like growth factor binding protein 5 (IGFBP5) and insulin-like growth factor binding protein 7 (IGFBP7). Expression cloning and re-testing of these candidates for their ability to promote photoreceptor survival revealed that CTGF and IGFBP5 were effective in protecting photoreceptors when applied in combination with the RMG-conditioned media. Taken together, these results indicate that such survival-promoting activity is multi-factorial. RMG are likely to support photoreceptors by either cell to cell-mediated paracrine signalling or by secreting factors into the intercellular space between retina and retinal pigment epithelium, which consists of a complex matrix of proteins and polysaccharides. This matrix, designated as interphotoreceptor matrix (IPM), directly borders three cell types: photoreceptors, RMG and the retinal pigment epithelium and predisposes the IPM to function as repository of neuroprotective molecules possibly secreted from adjacent cells to protect and support photoreceptors. In order to identify such novel neuroprotective substances, the composition of IPM was investigated in this thesis by comparative proteomics. Over 140 different proteins were identified, the majority of which had never been previously detected in the IPM. Among these, 13 candidates were found, which in other tissue systems have been already reported to have a functional role in neuroprotection.