Wednesday, 22 November 2017
Futures Volume 91, August 2017, Pages 46-52 Original research article Author links open overlay panelDianaWildschut https://doi.org/10.1016/j.futures.2016.11.010 Get rights and content Under a Creative Commons license open access Highlights • Society is moving towards a peer-to-peer society. • Citizens become the new decision makers. • Scientists should produce knowledge for citizens. • Citizen science is needed to make the sustainable transition happen. Abstract Society is changing towards a peer-to-peer society that is characterised by a new way to produce things, ranging from software to food, to cities, to scientific knowledge. This requires a new role for science. Instead of focusing on knowledge production for NGO's, governments and business, scientists should become aware that the citizen will be the new decision-maker in a future peer-to-peer (p2p) society, and produce suitable and accessible knowledge, and work together with citizen scientists. Citizens have proven to be capable of asking their own research questions, setting up their own projects, educating themselves and managing complex projects. It is time for them to get taken seriously. There is still a large gap between citizens and academic scientists when it comes to knowledge sharing. Knowledge collected by citizens hardly ever gets used by academic scientists, and outcomes from scientific research are still for a large part hidden behind pay walls. If we want the sustainable transition to take place, we need to open up the barriers between science and the public. The concerns of citizens have to be taken seriously and their knowledge used and valued. 1. Introduction Society is amid a transition towards a peer-to-peer (p2p) society that is characterised by a new way of produce of everything, ranging from software to food, to cities, to scientific knowledge (Bauwens 2012). In a p2p society, networks of individuals, or peers, take over tasks that were previously in the hands of institutions. This requires a new role for science. Instead of focussing on knowledge production for NGO's, governments and business, scientists should become aware that the citizen might be the new decision-maker in a future p2p society, and produce knowledge that is suitable and accessible to them. In this essay, when I talk about citizens I mean non professionals who engage with their surroundings, which could be a city, a street, the environment, the democratic system etc. When I talk about citizen scientists I mean people who practise science outside of an academic or industrial environment. Citizen scientists may or may not have had any formal scientific training. My definition of a neoliberal system is a system with a free market, small government in a globalised world. Looking around us we see old structures fail. The effectiveness of NGOs is doubted (Edwards & Hulme, 1996) and they seem to be mainly after their own survival. They are stuck to the methods of the 80′s; they dress up as pigs or bees, or wear gas masks and show up in a small unimpressive group at company or government headquarters. Their causes are legitimate and the problems they put on the agenda are urgent, but their methods are completely unfit for the world we live in. The focus of neoliberal governments is no longer on the well being of their citizens, it has long shifted towards concern for corporate interests (Chomsky, 1999; von Werlhof, 2008). Long term interests, including science, suffer (Saltelli & Giampietro, 2017). Corporations have no legal duty to act in the public interest, and no tendency to do so if that conflicts with short term economic interests (Banerjee, 2008; Chomsky, 1999). The future of the planet could lie in the hands of small groups of citizens and individuals, who are building a new society next to the existing one by setting up grassroots sustainability initiatives that are interconnected by p2p networks. Already, science is providing technologies that give people the power to do their own research, using their smart phones, webcams and laptops (Bonney et al., 2014). But here is still a large gap between citizens and academic scientists when it comes to knowledge sharing. Knowledge collected by citizens hardly ever gets used by academic scientists, and outcomes from scientific research are still for a large part hidden behind pay walls. If we want the sustainable transition to take place, we need to open up the barriers between science and the public. The concerns of citizens have to be taken seriously and their knowledge used and valued (Irwin, 1995). In this essay I argue that citizens are ready to do sound science and to use and understand science produced by academics. They are ready to use science to jump into some of the gaps that governments, businesses and NGOs do not fill. 2. Citizen science In the early days of the scientific revolution, any interested person with time to spare could look at the stars, gather data and make predictions. They did not need equipment, nor a lot of mathematical skills. Scientists were often also farmers, artists or statesmen. They were generalists, rather than specialists. Since the second half of the 19th century, science has become a practise for specialists, using state-of-the-art equipment and mathematics, requiring many years of university studies. Science was no longer something anybody could engage in (Vermij, 2006). In the last decades, computers have become cheap and powerful. The internet enabled people to get access to data as well as training. The development of cheap programmable micro-controllers has enabled many lay men to develop their own electronics. The popularity of these micro-controllers can mainly be attributed to Arduino, a cheap, open source micro controller board with an online programming environment. Programming them is easy because of the large, community run database of examples, tutorials and code. The boards can be connected to a circuit, the schematics of which can be found online. The Arduino community maintains an excellent collection of knowledge for beginners as well as experts on www.arduino.cc. The availability of cheap sensors is the next problem to be solved. The use of sensors combined with ATMegas (the micro controllers used in Arduino boards) is very popular. People measure whatever they can think of in their environment. They typically log all their data and look for opportunities to compare their data with other people's. This creates a demand for online open data sharing platforms. Communities form, not only around the hardware, but also around research topics. Examples are spectralworkbench.org, where people share the spectra they take of different light sources. They use a spectrometer made of a piece of cardboard and a piece of a CD (Fig. 1) connected to a webcam. They upload their spectra to the database, which contains results from both home made spectrographs and professional ones. It is a mix of useful spectra and blurry images. The database gets filled mostly by curious hobbyists, and as it grows it becomes a valuable resource for determination of chemicals. On the website's section ‘learn’ you can see what use is being made of the data. Citizens use it for measuring food contamination, GMO’s in food (Critical Art Ensemble, 2003), nitrogen levels in agricultural soil, detection of air pollution etc. It empowers them to be critical of the information they get from official sources, like governments and manufacturers. Fig. 1 Download high-res image (912KB)Download full-size image Fig. 1. A home made cardboard spectrograph, using a piece of a CD as grating, connected to a webcam. A recent development is the Lab-on-a-Chip, a tiny laboratory that can be used for fluid analyses. The Lab-on-a-Chip is low cost and easy to use. The purpose is to make a lab that is so user friendly that anybody can use it without much knowledge. For medical purposes, it enables patients to do their own in-vitro diagnostics. It can also shorten the time needed for decision-making because the patient does not have to wait for an appointment if he already has the lab in his home (von Lode, 2005). A Lab-on-a-Chip is a small piece of glass with tiny fluid channels engraved in it. It is mounted very close to a semi-conductor sensor, connected to a micro-controller that either does the analysis or sends the data to an online analysis tool. The recent boom of Fablabs, open workshops for digital fabrication which originated at MIT (Gershenfeld, 2012), have enabled citizen scientists to engrave their own Lab-on-a-Chip systems, by providing access to laser-cutters and 3D printers. Using Arduinos and open-source software for analysis, they can now do complex chemical fluid analyses themselves. These new technologies are now available for everyone, provided they are not afraid of technology. New tools often start out as toys for wizzkids and it takes a while before people start making them accessible for a larger audience by making user friendly interfaces. This process is already taking place and many tools are becoming useful to people who are interested in using them, rather than getting them to work. Not only the data collected by citizens but also their knowledge, intelligence, creativity and social networks can be valuable for academic scientists. In many citizen science projects run by academic scientists, use is made only of the participant's time or computer power. Usually the participant is only used for data collection or classification. The participant's intelligence or creativity is rarely needed and the project only offers very limited opportunities for personal growth (Rotman et al., 2012). Sometimes there is some education available where the participant learns to recognise patterns, species or types of galaxies, but he or she is hardly ever invited to participate in the design of the research. Citizens have valuable knowledge that is often out of reach for university scientists (see also Pereira & Saltelli, 2017). They have local knowledge, which Warren (Warren, 1991) describes as “Knowledge that is unique to a given culture or society. […] It is the basis for local level decision making in agriculture, health care, food preparation, education, natural resource management, and a host of other activities in rural communities.” But of course, not only in rural communities is local knowledge important. Citizens are much more capable of participation than they get a change to show (Fischer, 2000). Many local governments now realise that they need the input of their citizens to govern their cities to the satisfaction of their citizens. Starting to work with critical citizens is not an easy step to take, but once citizens are involved in producing the knowledge for decision making, they are more likely to accept the outcomes and the resulting measures. In the Dutch city of Amersfoort, the local government needed data about the impacts of climate change on a very local scale, where only low resolution data was available. After visiting a conference about citizen science, they decided not to give the job to a consultancy, but to find a group of interested citizens who wanted to investigate climate change in their neighbourhoods. The group was asked to set up the research, decide on what indicators should be measured and how, who to cooperate with and how to disseminate their results. They have now started their project, of which the results can be followed on www.meetjestad.net (Meet je Stad, 2015). Academic scientists see the advantages of cooperating with citizens, not only because of the qualitative value of their local knowledge, but also because of their extensive social networks. Active citizens know what is going on in their community, and they can tell what stakeholders should be involved. So they have to be involved in the very beginning of a research project, otherwise it is too late to make use of this part of their knowledge. Twenty years ago, Alan Irwin (Irwin, 1995) argued for the coming together of the worlds of academic science and citizen science. Now both the need and the possibilities have grown. Citizen scientists have more tools at their disposal to create knowledge with, the infrastructure is there to share the knowledge, and we have some big problems at our hands for which we need all the help we can get. Cash et al. (2003) conclude “[…] that efforts to mobilize science and technology for sustainability are more likely to be effective when they manage boundaries between knowledge and action in ways that simultaneously enhance the salience, credibility and legitimacy of the information they produce”. Many citizens are ready for action or already active. They need scientific knowledge. 3. Open access For this essay, I planned to use only references to open access articles, just to prove a point. It turned out to be impossible, which is a better proof than I would have liked. To be able to write an essay like this a citizen scientist would have to email friends who work for universities, use the Twitter hashtag #icanhazpdf and write emails to authors, hoping for their article in reply. Some of the closed access articles, like this one, are about citizen science and some of those could be interesting to citizens. But citizens who struggle to do their own no-budget science projects are unlikely to be able to pay $41.95 for an article that may or may not be of use. In most cases, science about citizen science will not reach citizens doing science or citizens in need of scientific input. In the p2p-society it is agreed on that whoever uses the services of another, if possible gives something in return to the community it feeds on. So studying citizen science and not sharing the results would be to violate these unwritten rules. Copyrights and patents hinder the availability and development of knowledge. It is often thought that copyrights are the only way to protect authors, but there are other ways to protect the rights of authors and developers of open source products. Some institutions develop their own licenses for open source software (MIT Public License, 1988) or hardware (CERN Open Hardware License, 2011). These institutions deploy their knowledge of copyright and ownership to help people who want to add their data, ideas, designs and products to the public domain. Once there, it can be used and built on by anyone (depending on the license), but it can never be claimed, patented or taken out of the public domain. Different licenses have different conditions, giving the developer the choice of who can use his product and under what conditions. Some licenses allow commercial use of the product, others do not. Some demand attribution to the maker. Some demand that any offspring of the product is published under the same license as the original. Designing these licenses and making them available is a very welcome way for institutions to give something back to the commons. 4. Education Well educated citizens are a condition for a functioning democracy (Hiis Hauge & Barwell, 2017), and equally important for the p2p society. However, a university education in for instance the Netherlands is not easily accessible to every intelligent citizen. People who already have a degree pay enormous fees. Part-time studying is discouraged and for most fields not even available. This is in conflict with the ideal of ‘Life Long Learning’ that is propagated by educational institutions and it will not create broadly interested, well-informed citizens. Yet, we rely on them to make wise choices when it is time to vote (Westheimer & Kahne, 2000). It is fashionable for governments to want citizens to participate, but hardly any efforts are made to provide the necessary tools and information. But now, a growing part of the public are finding their way to new, more accessible and less structured forms of education. New methods for knowledge sharing are being invented, often using the internet. Some universities stream lectures. This can be a helpful addition to an education, but without exercises, it is not complete. Khanacademy.org is a website where you can educate yourself in any high school topic, up to a university level. It uses a clever algorithm that allows students to keep track of their progress. However, Khan Academy is very top-down; a person is lecturing and a student is consuming knowledge. OpenTOKO.org (http://web.archive.org/web/20140927205928/http://www.opentoko.org/) uses a different approach. A topic is offered online, and both experts and lay persons sign up, creating a knowledge sharing group that comes together for an afternoon. The dynamics vary a lot, sometimes a TOKO is planned far in advance, sometimes on short notice. Topics can be popular or obscure, there can be many people or only two or three. It often turns out that beginners have skills, knowledge or questions that the experts learn from. The experts get a deeper understanding of the topic, while the beginners get a valuable jump start. Sometimes no expert signs up and the participants figure it out together. OpenTOKO.org is waiting be improved. An automatic website will be created, enabling anybody to suggest a topic, sign up as an expert or lay person, offer a location and pick a date. When all conditions are met, an OpenTOKO automatically takes place. Entrance is free, everybody benefits by gaining knowledge. Topics range from learning a programming language, electronics, mathematics and statistics to knitting socks and growing vegetables, depending on what participants need. For scientists who want to include citizens in their audience, there is no need for scientists to simplify their results or their language. Citizens can educate themselves and get used to the terminology used in different areas of science. As a starting point of a search for information on almost any topic, Wikipedia can be used. From there, it is easy to find scientific publications, but again the citizen's search will often end at a publisher's pay-wall. 5. Towards a p2p society During the last decade, we have seen a trend towards sharing on a p2p basis: from one individual to another. In 1999, a teenager programmed Napster, which enabled anybody to share digital files (Carlsson & Gustavsson, 2001). Napster used a central server. Because of this, the record industry was able to shut Napster down with law suits. The next generations of music sharing tools were p2p networks, where users shared files directly with other individuals. These networks had no hierarchy and were hard to shut down. Brafman and Beckstrom (2006) compare these leaderless networks to a starfish and hierarchical organisations to a spider; if you cut off the spider's head, it will die. The starfish, however, has no head. Cut of a leg and a new leg will form. Cut the starfish in half, two starfish will form. The p2p network seems indestructible as long as it has the will to live. Bauwens and Lievens (2013) see the transition towards a peer to peer society as the inevitable next step in human development. They give an overview of the history of western society, beginning at the Roman times. In those days, around 80% of society were slaves. The Roman society was utterly dependent on those slaves, and had an ever growing need for more. To keep expanding the number of slaves, they had to keep extending their reign. Eventually this became more expensive than alternatives like sharecropping. They started freeing slaves, allowing them to use land in return for a share in the harvest. This situation developed into the feudal system, which lasted many centuries. In the 19th century, industrialisation caused workers to come to cities, buying their food instead of growing it. Workers got wages, and the time was right for capitalism. Also, people became specialised parts of big hierarcical structures. Now, automation has reduced the amount of human labour necessary to produce our society's basic needs. Political economist Skidelsky (2012) concludes: “The truth is that we cannot go on successfully automating our production without rethinking our attitudes toward consumption, work, leisure, and the distribution of income.” In the western society only a small percentage of our labour is used for society’s basic needs. Most people have jobs that can easily be missed (Graeber, 2013) Most of them know this, with often negative effects on their health and psychology. There is also a growing amount of unemployed citizens for whom the old system has failed. Their former employers have discarded of them, often after decades of dedicated work and loyalty from the employee’s side. A large part of the people that got fired have become too expensive because of their age. Employers tend to choose cheaper employees, rather than the more experienced ones. Here, money is preferred over quality and humanity. Some of the unemployed people choose to do things differently from now on, and start looking for a new system that is more respectful of people and that values real quality. Like the freed slaves, they are a growing group in our society who have the energy to start working in a new system. Bauwens and Lievens 22] call this new system ‘the p2p economy', which is based on exchange between individuals. The combination of available knowledge and a growing dissatisfaction with the way governments handle environmental problems, encourages people to get involved in experiments with small scale solutions for energy production, local food production, recycling of waste and democratic and social innovation. Some of these experiments fail, but others succeed and render stable, small, local alternatives that can be an inspiration to others. Not everything can easily be done locally. Specialised health care is best done in dedicated hospitals. Justice is best handled by experts, although the system of jury law is a bit more p2p than law systems with professional judges only, and is in many countries considered fair. Production processes that are said to be more efficient on a large scale, may not be if the real costs and efforts of transport, infrastructure, resources and waste are included in the calculation. These so called “externalities” are often not payed for by multinationals (Mansfield, 2011; Scherhorn, 2005). 6. When systems clash In many cases the p2p society can coexist with the capitalist society, as can the citizen scientist coexist with the academic scientist. There can be conflicts of a financial nature, like in the case of the record companies versus the p2p networks for music distribution, where both sides try to maximise their profit. The more interesting situations, however, occur when both viewpoints are valid, but incompatible. The p2p society is based on trust, earned by previous work. If you contribute to the community, you gain respect and trust. In the capitalist society however, trust comes with credentials. If you want a job as a software engineer, you need to have diplomas and certificates to prove you can write code. In the p2p society you prove you can write code by writing code. The code is open source so users can check if it works and experts can check if it is well written and contains no malware. When the two worlds meet, they are often skeptical about each other’s approach. Some individuals see the flaws and benefits of both systems, and a software engineer may get a job without a diploma, if he happens to run into the right employee manager. The connection between the two worlds comes from those who recognise the possibilities to cooperate and are in a position where they have the freedom not to stick to the protocol. In any case, the p2p way of assessing the quality or reliability of a peer will take more effort than assessing the quality or reliability of, for instance, an academic scientist. Some research into the person will be required, through personal contact or by looking at the peer’s reputation and work. For newcomers it is a completely different situation. But what about other differences between citizen scientists and academic scientists? To do real science, you have to work according to many rules, and citizens can just do whatever they want. What about quality and ethics? This seems to be the concern of many academic scientists. Citizens’ motivations and the quality of their work are suspect (Show, 2015). Even projects set up and run by academic scientists that use data collected by volunteers have trouble getting published (Bonney et al., 2014). It is true that citizen science does not necessarily have a fixed set of rules for ethics or methods. Even though there are many examples of networks that share a code of ethics or list of methods , like some diy-biolabs (Diybio.org, 2016) and makerspaces (Fablab.nl), there are plenty of people who never think of it nor discuss it and are simply not interrested. But in the same way any programmer can check open source computer code, any academic scientist can check if a citizen science project is well done, by the academic scientist’s standards. In my opinion this does not mean that the academic standards should be the ones we should measure citizen science by, but we could if we wanted to. In some cases, the university standards are less strict than the ones used in citizen science. For instance, in regular science it is not common to open up all data, while in citizen science it is. In this aspect citizens science is much more reproducible and fraud is more easily detected. Citizen scientists’ experiments are often repeated and improved on. Citizen scientists have no publication pressure (Saltelli & Giampietro, 2017, discuss the desperation to publish or perish as a key ingredient of the crisis in science), they publish when they think they have produced something interesting. They open their work for peer review right from the first attempts to the final conclusions. Citizen scientists are also more likely to publish negative results. They are not at all embarrassed of their errors. Publications of positive results often also include a section about previous attempts that failed, and a discussion about why they failed. These negative results are in my opinion as valuable as positive results, yet in regular science there is a strong tendency to only publish positive results, which makes academic science incomplete (Dwan et al., 2008). Citizen scientists are often suspected of having biases, hidden motives or agendas. We know by now that professional scientists have biases too. There are even types of biases that citizen scientists are less likely to have, like biases that are related to prestige or funding, and the bias towards positive results. But the fact that academic scientists do not necessarily perform any better than citizen scientists, does not mean we should ignore possible problems with citizen scientists’ quality. In order to enable more cooperation between citizen scientists and academic scientists we should insist on full transparency on possible conflicts of interest, for both citizen scientists and academic scientists. In academic science there is a healthy discussion going on about quality, biasses and conflicts of interest. In citizen science the subject is hardly ever raised, which is a shame since some biasses are less likely to occur when their owner is aware of them. Quality is often described as being ‘fit for function”. Sometimes we may need accurate data from expensive sensors. In this case academic science could deliver a higher quality. But at other times we may need a high resolution, and here large groups of citizens are more likely to achieve high quality. Knowledge is only fit for function if it is open to those that need it. It is therefore important that knowledge related to climate change and other global problems is completely open. I think it would be good to have a conversation between academics and citizen scientists about what quality results are useful both for other citizens, local policy makers and academic scientists, depending on the function. If we want to share data between academic scientists and citizen scientists, or between citizen scientists and decision makers, what barriers are there and how can we overcome them? Should we find a set of criteria for quality (including accessibility) that is acceptable for academic scientists and manageable for citizens? 7. The commons Most of the issues mentioned in the above paragraphs lead us to the concept of the commons. The commons includes everything that belongs to everybody. It includes our atmosphere, our planet's ecosystem, our culture and our knowledge. Most of the private wealth in the world exists because goods or services that belong to the commons can often be taken without payment, and there is no obligation to give something back to the commons. This applies to businesses that pollute or take resources, commercial entertainment companies that take folk stories from the public domain and protect them with copyrights, companies that patent genes that are for the largest part natural, as well as to scientific research that takes input from the commons, with results that are not given back to the commons (Barnes, 2006). Climate change, pollution and the depletion of resources are everybody's problem. These problems are as much part of the commons as the solutions are. Solving them does not have to be a private undertaking. By sharing the knowledge between academic scientists and citizens, we can work on these problems together. 8. Discussion and conclusion Citizen scientists are not angels, sent from above to save science. Nor have they come to destroy academic institutions and take over. They have their own agenda's, flaws and biasses, as do academic scientists. More awareness of these biasses can improve the quality of their work. Any discussion about quality should be respectful and open, with consideration of the limitations of citizen science and its practitioners. We know that citizens don't always take the right decisions when they vote, do not vote or buy products. So why should we count on them to solve societies' problems? We should not wait anybody, but we need to engage all the help we can get, and if people are already intrinsically motivated, we should not marginalise them. Even though the groups that use citizen science to solve problems that they feel are not being addressed by institutions are often still small, the interest they receive from others and the availability of user friendly tools and infrastructure can result in more and larger groups, and a stronger network of individuals. What we see now is the beginning of a trend of independent thinkers and do-ers. They might one day develop into institutions of their own, but they may also stay loose groups of individuals. The same goes for the transition towards a p2p society. This transition is already taking place. It does not need a revolution but grows inside the current system. It accellerates in areas where the current system fails. It needs those impulses, and if the current system suddenly solves the problems, or if the p2p system turns out not to, this trend may stop. For now, it is growing. Citizens are eager to contribute to the solution of problems that the neoliberal system fails to solve, like environmental problems and democratic representation (Publiclab.org). Citizens are increasingly sharing in decision-making as our society moves towards a p2p model (Public Laboratory, 2016). Citizens have proven to be capable of asking their own research questions, setting up their own projects, educating themselves and managing complex projects. It is time for them to get taken seriously. Scientists already contribute to the empowerment of citizens by developing for instance new technologies and licenses, but those are offspring of scientific knowledge. It is also necessary to share the knowledge itself. If scientists want their results to be useful, they should make them accessible to citizens. The knowledge created by citizens can be very valuable for academic scientists. However, the act of giving something back to the community has to be embraced by academic scientists who engage in citizen science projects. We are not so far away from getting rid of everything that stands in the way of a collaborative production of useful knowledge. It takes some adjustments from both sides to bring citizen science and academic science together, so we can join efforts in making the sustainable transition happen. References Banerjee, 2008 S.B. Banerjee Corporate social responsibility: The good, the bad and the ugly Critical Sociology, 34 (1) (2008), pp. 51-79 Barnes, 2006 P. 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https://www.massagemag.com/mayan-fertility-massage-technique-87497/ November 21, 2017Diane MacDonald, R.N. Technique Articles The abdominal fertility massage applications move congested lymph fluid, oxygenate blood, increase immune function and maintain proper nerve flow in pelvic organs. By combining her extensive knowledge of anatomy, physiology, herbalism and naprapathy, Rosita Arvigo, D.N., has established a credible Western explanation of causes, signs and successful treatment of digestive and reproductive ailments for both men and women. The Arvigo Techniques of Maya Abdominal Therapy® are based Arvigo’s 13-year apprenticeship with Don Elijio Panti (1893-1996) and her more than 40 years in the field of natural healing as a naprapath and herbalist. Since 1992, practitioners trained by The Arvigo Institute LLC have worked with couples to enhance fertility. The Arvigo Techniques of Maya Abdominal Therapy restore and balance chu’lel, the Mayan word for qi, or vital life-force energy. Fertility Massage The abdominal fertility massage applications move congested lymph fluid, oxygenate blood, increase immune function and maintain proper nerve flow in pelvic organs. No matter what fertility-related complaints or ailments a client or couple presents to their Arvigo practitioner, the practitioner addresses the five systems of flow: arterial, venous, nerve, lymphatic and energetic, in abdominal organs, to normalize functions according to nature’s original plan. Like other normal bodily functions, conception and pregnancy can be restored to the functions nature intended. Our noninvasive, external fertility massage techniques restore homeostasis, or balance within, as well as hemodynamics, or unimpeded flow of blood and body fluids. Homeostasis and hemodynamics are the two rudders of our physical ship. “Give nature half a chance, and there is a miracle in store for everyone,” says Arvigo. Arvigo in Action Practitioners of The Arvigo Techniques of Maya Abdominal Therapy have two protocols to offer couples seeking fertility enhancement. One protocol is a one-month protocol streamlined for couples who want to conceive immediately, and includes professional sessions until ovulation; herbal, lifestyle and nutritional support; and home-based, self-care massage. For the client who opts for a three-month protocol, professional sessions are scheduled twice monthly, usually prior to ovulation and menses; herbal, lifestyle and nutritional support are included as well. (Because providing nutritional information is not in the scope of massage therapy, unless a massage therapist holds dual licensure, she must refer the client to a dietitian or nutritionist for that component of the Arvigo protocol.) Arvigo practitioners tend to prefer the three-month program, as it provides ample time to assist the clients’ body into a state of balance; however, sometimes there is urgency for clients to conceive sooner rather than later. In some cases, conception occurs in the first cycle. It is essential to know if ovulation occurs; therefore, menstrual charting is taught to clients and reviewed at each visit. The Arvigo practitioner’s goal for all clients, without regard to the one- or three-month protocol, is two-fold: uterine lavage to cleanse a congested uterine membrane, presentation of which includes painful periods and dark blood at the start and end of cycles; and realignment of reproductive organs to their optimal position. Organs may have shifted due to falls that impacted the sacrum, misalignment of the sacroiliac joint, surgeries and adhesions to the 14 ligaments that hold the uterus in its proper pelvic position. Katinka Locasio, L.M.T., is a certified practitioner of The Arvigo Techniques of Maya Abdominal Therapy, with a practice based in New York, New York, who supports clients on their path to fertility. She began working with 30-year-old client, “Vivian,” in February 2012. Vivian had been trying to conceive for a year without success, utilizing ovulation predictor kits and charting her cycles, but to no avail. After reviewing her initial intake form, Locasio saw Vivian’s main complaints were stagnation related to her menstrual cycle, along with heavy bleeding, painful periods and low-back pain. Initially, Vivian’s lower pelvic bowl was quite congested. She received three monthly sessions along with home instruction in self-care fertility massage. Vaginal steam baths as well as nutritional and lifestyle support were included in her plan. After seeing Locasio for Arvigo sessions and following the home-care plan, she canceled her appointment with a fertility specialist in July 2013, as she was already pregnant the natural way. “I feel the combination of The Arvigo Techniques of Maya Abdominal Therapy sessions, practicing daily self-care massage and vaginal steams were the key to [me] becoming pregnant,” says Vivian. Care for Men Optimal reproductive organ position is critical for both male and female reproductive health. For women, a misaligned uterus restricts arterial blood flow and outward flow of toxins, allowing buildup of acid and carbon dioxide in muscles, lymph and surrounding tissue. The result of that buildup is pathology and malfunction. For men, a congested prostate decreases function of that organ, which provides nutrition and enzymes for healthy sperm. To assure greater success, the Arvigo practitioner prefers to treat couples. Once-monthly sessions can prevent and relieve prostatic congestion and improve sexual function in men. Arvigo self-care techniques can be taught to couples in tandem with each other. Depending on the situation of each male client, practitioners may also recommend herbal and nutritional therapies. Chronic digestive complaints are common in both men and women with pelvic dysfunction and reproductive problems. Upper abdominal massage is included in The Arvigo Techniques of Maya Abdominal Therapy, and relieves chronic tension in the diaphragm that can obstruct blood flow to the digestive tract and reproductive organs. Clients often report great improvement in digestive function within a few treatments—even more quickly if they are faithful to self-care massage. Self-Care Massage Teaching clients self-care massage techniques is integral to the success of both the one- and three-month protocol, as self-care massage helps maintain proper position and function of pelvic organs without depending exclusively on practitioners. Using techniques unique to The Arvigo Techniques of Maya Abdominal Therapy, self-care massage is intended to support relief of complaints between sessions with the practitioner. It educates and empowers clients to effect change themselves, allowing for steady, ongoing improvement. Our approach is holistic; thus, to address emotional and spiritual issues of the couple, practitioners can also offer Maya spiritual healing, as taught by Don Elijio Panti to Rosita Arvigo, which includes spiritual baths, prayers and use of copal, or incense, in a healing session. Arvigo also developed a guided-imagery uterine meditation to help clients’ access deeply rooted, hidden emotional traumas. Bridging Ancient & Modern Many clients seek assisted reproductive technology (ART) treatments alongside Arvigo techniques, as the Arvigo process is a supportive treatment approach that provides nurturing to physical, emotional and spiritual components of the person. Beth Townsend is a certified practitioner of The Arvigo Techniques of Maya Abdominal Therapy in Grand Rapids, Michigan, who works with a variety of clients, many of whom receive ART fertility treatments as well. “One client, ‘Sharon,’ came to see me as she was preparing for her fourth round of in vitro fertilization (IVF),” Townsend recalls. “She had been unable to hold the previous transfers, as her uterine lining never increased beyond 8 millimeters of thickness with conventional medicine. This was going to be her final attempt at conception after several years of assisted reproductive technology, including intrauterine insemination and IVF cycles. “After four professional [Arvigo] sessions, self-care massage at home and other supportive therapies, Sharon conceived via IVF after her uterine lining had increased to 11 millimeters,” Townsend continues. “She eventually gave birth to twins, a boy and a girl.” Sharon says after receiving The Arvigo Techniques of Maya Abdominal Therapy, she “would leave feeling lighter and more balanced. Doing the self-care massage at home gave me something to do that was relaxing and nurturing, as I imagined my uterine lining becoming thick and ready for our baby. “It was amazing to see my uterine lining at 11 millimeters as we prepared for the transfer,” she adds. “This had never happened before.” A Healing Gift The Arvigo Institute LLC’s training program provides practitioners with a foundation of theory and hands-on training to offer this work to clients who seek to enhance fertility. Since the early 1990s, there has been a steady growth of Arvigo practitioners in the U.S. and other countries around the world. Our practitioners are primarily massage therapists, but include naturopathic and medical doctors, nurses, nurse practitioners, acupuncturists, physical and occupational therapists and chiropractors. In 2014, Oxford University Press published a book of case studies that highlight the most common conditions The Arvigo Techniques of Maya Abdominal Therapy address, titled Message from the Gods: Ethnobotany of Belize, by Michael Ablik and Rosita Arvigo. In early 2017, the San Jose, California newspaper The Mercury News reported on the techniques in “Maya abdominal massage: An answer to ending infertility, miscarriages?” The Arvigo techniques are a healing gift for clients and practitioners. Rosita Arvigo’s commitment to preserve and bridge ancient Mayan medicine into our modern world is valuable to today’s couples striving to become pregnant. Simple and elegant, these ancient techniques combined with modern knowledge bring us back into alignment with our natural selves. About the Authors Diane MacDonald, R.N., has served as the program administrator and is a certified instructor for The Arvigo Institute LLC. She has worked in nursing since 1982, and maintains a private Arvigo Therapy practice in Antrim, New Hampshire. In addition, she has helped develop The Arvigo Institute LLC and its core content since 2001. Rosita Arvigo, D.N., is a naprapathic physician, herbalist, international lecturer and author. She directs the Ix Chel Tropical Research Foundation in Belize, is a founding member of The Traditional Healers Foundation, and operates the Ix Chel Wellness Center in Santa Elena, Belize.
PIKSI summer institutes are designed to encourage undergraduates from underrepresented groups to consider future study of philosophy.
> Undergraduates and recent graduates from underrepresented groups such as women, African Americans, Chicano/as and Latino/as, Native Americans, Asian Americans, Pacific Islanders, LGBTs, economically disadvantaged communities, and people with disabilities are urged to apply. Transportation and lodging are provided. Stipends are awarded to all. > > APPLICATION DEADLINES > > Undergraduates -- JANUARY 31, 2018 > > Graduate Assistants (PIKSI-Rock only) -- JANUARY 31, 2018 > > For more information visit: piksi.org > > PIKSI ROCK > > Rock Ethics Institute/Penn State > > Date: June 27-July 6, 2018 > > Director: Kris Sealey > > Fairfield University > > Theme: Philosophy and Public Life > > Speakers: > > Alfred Frankowski > > Southern Illinois University at Carbondale > > Nathifa Greene > > Gettysburg College > > Shay Welch > > Spelman College > > Kyle Powys Whyte > > Michigan State University > > > PIKSI BOSTON > > MIT/UMB > > Date: June 19-26, 2018 > > Directors: Lisa Rivera > > University of Massachusetts Boston > > Keota Fields > > University of Massachusetts Dartmouth > > Speakers: > > Otávio Bueno > > University of Miami > > Myisha Cherry > > Harvard University/University of Illinois > > Nathifa Greene > > Gettysburg College > > Kevin Richardson > > North Carolina State University > > > > For more information visit: piksi.org > > Contact: email@example.com > > SPONSORS: THE ANDREW W. MELLON FOUNDATION, AMERICAN PHILOSOPHICAL ASSOCIATION – PENN STATE’S ROCK ETHICS INSTITUTE, COLLEGE OF THE LIBERAL ARTS, AND DEPARTMENT OF PHILOSOPHY - MASSACHUSETTS INSTITUTE OF TECHNOLOGY MICHIGAN STATE UNIVERSITY - STONY BROOK UNIVERSITY - UNIVERSITY OF OREGON - UNIVERSITY OF IOWA - IRIS MARION YOUNG DIVERSITY SCHOLARS FUND - ANN ARBOR PHILOSOPHERS’ PIKSI FUNDING INITIATIVE - ASSOCIATION OF FEMINIST ETHICS AND SOCIAL THEORY - PRINCETON UNIVERSITY PRESS-HARVARD UNIVERSITY-TUFTS UNIVERSITY
Curcumin downregulates human tumor necrosis factor-α levels: A systematic review and meta-analysis ofrandomized controlled trials
Volume 107, May 2016, Pages 234-242 Pharmacological Research Review Author links open overlay panelAmirhosseinSahebkarabArrigo F.G.CicerocLuis E.Simental-MendíadBharat B.AggarwaleSubash C.Guptaf a Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran b Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia c Medicine and Surgery Sciences Dept.,University of Bologna, Italy d Biomedical Research Unit, Mexican Social Security Institute, Durango, Mexico e Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX USA f Department of Biochemistry, Faculty of Science, Banaras Hindu University, Varanasi, India Received 17 January 2016, Revised 23 March 2016, Accepted 24 March 2016, Available online 26 March 2016. crossmark-logo https://doi.org/10.1016/j.phrs.2016.03.026 Get rights and content Abstract Background Tumor necrosis factor-α (TNF-α) is a key inflammatory mediator and its reduction is a therapeutic target in several inflammatory diseases. Curcumin, a bioactive polyphenol from turmeric, has been shown in several preclinical studies to block TNF-α effectively. However, clinical evidence has not been fully conclusive. Objective The aim of the present meta-analysis was to evaluate the efficacy of curcumin supplementation on circulating levels of TNF-α in randomized controlled trials (RCTs). Methods The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases by up to September 21, 2015, to identify RCTs investigating the impact of curcumin on circulating TNF-α concentration. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analyses were performed to assess the modifiers of treatment response. Results Eight RCTs comprising nine treatment arms were finally selected for the meta-analysis. There was a significant reduction of circulating TNF-α concentrations following curcumin supplementation (WMD: 4.69 pg/mL, 95% CI: 7.10, 2.28, p < 0.001). This effect size was robust in sensitivity analysis. Meta-regression did not suggest any significant association between the circulating TNF-α-lowering effects of curcumin with either dose or duration (slope: 0.197; 95% CI: 1.73, 2.12; p = 0.841) of treatment. Conclusion This meta-analysis of RCTs suggested a significant effect of curcumin in lowering circulating TNF-α concentration. Graphical abstract Unlabelled figure Download high-res image (143KB)Download full-size image Keywords Curcumin TNF-α Curcuma longa Inflammation Randomized controlled trial Meta-analysis 1. Introduction Evidence from both preclinical and clinical studies over the past several years has indicated that chronic inflammation is closely linked with numerous human chronic diseases such as cardiovascular, pulmonary, autoimmune, degenerative diseases, cancer, diabetes, and Alzheimer disease . The inflammatory cytokine, tumor necrosis factor-α (TNF-α) is one of the major molecular mediators of chronic inflammation . Thus blockers of TNF-α such as monoclonal antibodies and circulating receptor fusion protein have been developed. However, these blockers are highly expensive and produce adverse effects . Therefore, agents that are safe, cost effective and readily available are required. Curcumin (diferuloylmethane), a naturally occurring polyphenol, is one such agent that is derived from turmeric (Curcuma longa L.). Clinical trials have demonstrated the efficacy and safety of curcumin supplementation in several human diseases such as osteoarthritis , metabolic syndrome , solid tumors , chronic obstructive pulmonary disease , anxiety and depression , rheumatoid arthritis , psoriasis , pruritic skin disease  and hypertriglyceridemia . The underlying mechanism for curcumin clinical efficacy seems to be modulation of numerous signaling molecules. Numerous studies from both in vitro and animal models have indicated that curcumin can block the action and production of TNF-α . As referred above, curcumin has been evaluated for its potential against numerous chronic diseases in humans. This polyphenol reportedly possesses activities against all those diseases for which TNF-α blockers are currently being used. Curcumin has been reported to inhibit cell signaling pathways activated by TNF-α. In humans, curcumin has been shown to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, nuclear factor (NF)κB, signal transducer and activator of transcription 3 (STAT3), adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, endothelin-1,cyclooxygenase-2, 5-lipooxygenase, C-reactive protein, prostaglandin E2, prostate-specific antigen, creatinine, heme oxygenase-1, aspartate aminotransferase, and alanine aminotransferase . In clinical studies, curcumin has been tested either alone or in combination with other agents. To increase the efficacy and bioavailability, various formulations of curcumin have also been used. In this study, we thoroughly reviewed nine randomized controlled clinical trials (RCTs) in which curcumin effects on plasma concentrations of TNF-α have been studied. The aim was to obtain a conclusive finding on the significance and magnitude of the TNF-α-lowering activity of curcumin in clinical practice. 2. Methods 2.1. Search strategy This study was designed according to the guidelines of the 2009 preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement . Medline (http://www.ncbi.nlm.nih.gov/pubmed), SCOPUS, Web of Science and Google Scholar databases were searched using the following search terms in titles and abstracts (also in combination with MESH terms): (curcumin OR curcuminoid OR curcuminoids OR Curcuma OR C. longa OR turmeric) AND (TNF-α OR TNFα OR TNF α OR tumor necrosis factor-α OR tumor necrosis factor α OR tumor necrosis factor α) AND (random OR randomized OR randomly OR randomization OR randomized controlled trial OR randomized trial OR randomized study OR random number). The wild-card term * was used to increase the sensitivity of the search strategy. The search was limited to studies in English language. The literature was searched from inception to September 21, 2015. 2.2. Study selection Original studies were included if they met the following inclusion criteria: (i) being a RCT with either parallel or cross-over design or a post-hoc analysis of a RCT, (ii) investigating the impact of supplementation with curcuminoids or turmeric preparations with a determined amount of curcuminoids on plasma TNF-α concentrations, and (iii) presentation of sufficient information on changes in circulating TNF-α in the study groups. Exclusion criteria were (i) non-randomized trials, (ii)an active control group in the study design, (iii) observational studies with case-control, cross-sectional or cohort designs, (iv) using non-standardized turmeric extracts with unknown curcumin content, (v) trials with treatment durations of <2 weeks, and (vi) incomplete data on circulating concentrations of TNF-α. In case of the latter item, authors of the article(s) were contacted and requested to provide necessary numerical data. 2.3. Data extraction Eligible studies were reviewed and the following data were abstracted: (1) first authors name; (2) year of publication; (3) study location; (4) study design; (5) number of participants in the fibrate and placebo groups; (5) type and dose of curcumin supplement used; (6) duration of treatment; (7) age, gender and body mass index (BMI) of study participants; (8) inclusion criteria defined in the study; (9) systolic and diastolic blood pressures; and (10) baseline and follow-up TNF-α concentrations. 2.4. Quality assessment A systematic assessment of bias in the included studies was performed using the Cochrane criteria . The items used for the assessment of each study were as follows: adequacy of sequence generation, allocation concealment, blinding, addressing of dropouts (incomplete outcome data), selective outcome reporting, and other potential sources of bias. According to the recommendations of the Cochrane Handbook, a judgment of yes indicated low risk of bias, while no indicated high risk of bias. Labeling an item as unclear indicated an unclear or unknown risk of bias. 2.5. Quantitative data synthesis Meta-analysis was conducted using Comprehensive Meta-Analysis (CMA) V2 software (Biostat, NJ) . Plasma TNF-α concentrations were collated in pg/mL.Net changes in measurements (change scores) were calculated as follows: measure at end of follow-upmeasure at baseline. For cross-over trials with a 2 ÿ 2 design, each treatment arm was analysed separately, and net change in each arm was calculated by subtracting the value after control intervention from that reported after treatment. Standard deviations (SDs) of the mean difference were calculated using the following formula: SD = square root [(SDpre-treatment)2 + (SDpost-treatment)2 (2R ÿ SDpre-treatment ÿ SDpost-treatment)], assuming a correlation coefficient (R) = 0.5. Where standard error of the mean (SEM) was only reported, standard deviation (SD) was estimated using the following formula: SD = SEM ÿ sqrt (n), where n is the number of subjects. Selection of fixed-effects and random-effects (using Der Simonian-Laird method) models was performed in cases of heterogeneity values <50% and 50%, respectively . Heterogeneity was quantitatively assessed using I2 index. In order to evaluate the influence of each study on the overall effect size, sensitivity analysis was conducted using leave-one-out method, i.e. removing one study each time and repeating the analysis . 2.6. Meta-regression Random-effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the association between calculated WMD and potential confounders including dose and duration of supplementation with curcumin. 2.7. Publication bias Potential publication bias was explored using visual inspection of Beggs funnel plot asymmetry, fail-safe N test, and Beggs rank correlation and Eggers weighted regression tests. Duval & Tweedie trim and fillmethod was used to adjust the analysis for the effects of publication bias . 3. Results 3.1. Flow and characteristics of included studies First, after multiple database searches 267 published studies were identified and the abstracts reviewed. Then, 38 non-original articles were excluded. Next, 213 did not meet the inclusion criteria and were also excluded. Thus, 16 full text articles were carefully assessed and reviewed; of which eight trials were excluded for not measuring plasma TNF-α concentrations (n = 5), incomplete data on serum TNF-α levels (n = 2), and short treatment duration (n = 1). Finally, eight studies were eligible and included in the systematic review and meta-analysis. The study selection process is shown in Fig. 1. Fig. 1 Download high-res image (487KB)Download full-size image Fig. 1. Flow chart of the number of studies identified and included into the meta-analysis. Data were pooled from eight eligible studies comprising nine treatment arms which included 549subjects, with 275 in the curcumin arm and 274 in the control arm (participants enrolled from the cross-over trial were considered in both arms). Included studies were published between 2008 and 2015. The clinical trials used different doses of curcumin. Two studies investigated curcumin 300 mg/day [25,26], three studies investigated curcumin 1 g/day  and two studies investigated curcumin 1.5 g/day [4,30]. The range of intervention periods was from four weeks  up to three months . Study design of all included studies was parallel-group, except one which was cross-over design . Selected studies enrolled subjects with obesity [26,28], type 2 diabetes [25,26], type 2 diabetic nephropathy , major depressive disorder , knee osteoarthritis , metabolic syndrome , and sulfur mustard-exposed veterans . Demographic and biochemical characteristics of the evaluated studies are presented in Table 1. Table 1. Demographic characteristics of the included studies. Reference Study design Target Population Treatment duration n Treatment groups Age, years Female (n, %) BMI, (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Glucose (mg/dl) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) C-reactive protein (mg/l) Baseline TNF-α (pg/ml) (22) Randomized, double-blind, placebo-controlled Type 2 diabetic nephropathy 2 months 20 Curcumin 1.5 g/day 52.9 ± 9.2 11 (55.0) ND 129.0 ± 15.5 79.0 ± 7.4 179.0 ± 65.5 214.2 ± 66.5 114.1 ± 34.6 43.8 ± 12.6 236.2 ± 146.5 12.8 ± 2.9 20 Placebo 52.6 ± 9.7 7 (35.0) ND 130.5 ± 25.3 80.5 ± 5.3 169.5 ± 76.3 193.3 ± 45.7 108.3 ± 39.9 39.8 ± 9.5 220.4 ± 106.9 16.4 ± 14.2 (20) Randomized, double-blind, placebo-controlled cross-over Obesity 1 month 15 Curcumin 1 g/day ND ND ND ND ND ND ND ND ND ND 2.63 ± 2.81 15 Placebo 2.72 ± 1.17 (18) Randomized, double-blind, placebo-controlled Overweight or obese with type 2 diabetes 3 months 50 Curcumin 300 mg/day ND ND ND ND ND 131.1 ± 31.9 ND ND ND 157.7 ± 49.6 1.72 ± 0.74 50 Placebo ND ND ND ND ND 147.2 ± 37.1 ND ND ND 186.9 ± 66.4 2.14 ± 0.84 (17) Randomized, placebo-controlled Type 2 diabetes 8 weeks 23 Curcumin 300 mg/day 55.5 ± 10.7 11 (47.8) 24.6 ± 2.4 130.4 ± 18.5 81.8 ± 10.0 155.0 ± 17.9 195.0 ± 41.1 120.3 ± 42.1 38.7 ± 7.6 176.3 ± 27.6 4.10 ± 2.10 21 Placebo 49.7 ± 8.1 10 (47.6) 23.9 ± 2.3 126.3 ± 15.4 80.7 ± 7.4 161.1 ± 19.9 196.9 ± 35.7 125.2 ± 34.9 36.3 ± 7.6 170.1 ± 47.5 3.60 ± 1.57 (19) Randomized, double-blind, placebo-controlled Major depressive disorder 6 weeks 50 Curcumin 1 g/day 44.1 ± 8.0 0 (0.0) ND ND ND ND ND ND ND ND ND ND 50 Placebo 45.2 ± 7.6 0 (0.0) ND ND ND ND ND ND ND ND ND ND (7) Randomized, double-blind, placebo-controlled Sulfur mustard-exposed veterans 4 weeks 39 Curcumin 1.5 g/day 50.9 ± 7.2 0 (0.0) 28.0 ± 4.8 ND ND ND ND ND ND ND 6.98 ± 1.83 28.03 ± 2.63 39 Placebo 53.9 ± 8.6 0 (0.0) 25.9 ± 4.0 ND ND ND ND ND ND ND 8.54 ± 1.64 26.13 ± 4.01 (48) Randomized, double-blind, placebo-controlled Knee osteoarthritis 6 weeks 19 Curcumin 1.5 g/day 57.3 ± 8.7 14 (73.6) 28.7 ± 3.1 ND ND ND ND ND ND ND 5.56 ± 1.74 31.75 ± 3.93 21 Placebo 57.5 ± 9.0 17 (80.9) 29.6 ± 4.4 ND ND ND ND ND ND ND 5.00 ± 0.00 31.99 ± 3.99 (21) Randomized, double-blind, placebo-controlled Metabolic syndrome 8 weeks 59 Curcumin 1 g/day 44.8 ± 8.6 23 (46.0) 25.4 ± 2.4 135.5 ± 13.1 88.3 ± 7.8 155.4 ± 40.8 220.2 ± 37.7 190.4 ± 20.0 31.5 ± 4.6 199.6 ± 23.4 6.52 ± 2.16 79.24 ± 8.55 58 Placebo 43.4 ± 9.7 27 (54.0) 22.8 ± 5.3 135.7 ± 14.7 88.7 ± 8.1 136.9 ± 52.4 184.0 ± 17.3 157.0 ± 17.2 35.4 ± 6.5 185.6 ± 38.4 7.10 ± 1.80 77.48 ± 6.54 Values are expressed as mean ± SD. *Final condition. Abbreviations;: ND, no data; BMI, body mass index. 3.2. TNF-α assay methods Different assays methods were used to measure serum TNF-α concentration. Most of the studies[2527,29,30] measured serum TNF-α levels by enzyme-linked immunoassay. Ganjali et al.  analyzed TNF-α concentrations using the Biochip Array Technology on the Randox Evidence Investigator (Randox Laboratories, Belfast, Northern Ireland) by chemiluminescent immunoassay. 3.3. Risk of bias assessment Most of the included studies were characterized by lack of information about the random sequence generation, allocation concealment, and blinding of outcome assessment. In addition, some trials did not provide sufficient information of blinding of participants and personnel, andone of them showed high risk of bias . On the other hand, all evaluated studies had a low risk of bias according to selective reporting. Details of the quality of bias assessment are shown in Table 2. Table 2. Quality of bias assessment of the included studies according to the Cochrane guidelines. Reference Random sequence generation Allocation concealment Selective reporting Other bias Blinding of participants and personnel Blinding of outcome assessment Incomplete outcome data (22) U L L L L U L (20) U U L L U U U (18) U U L U U U U (17) U U L U H U L (19) L U L U U U U (7) L L L L L L L (48) U U L L U U L (21) U U L U U U L L, low risk of bias; H, high risk of bias; U, unclear risk of bias. 3.4. Effect of curcuminon circulating TNF-αconcentration Overall, the impact of curcumin on circulating TNF-α concentration was reported in eight RCTs comprising nine treatment arms. Meta-analysis suggested a significant reduction in plasma TNF-α concentrations following curcumin supplementation (WMD: 4.69 pg/mL, 95% CI: 7.10, 2.28, p < 0.001) (Fig. 2). Fig. 2 Download high-res image (793KB)Download full-size image Fig. 2. Forest plot displaying weighted mean difference and 95% confidence intervals for the impact of curcumin on plasma TNF-αconcentrations. Lower plot shows leave-one-out sensitivity analysis. Leave-one-out sensitivity analysis showed that this effect size is robust and not sensitive to any single study(Fig. 2).Subgroup analysis for the studies administering bioavailability enhanced curcumin preparations (WMD: 5.33 pg/mL, 95% CI: 10.84, 0.019, p = 0.058) versus those administering unformulated curcumin (WMD: 3.84 pg/mL, 95% CI: 7.00, 0.683, p = 0.017) revealed a numerically larger effect size in favor of the former, though the difference was not of statistical significance (Fig. 3). Fig. 3 Download high-res image (538KB)Download full-size image Fig. 3. Forest plot displaying weighted mean difference and 95% confidence intervals for the impact of bioavailability-enhanced (upper plot) and unformulated (lower plot) curcumin preparations on plasma TNF-α concentration. 3.5. Meta-regression Random-effects meta-regression was performed to evaluate if changes in plasma TNF-α concentrations are dependent to dose and duration of treatment. Meta-regression analysis did not suggest any significant association between the plasma TNF-α-lowering effects of curcumin with either dose (slope: 0.005; 95% CI: 0.02, 0.01; p = 0.336) or duration (slope: 0.197; 95% CI: 1.73, 2.12; p = 0.841) of treatment (Fig. 4). Fig. 4 Download high-res image (487KB)Download full-size image Fig. 4. Meta-regression plots of the association between mean changes in plasma TNF-α concentrations with dose (upper plot) and duration (lower plot) of curcumin supplementation. The size of each circle is inversely proportional to the size of the respective study. 3.6. Publication bias The funnel plot of standard error versus effect size (mean difference) was slightly asymmetric but no potential publication bias requiring trim and fill correction was suggested (Fig. 5). Fig. 5 Download high-res image (180KB)Download full-size image Fig. 5. Funnel plot detailing publication bias in the studies reporting the impact of curcumin on plasma TNF-α concentrations. Consistently, the presence of publication bias was excluded by Eggers linear regression (intercept = 4.30, standard error = 2.43; 95% CI = 10.05, 1.46, t = 1.76, df = 7, two-tailed p = 0.121) and Beggs rank correlation(Kendalls Tau with continuity correction = 0.25, z = 0.94, two-tailed p-value = 0.348) tests. The fail-safe N test showed that 492 studies would be needed to bring the WMD down to a non-significant (p > 0.05) value. 4. Discussion Results of the present systematic review and meta-analysis of RCTs indicated that curcumin could significantly reduce plasma TNF-α concentration. Furthermore, curcumin formulations with improved bioavailability exhibited better activity as compared to unformulated preparations. The blockers of TNF-α such as infliximab, adalimumab and etanercept have been approved by the United States Food and Drug Administration for inflammatory chronic diseases. However, one of the major problems with most of these TNF-α blockers is that they produce numerous side effects in humans. Some of these adverse effects are development of liver injury, lymphoma, leukopenia, neutropenia, thrombocytopenia, and pancytopenia . In addition, these blockers are highly expensive. Thus, alternatives that are safe, affordable and effective are needed. Based on the present results, curcumin may serve as an inexpensive, orally bioavailable and safe polyphenol that can effectively reduce TNF-α level in humans. Originally discovered as an anticancer agent, TNF-α is now linked with an array of pathophysiological conditions, including cancer, neurologic diseases, cardiovascular diseases, pulmonary diseases, autoimmune diseases, and metabolic diseases. Our analysis from 8 RCTs comprising nine treatments indicated that curcumin can significantly reduce serum/plasma concentrations of TNF-α in patients with depression , solid tumor , osteoarthritis , pulmonary complications , end-stage renal disease  and metabolic syndrome (unpublished). Although the exact mechanism of modulation of TNF-α production by curcumin is unclear, there are several possibilities by which this polyphenol can regulate TNF-α production as reported by in vitro and animal studies. Curcumin is a pleiotropic molecule and has been reported to modulate TNF-α-associated inflammatory pathways. One of the important pathways by which curcumin can modulate TNF-α production is through negative regulation of pro-inflammatory transcription factors, NF-kB, activator protein-1, and STAT proteins . NF-kB could be also activated by the modulating effect of curcumin on protein kinases, epidermal growth factor receptor, activity of extracellular signal-regulated kinase 1/2, and PI-3-K/AKT pathway [33,34]. Curcumin has also been shown to influence or even interrupt the signal transduction between TNF-α and its receptor via direct binding, and may thereby suppress inflammation induced by this cytokine . Both non-covalent and covalent interactions were found to contribute to the direct interaction between curcumin and TNF-α . One of the major limitations of curcumin use in humans is its limited bioavailability which appears primarily due to low oral absorption, rapid metabolism, and rapid systemic elimination . Several strategies including use of nanoparticles , liposomes , micelles , structural analogues [41,42], co-administration with piperine  and complexation with phosphatidylcholine, has been employed to enhance the bioavailability of curcumin. While co-administration of curcumin with piperine is associated with an increased risk of drug interactions, phosphatidylcholine does not introduce risk of drug interactions but enhances the bioavailability via preserving from hydrolytic degradation and increasing intestinal absorption [45,46]. Our analysis indicated that the efficacy of bioavailability-boosted curcumin formulations in reducing circulating TNF-α concentration was higher in comparison to non-formulated curcumin. Several factors may contribute to the improved efficacy of formulated curcumin. For example, Panahi and colleagues examined the efficacy of phosphatidylcholine formulations of curcumin (Meriva®) in patients with solid tumors and found that almost all parameters evaluated in their study including TNF-α were significantly suppressed(6). These observations are further supported from a previous study where absorption of curcuminoids with Meriva® was found to be about 30 folds higher compared with unformulated curcuminoids . Some limitations of the present meta-analysis deserve acknowledgment. First, included studies recruited relatively few subjects and thus further confirmatory evidence from large-scale trials is required. Second, assessment of TNF-α was not among the primary objectives of the included studies, suggesting the need for further studies exclusively performed in populations with elevated baseline levels of this cytokine. Third, included studies were performed in populations with different pathophysiological characteristics, thus increasing the inter-study heterogeneity. Nevertheless, we tried to minimize heterogeneity by applying a random-effects model of analysis and performing subgroup and meta-regression analyses. However, all these limitations, added to the fact that curcumin formulation with presumed different bioavailability have been tested in the different trial could partly explain why we did not observed a clear direct dose-effect nor duration-effect relationship. 5. Conclusion Our analysis indicated a promising impact of curcumin on circulating TNF-α concentration. However, lowering of TNF-α concentrations was independent of curcumin dose and duration of treatment. Our finding is consistent with previous studies that have demonstrated the efficacy of curcumin against several TNF-α-associated diseases . To our knowledge, this is the first meta-analysis demonstrating the beneficial effects of this polyphenol on TNF-α in humans. The most of the currently available TNF-α blockers have a low tolerability, while they are very expensive, thus curcumin could be an interesting therapeutic tool for a large number of TNF-α-associated diseases. 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Life Sciences Volume 148, 1 March 2016, Pages 183-193 Life Sciences Review article ☆ Author links open overlay panelVibhaRaniaGaganDeepbRakesh K.SinghcKomaraiahPalledUmesh C.S.Yadave a Department of Biotechnology, JayPee Institute of Information Technology, A-10, Sector-62, Noida 201 307, UP, India b Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd, Aurora, CO 80045, USA c Translational Science Laboratory, College of Medicine, Florida State University, 1115 West Call St., Tallahassee, FL 32306-4300, USA d Department of Oncologic Sciences, USA Mitchell Cancer Institute, 1660 Spring Hill Avenue, Mobile, AL 36604, USA e Metabolic Disorder & Inflammatory Pathologies Laboratory, School of Life Sciences, Central University of Gujarat, Gandhinagar 382030, India Received 20 November 2015, Revised 15 January 2016, Accepted 2 February 2016, Available online 3 February 2016. crossmark-logo https://doi.org/10.1016/j.lfs.2016.02.002 Get rights and content Abstract Increased body weight and metabolic disorder including insulin resistance, type 2 diabetes and cardiovascular complications together constitute metabolic syndrome. The pathogenesis of metabolic syndrome involves multitude of factors. A number of studies however indicate, with some conformity, that oxidative stress along with chronic inflammatory condition pave the way for the development of metabolic diseases. Oxidative stress, a state of lost balance between the oxidative and anti-oxidative systems of the cells and tissues, results in the over production of oxidative free radicals and reactive oxygen species (ROS). Excessive ROS generated could attack the cellular proteins, lipids and nucleic acids leading to cellular dysfunction including loss of energy metabolism, altered cell signalling and cell cycle control, genetic mutations, altered cellular transport mechanisms and overall decreased biological activity, immune activation and inflammation. In addition, nutritional stress such as that caused by high fat high carbohydrate diet also promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation, and decreased antioxidant system and reduced glutathione (GSH) levels. These changes lead to initiation of pathogenic milieu and development of several chronic diseases. Studies suggest that in obese person oxidative stress and chronic inflammation are the important underlying factors that lead to development of pathologies such as carcinogenesis, obesity, diabetes, and cardiovascular diseases through altered cellular and nuclear mechanisms, including impaired DNA damage repair and cell cycle regulation. Here we discuss the aspects of metabolic disorders-induced oxidative stress in major pathological conditions and strategies for their prevention and therapy. Graphical abstract Unlabelled figure Download high-res image (197KB)Download full-size image Keywords Oxidative stress Antioxidant Metabolic disorders Inflammation Diabetes Cardiovascular diseases Insulin resistance Carcinogenesis Phytochemicals 1. Introduction Disruption of normal metabolic processes resulting in energy and redox imbalance sets the seed of many pathophysiological conditions in body which are collectively called metabolic disorders. The key hallmarks of metabolic disorder include risk factors such as dyslipidaemia, leptin resistance, reduced adiponectin, insulin refractoriness, defective insulin secretion, glucose intolerance which collectively referred to as metabolic syndrome . According to National heart, lung and blood institute an individual must have at least three risk factors to be diagnosed with metabolic syndrome . These risk factors contribute to cellular dysfunction and redox imbalance that contribute towards progression of pro-oxidative environment leading to damaged biomolecules, which are highly reactive in nature and can promote cell and tissue dysfunction leading to metabolic diseases. A clear correlation has emerged between oxidative stress and metabolic disorders which can be helpful in the identification of novel biomarkers, molecular targets, and effective drug development for prevention and therapy of these diseases. Metabolic disorder, emanating from elevated body weight and obesity, has reached epidemic proportions in industrialized countries. According to World Health Organisation (WHO) in 2014, more than 1.9 billion adults, which included 18 years and older, were overweight. Of these more than 600 million were obese . According to a systematic analysis for the Global Burden of disease study in 2013, the USA led the list of countries with maximum obese persons followed by China and India, respectively . The prevailing oxidative and inflammatory conditions constitute major risk factors for the development of a number of pathologies such as tumour development, diabetes and cardiovascular complications. Obese people have relatively enhanced risk of developing colon cancer, gastric cardia, oesophageal adenocarcinoma and cholangiocarcinoma , whereas diabetes is reported to predict mortality from cancer of the colon, pancreas, female breast, male liver and bladder . Furthermore, a high BMI could lead to increased risk of developing non-Hodgkins lymphoma and multiple myeloma in gender independent manner . Although a clear mechanism is not available, however, increased oxidative stress in obesity and metabolic syndrome has been linked with DNA damage and subsequent malignancies . A positive correlation between serum 8-hydroxy 2′-deoxy-guanosine (8-OHdG) and increased body mass index has been shown which suggests that oxidative DNA damage may be caused due to obesity condition . DNA damage can alter regulation of cell cycle along with other cellular process including transcription, signal transduction pathways, replication mismatch, DNA damage repair and resultant genomic instability, which may eventually lead to tumorigenesis . Furthermore, reactive oxygen species (ROS) generated during metabolic disorder can cause increased inflammatory condition in body by upregulating redox signalling pathways, altered gene expression of inflammatory cytokines, chemokines and growth factors resulting in the development of pathologies such as insulin resistance, diabetes and cardiovascular damage . The preceding evidences suggest that metabolic disorder and obesity have myriads of effect on cellular physiology and affect the body negatively leading to development of pathological conditions. Since ROS and oxidative stress have been implicated in several cellular signalling and pathological conditions, in the present review we have particularly focused on how metabolic disorder creates redox imbalance that lead to complications such as carcinogenesis, diabetes, and cardiovascular diseases and how understanding the mechanisms may be helpful in developing potential preventive and therapeutic strategies. 2. Oxidative stress in metabolic disorders Oxidative stress is mainly defined as a disparity in the production and degradation of ROS. Available evidences indicate that elevated systemic oxidative stress is closely associated with metabolic syndrome [11, 12]. A positive correlation has been established between presence of oxidative stress and increased low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) in the animal models. Several mechanisms have been proposed that elevate the oxidative stress in metabolic disorder. One of these mechanisms is dysfunctional high-density lipoprotein (HDL)-enabled antioxidant mechanism which may result from decreased HDL levels in metabolic disorders . The sub-fraction of small HDL particle are known to play protective role but have been found with low antioxidant activity in metabolic syndrome . The anti-oxidant activity of dense HDL sub-fractions has been found impaired and associated with elevated oxidative stress and insulin resistance in metabolic syndrome. Presence of oxidative stress markers in plasma correlates inversely with low levels of HDL while lipid peroxidation products correlate with low HDL in metabolic syndrome [14, 15]. Oxidative process may modify LDL into oxidized-LDL (oxLDL) due to prevalent oxidative condition during metabolic disorder such as glycoxidation, ROS, reactive nitrogen species (RNS), and activation of various oxidases and oxygenases along with decreased activity of cellular antioxidant system. Further, LDL oxidation may also become highly likely due to changes in the distribution of smaller and denser LDL particles. Studies have also shown increased levels of oxLDL in the blood circulation in patients with metabolic syndrome, which indicates increased risk for atherosclerosis and myocardial infarction as well as increased oxidative stress in these patients . Furthermore, increased lipid peroxidation, carbonylation of cellular proteins and NADPH oxidase activity as well as decreased levels of GSH can occur in metabolic syndrome leading to enhanced ROS formation . In fact, in metabolic syndrome patients, elevated levels of oxLDL correlate well with low HDL and oxidative stress, and pose increased risk for developing pathological conditions . Mitochondria are also an important source of ROS. The respiratory circuit in mitochondria comprising of the four complexes which work as electron transport chain (ETC) can become dysfunction resulting in leakage. According to an estimate up to 2% oxygen consumed can be diverted to the production of ROS formation by mitochondria, especially at complexes I and III . High energy diet, which is one of the risk factor for metabolic disorders, could lead to increased metabolic load of the mitochondria resulting in over active ETC that can form excessive ROS as by-products. The ROS produced in the mitochondria also contribute to mitochondrial damage which affect the cellular redox signalling on the one hand while on the other hand they cause a range on pathologies that comprise metabolic disorders  indicating that mitochondria can be an important target in such pathologies. The secretion of 8-epiprostaglandin F2a in urine of people with high BMI indicates strong association of metabolic disorder with systemic oxidative stress . Further, generation of adipocytokines such as tumour necrosis factor-alpha (TNF-α), free fatty acids, angiotensin and leukotrienes can also be linked with oxidative stress and inflammatory condition [22, 23]. The production of free radicals during metabolic disorder can also be attributed to redox imbalance and decreased potency of free radical scavenging system. Cu–Zn superoxide dismutase (SOD) is downregulated along with other antioxidant system in body such as catalase and glutathione peroxidase (GPx) . A number of studies have also demonstrated strong correlation between NADPH oxidase (NOX) activity and increased oxidative stress in metabolic syndrome . Further, animal models of obesity, both diet-induced and genetic, have shown overexpression of NOX subunits e.g. high fat diet-fed rats showed increased expression of NOX2 and p47phox. Similarly, NOX2, p22phox, p47phox and p67phox subunits are up-regulated in the genetic model of obese mouse had NOX subunits overexpressed in heart tissue . Furthermore, systemic up-regulation of NOX in diet-induced obesity in rats has been linked with adiponectin . Increased activity of NOX in metabolic syndrome leads to excessive production of superoxide ions (O2−) in obese, which may react with nitric oxide (NO) and form RNS such as peroxynitrite, nitroxyl anion, nitrosonium cation, nitrogen oxides and s-nitrosothiols . These species have the ability to post-translationally change the biomolecular targets such as lipids, proteins, DNA and low molecular weight antioxidants. Further, peroxynitrite may react with other ROS and form an array of different types of RNS and cause nitrosative stress resulting in cellular and organ damage. Consequently, the altered NO bioactivity may lead to the development of endothelial dysfunction and cardiovascular complications in obese . Superoxide anions may also cause oxidative changes to cellular proteins by nitrosylation of tyrosine residues, an important marker of cardiovascular problem, and render them dysfunctional . The mechanisms of ROS and RNS formation during metabolic disorder and their cellular impact have been summarised in Fig. 1. Schematic diagram showing sources of ROS/RNS in metabolic disorder leading to… Download high-res image (272KB)Download full-size image Fig. 1. Schematic diagram showing sources of ROS/RNS in metabolic disorder leading to macro-biomolecular damage and subsequently to the various related diseases. Enzymes in green boxes show antioxidative system in the cells. Abbreviations have been explained in text. 3. Oxidative stress in metabolic disorder leading to Carcinogenesis Obesity and metabolic disorder have been identified as a major risk factor associated with cancer. Individuals with high BMI are at risk of developing several types of cancer including endometrial, colorectal, and ovarian and breast cancers [28–30]. The incidence of cancer due to obesity is estimated to be approximately 20% of all causes of cancers . The development of cancer in obese population is associated with the redox alteration caused by adipokines such as leptins, adiponectin, vascular endothelial growth factor (VEGF), TNF-α and interleukin (IL)-6 . Several studies have shown that obesity enhances oxidative stress by increasing the concentration of ROS, which is one of the major contributor to cancer development [11, 32]. The persistent oxidative stress in cancer cells is due to several factors including activation of oncogenes (Ras2, c-Myc, and Bcr-Abl), inactivation of antioxidant enzymes, inflammation, activation of NOX system as well as by-products of cellular metabolism [33, 34]. Cancer growth and progression has been associated with the disrupted redox balance that impacts several signalling pathways associated with cell proliferation, apoptosis, invasiveness, drug-resistance and energy metabolism [33–35]. Inhibition of adenosine nucleotide translocator (ANT) by intracellular triglycerides leads to the accumulation of ATP within mitochondria and that lowers the oxidative phosphorylation due to decreased levels of ADP. This uncoupling effect results in the leakage of electrons and partial reduction of molecular oxygen in form of superoxide ions . The accumulated level of ROS may contribute to tumour development either by acting as signalling molecule or promoting the mutation of genomic DNA. ROS can also promote tumour growth by activating redox sensitive kinases such as mitogen activated protein kinase (MAPK), extracellular-signal regulated kinases (ERKs), by phosphorylation, or by increasing the expression of cyclin D1 and activation of c-JUN which are instrumental in growth and survival of cancer cells [37, 38]. One of the main mechanisms by which oxidative stress manifests its damaging effects is by causing genomic instability. ROS are known to induce DNA damage by causing base/nucleotide damages as well as DNA strand breaks. The species of 8-hydroxylated guanine such as 8-oxoguanine (8-oxoG) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG), products of oxidized guanine lesions, are primarily induced by ROS which has been shown to play important role in tumour development [9, 39]. These modified guanines can pair with both adenine and cytosine bases and therefore can cause transversion mutations such as G:C to T:A (Fig. 2). The increase of the mutagenic base 8-oxo-dG may enhance the mutational rate of cells and/or interfere with DNA repair mechanism which eventually characterizes tumour development . Interestingly, tumours under oxidative stress have been shown to exhibit up to 10-fold increase in 8-oxoG levels compared to neighbouring normal cells . Schematic diagram showing ROS-induce DNA damage (base/nucleotide damages, DNA… Download high-res image (100KB)Download full-size image Fig. 2. Schematic diagram showing ROS-induce DNA damage (base/nucleotide damages, DNA strand break) by formation of oxidized guanine lesions 8-hydroxylated guanine species such as 8-oxoguanine (8-oxoG) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG). ------ indicates nascent strand; ------- indicates template strand. Genome integrity can also be altered by epigenetic changes. The most important and widely studied epigenetic modification is DNA methylation at cytosine residues. The reaction is catalysed by DNA methyltransferases, which uses S-adenosyl methionine (SAM) as the methyl group donor leading to formation of 5-methyl cytosine . Several diabetes-related genes such as IL2RA, PPARGC1A, GLP1R, PDX-1 and CTGF are regulated by DNA methylation [43–46]. In recent years, a number of studies have shown that obesity can alter DNA methylation, however the mechanistic details are still sketchy. Besides DNA modification, histone modifications are also known to play critical role in genome maintenance and carcinogenesis [47, 48]. Histone methylation and acetylation, catalysed by histone methyl transferases and histone acetyl transferases enzymes, respectively, are primary modulators of gene expression. Role of ROS in histone modification and subsequent effect on cell survival has been demonstrated . Another study has shown a novel nucleophilic mechanism of ROS-dependent epigenetic changes in cancer cells where enhanced DNA methylation caused the silencing of tumour suppressor and antioxidant genes and enhanced the proliferation of cancer cells under oxidative stress conditions . The tumour suppressor protein p53, considered the guardian of the genome, has been shown to over express in adipocytes of ob/ob mice and negatively regulate fat accumulation in adipocytes by transcriptional regulation of lipogenic enzymes . Further, p53 overexpressing transgenic mice showed decreased body mass and reduced adipose deposition . This negative correlation between p53 expression and adipogenesis may be linked with altered metabolism suitable to develop cancer e.g. lack of p53 may lead to excessive fat accumulation leading to obesity and subsequently development of cancer. The p53 protein has been shown to regulate oxidative phosphorylation as well as glycolysis, which may be related to its ability to suppress tumorigenesis . It has been observed that p53-deficient cells metabolism shifts from oxidative phosphorylation towards glycolysis, a hallmark of cancer cells . Such alteration may serve dual purpose of increasing the availability of acetyl-CoA for fatty acid synthesis which is required for fast dividing cancer cells and also contribute to the accumulation of fat leading to obesity. However, this correlation merits detailed investigation. 4. Oxidative stress in metabolic disorder leading to obesity, diabetes and cardiovascular diseases A balanced metabolic system and cellular homeostasis are fundamental requirements for normal functioning of cells and maintaining fundamental attributes of life and health. Any dysregulation in the metabolism and nutrient sensing mechanism can lead to a cluster of metabolic disorders including obesity, type 2 diabetes and cardiovascular diseases. Diabetes and obesity are closely inter-related and frequently occur together in patients and result from poor metabolic conditions. Together, they are described as ‘diabesity’ and marked by concomitant increase in morbidity and mortality due to cardiovascular diseases (CVD) . Often both, diabetes and obesity, cause cellular dysfunction which is mainly associated with redox imbalance and an environment of oxidative stress. In such case where these two conditions coexist, it becomes difficult to understand which one activates which molecular pathway. Even though an overlap of the pathways occurs some common nodes in terms of mediators of oxidative stress also exist. Hence, understanding the mechanisms involved in the activation of these pathways and nodes could be helpful in unfolding the process how metabolic disorder leads to conditions such as obesity, diabetes and cardiovascular complications. 4.1. Oxidative stress in metabolic disorder leading to obesity Oxidative stress is a dual sword, it can be the trigger as well as the outcome of obesity. The outcome of a number of studies including epidemiological, animal and clinical studies suggest that obesity can be associated with redox alteration [56–58]. Various factors including high-fat high-carbohydrate diet and continuous hyper nutrition can cause increased oxidative stress through activation of intracellular pathways such as NOX, oxidative phosphorylation in mitochondria, glycoxidation, protein kinase C (PKC) and polyol pathway [59–62]. Indeed, evidences from in vitro and in vivo studies suggest that oxidative stress can cause obesity through proliferation of pre-adipocytes and increased size of differentiated adipocytes [63, 65]. Increased adipose tissue mass develops when terminally differentiated pre-adipocytes re-enter the cell cycle and undergoes proliferation, a process called adipogenesis. The two-step adipogenesis includes the proliferation of pre-adipocytes and their differentiation into mature adipocytes . ROS have been shown to be involved in both of these events. Murine 3T3-L1 cells and human pre-adipocytes when treated with H2O2 resulted in adipogenic differentiation in the absence of insulin . Further, ROS generated by NOX4 as well as mitochondria have been shown to induce adipocyte differentiation in adipose-derived stem cells [64, 67]. All such evidences clearly indicate that ROS-induced proliferative potential in pre-adipocytes plays important role in the development of metabolic disorders, which generate more ROS by various mechanisms including chronic adipocyte inflammation, fatty acid oxidation, over consumption of oxygen, accumulation of cellular damage, diet and mitochondrial activity [65–69]. Abnormal generation of ROS induces cellular dysregulation in many other tissue and promotes obesity. Increased cell cycle proliferation markers such as cyclin D1 and cyclin E are found to be increased during adipogenesis . In vitro modulation of cellular redox conditions by glutathione depletion induces rapid dephosphorylation of retinoblastoma protein (pRb), which in turn activates the transcription factor E2F , a critical regulator of the expression of cell proliferation genes, particularly those involved in progression through G1 and S-phase of cell cycle . E2F also regulates 3T3-L1 adipocyte differentiation in growth-arrested and post-confluent pre-adipocytes by forcing them to re-enter the cell cycle prior to terminal differentiation . Subsequent to the clonal expansion of adipocytes, cyclin dependent kinase inhibitor p21 and p27 are overexpressed in the cells which arrest the proliferation and facilitate the differentiation . ROS also regulate adipocyte differentiation in human mesenchymal stem cells (hMSCs) by activating peroxisome proliferator-activated receptor gamma (PPARγ), a downstream target of E2F . The antioxidant N-acetyl-l-cysteine (NAC), a well-known ROS quencher, significantly inhibits adipocyte differentiation. These evidences confirm the role of ROS-mediated oxidative stress signals in inducing adipogenesis by regulating the cell cycle that promotes obesity. Thus, obesity and oxidative stress appear to be connected to each other through mutual sustenance mechanisms. Obesity can cause systemic oxidative stress through NOX activation and ER stress in adipocytes besides creating a sustained chronic inflammatory condition through excessive ROS generation subsequent to high-fat high-carbohydrate diet and suppressed antioxidative system [75–77]. In fact, obesity appears to harbour both oxidative stress and inflammation even though it is difficult to precisely trace which one precedes the other . The redox sensitive transcription factors such as NF-kB and activator protein (AP)-1 get activated by the ROS and transcribes several proinflammatory cytokines, which may further increase the overproduction of ROS . It leads to a cyclical event which churns out many diseases such as insulin resistance, type 2 diabetes, atherosclerosis and cancer that collectively referred to as metabolic syndrome . 4.2. Oxidative stress in metabolic disorder leading to diabetes Diabetes is a group of a number of diseases which include increased blood glucose and diminished insulin sensitivity leading to the development of diabetic complications such as nephropathy, retinopathy, neuropathy, micro- or macro-vascular injuries. In most of the obese people diabetes develops due to insulin resistance and subsequent hyperinsulinemia as a compensatory mechanism. Oxidative stress has been linked with the development of insulin resistance and subsequent disruption of insulin signalling and adipocytokines . Increased ROS production in the liver and adipose tissue of high fat diet-fed mice has been linked with insulin resistance  which was reversed by the use of antioxidants . Strong correlation between obesity and insulin resistance could be through the mediator of oxidative stress derived from adipocytes including leptins and free fatty acids (FFA) [83, 84]. The elevated levels of FFA can cause mitochondrial dysfunction by activating uncouplers of oxidative phosphorylation in mitochondria . In the disruptive metabolic state that results from high energy diet leading to increased glucose, free fatty acid and insulin levels, there is further increase in ROS production through dysfunctional mitochondria as discussed above. Insulin resistance can cause incessant variations in compensatory responses of insulin secretion which results in impaired glucose tolerance. This can cause insulin activity inhibition and secretion to accelerate the onset of type 2 diabetes. In pre-diabetic condition, excessive insulin secretion leads to beta-cells death which is also augmented due to prevailing redox imbalance as pancreatic β-cells lack major antioxidants against oxidative stress . This results in ROS-induced β-cell dysfunction, defective proliferation and growth, leading to type-2 diabetes [87, 88]. The altered secretion of adipokines in obesity also leads to beta-cell loss . Excessive ROS generated in obese also induce proliferative arrest of pancreatic beta (β)-cells resulting in diabetes. Besides having short cell cycle duration, most of the β-cells do not have the ability to re-enter the cell cycle. ROS plays an important role in dysregulation of pancreatic β-cell proliferation by altering the cell cycle regulators and thus contribute to the development and progression of diabetes  (Fig. 3). Genomic analysis of insulin resistant cellular models showed that increased ROS causes insulin resistance while ROS scavengers prevent it. Also, it showed 2- to 5-fold decrease in the proteins responsible for G0/G1 switch that is believed to regulate quiescent cell transition into the proliferative cycle . This is directly associated with decreased CDK1 and cyclin B1 mRNA levels in these cells, which are responsible for G1/S and G2/M transitions, respectively . Other proteins associated with defective β-cell proliferation are CDK4, cyclin D1 and cyclin D2, which are important for G1/S progression. Adenovirus expression of CDK4 and cyclin D1 resulted in enhanced pRb phosphorylation and increased proliferation of β-cells . On the other hand, CDK4 knockout mice, fertile but smaller in size, developed insulin-deficient diabetes due to the reduction in β-cell mass. Mice expressing mutant CDK4 displayed pancreatic hyperplasia due to non-binding of the cell-cycle inhibitor P16INK4a (G1 arrest) leading to abnormal proliferation of β-cells . These data indicate that alteration in the levels of cell cycle components could affect the maintenance of β-cell mass in basal states as well as their adaptation to pathological states resulting in diabetes . Thus, ROS induce the pathogenesis of metabolic disorders by regulating the cell cycle machinery. ROS-induced abnormal activation of cyclin-dependent kinase (CDK) inhibitors… Download high-res image (287KB)Download full-size image Fig. 3. ROS-induced abnormal activation of cyclin-dependent kinase (CDK) inhibitors causes cell cycle arrest in pancreatic β-cells resulting in diabetes. ROS induce the activation of cell cycle inhibitors such as p16 and p27, which inhibit the activity of cyclins D, A and B, respectively. Inhibition of these cyclins and CDKs blocks the cells from dividing and sometimes induces cell death in β-cells of pancreas that may result in diabetes. Diabetes also involves changes in cell cycle regulation during altered redox state in body. The primary source of oxidative stress during diabetes is hyperglycaemia and glucotoxicity [95, 96]. Diabetes-induced ROS are known to cause overexpression of CDK inhibitor p27, whereas cyclin D1 and D2 were repressed [97, 98]. Additionally, diabetes-induced inflammation and elevated ROS are also known to induce FOXO transcription factors, which in turn alter the expression of certain proteins important for cell cycle regulation, especially those involved in G1/S transition [99, 100]. 4.3. Oxidative stress in metabolic disorder leading to associated cardiovascular diseases Cardiovascular diseases, major health issue across the world, are also associated with metabolic disorder as it is frequently a consequence of dyslipidaemia and diabetes. Metabolic disorder contributes majorly towards progression of pro-oxidative environment . Increased cardiac lipid accumulation and altered substrate metabolism in obesity is known to alter the hemodynamic load and cause cardiovascular complications. For example decreased systolic function has been shown to be associated with enhanced myocardial triacylglycerol deposition and concentric left ventricular hypertrophy . Further, various chemical mediators including plasminogen activator inhibitor-1 (PAI-1), cholesteryl ester transport protein, retinal binding protein, acylation stimulating protein, lipoprotein lipase, oestrogen and insulin growth factor-1 (IGF-1) are also implicated in cardiovascular abnormalities. In addition, adipose-derived factors and adipocytokines such as leptin, adiponectin, resistin and fatty acid binding protein 4 (FABP4) can directly affect cardiac structure and function . Adiponectin, a white and brown adipose tissue-derived cytokine, plays a central role in metabolic disorders leading to cardiac failure . Levels of Adiponectin are inversely correlated with BMI in adults such that people with obesity and/or diabetes have low levels of adiponectin which contribute to higher LDL and lower HDL levels. In obesity, similar correlation exist between adiponectin and inflammatory cytokines such as TNF-α and IL-6, which also contribute to higher LDL levels and lower HDL levels. Inflammatory conditions also persist during insulin resistance and Type-2 diabetes which increases the C-reactive protein (CRP) and ROS levels and trigger endothelial dysfunction, a well-established response to cardiovascular risk factors. These changes increase the levels of ICAM-1 and VCAM-1 that further bind LDL molecules to the blood vessel walls leading to increased monocytes chemo-attraction and elevate the risk of CVD . Low levels of adiponectin also promote left ventricular hypertrophy especially in patients with diabetes and obesity . Cardiac hypertrophy occurs as a compensatory response to the stress where cardiac myocytes get enlarged in order to increase their work output. This results in increased protein synthesis, addition of sarcomeres, activation of early response genes, such as c-jun, c-fos and c-myc and re-expression of the foetal genes such as atrial natriuretic factor (ANF), beta-myosin heavy chain (β-MHC), skeletal alpha actin and GATA-1 [106, 107]. In hypertrophic conditions various signalling pathways such as tyrosine kinase Src, GTP-binding protein Ras, PKC, MAPK, ERKs and phosphoinositol 3-kinase (PI3K) are activated. These changes initially help to combat the increased workload, however, prolonged hypertrophy leads to cardiac cell death and ultimately to heart failure . Thus, a close relationship between adiponectin in diabetes and obesity is well documented risk marker of CVDs (Fig. 4). Schematic representation of mechanism of association of metabolic disorder with… Download high-res image (414KB)Download full-size image Fig. 4. Schematic representation of mechanism of association of metabolic disorder with obesity, diabetes and cardiovascular diseases. Oxidative stress, decreased adiponectin, increased inflammatory markers and insulin refractoriness characterize metabolic syndrome. Diabetes and obesity trigger the hypertrophic responses by activation of early response genes, such as c-jun, c-fos and c-myc and re-expression of the foetal genes such as Atrial natriuretic factor (ANF), beta-myosin heavy chain (β-MHC), and GATA-1. Insulin resistance contributes to overproduction of ROS, pro-inflammatory cytokines (TNF-α, IL-6), subsequent endothelial dysfunction and increased levels of ICAM-1 and VCAM-1, which further lead to cardiovascular diseases, including cardiac hypertrophy. Several other signalling pathways such as GTP-binding protein Ras, MAPK, ERK are also involved in hypertrophic condition. Prolonged hypertrophy leads to activation of various apoptotic pathways inducing cardiac cell death which eventually lead to cardiac failure. Metabolic disorder can also induce endoplasmic reticulum stress, which may disturb the equilibrium of free radical productions and antioxidant capability leading to cardiac stress. Glycoxidative stress has been suggested to be the unifying link between various molecular disorders . Diabetes and obesity increase glycoxidation leading to changed enzymatic activities, altered binding of ligands to their receptors and modified protein functionality and immunogenicity. Hyperglycaemia-induced oxidative stress results in accumulation of advanced glycation end products (AGEs), which further cause cellular damage . The AGEs are formed by a non-enzymatic reaction between amino groups of proteins, lipids and nucleic acids and reducing sugars contribute to the aging of macromolecules, leading to the pathological conditions. AGEs can also act directly to induce cross-linking of proteins such as collagen to promote vascular stiffness and thus alter extracellular matrix, vascular structure and function . High glucose induces activity of endothelial nitric oxide synthase (eNOS) and NOX leading to over production of NO and ROS, respectively which may cause nitrosative stress-mediated vascular endothelial cell dysfunction . NO is believed to be a major player in endothelial dysfunction that influences vascular homeostasis and contributes towards development of vascular complications such as atherosclerosis . Further, highly reactive molecules ROS and RNS have been identified as major mediators of endothelial dysfunction in diabetes leading to abnormal cardiovascular events . Also, high glucose-induced oxidative stress promotes inflammatory condition by modulating the expression of various cytokines such as TNF-α, IL-6, IL-1β, and IL-18 which further act as autocrine/paracrine agonists and trigger hypertrophy-mediated myocardial remodelling leading to cardiovascular diseases [115, 116], which establishes the fact that there is a close association between metabolic disorders and oxidative stress which instigates mechanisms of cardiac insult. Functional significance of the oxidative modifications during metabolic disorder is availability of a number of potential biological markers of CVDs including lipid peroxidation products, oxidative protein modification products, enzymatic biomarkers, oxLDL, phospholipids and changes in genetic expression of ROS-sensitive genes . Abnormal increase in ROS also promotes vascular smooth muscle cells (VSMCs) proliferation resulting in cardiovascular diseases . The association between ROS and cardiovascular pathologies such as atherosclerosis is well documented and summarised in Fig. 5. Studies have demonstrated that ROS induces mutagenic signals and proliferation of VSMCs. For example, H2O2 exposure stimulated growth, DNA synthesis and the expression of proto-oncogenes c-Myc and c-Fos in VSMCs [119, 120]. The ROS-induced increase in the proliferation of VSMCs also correlated with the activation of MAPK through ERK activation  and cyclin D1 up regulation . ROS-induced cell cycle entry is mostly regulated by cell cycle regulatory protein cyclin D1, which plays a primary role in allowing G0 phase cells to enter into G1 phase . Further, redox factor-1 (Ref-1/APE), a DNA base excision repair and redox regulation enzyme, has been implicated in regulation of platelet-derived growth factor (PDGF)-stimulated cell cycle progression from G0/G1 phase to S phase in VSMCs . ROS-induced abnormal cell cycle initiation and proliferation of adipocytes and… Download high-res image (257KB)Download full-size image Fig. 5. ROS-induced abnormal cell cycle initiation and proliferation of adipocytes and VSMCs results in obesity and cardiovascular diseases, respectively. ROS-induced mitogenic activation of cyclin D allows the resting adipocytes and VSMCs to enter into the cell cycle. In addition, ROS also regulates cyclins E and A, and transcription factors E2F and c-Myc which promote the cell cycle initiated cells to progress through the complete cell cycle smoothly until it divides. Dysregulated activation of adipocytes or VSMCs by ROS modulates the cell cycle regulatory proteins that result in the development of obesity or cardiovascular diseases, respectively. Ezetimibe, a lipid lowering agent, abrogated VSMCs proliferation by abolishing cyclin D1, CDK2, pRb, and E2F protein expressions and caused cell cycle arrest at the G0/G1 phase. Ezetimibe also abolished increase in phospho-ERK1/2 and nuclear accumulation of ERK1/2, which repressed MAPK Pathway in VSMCs halting its growth . Similarly, scoparone, a hypolipidaemic and an antioxidant drug molecule, abrogated VSMCs proliferation by decreasing the expression of cyclin D1 via inhibiting the activity of transcription factor STAT3 . Further, treatment of VSMCs with butyrate, a histone deacetylase inhibitor, upregulated glutathione peroxidase, a family of antioxidant enzymes, and arrested its proliferation . These studies clearly indicate important roles for ROS in dysregulation of cell cycle in VSMCs and development of cardiovascular diseases, and further establish that strong relationship between the metabolic disorder-induced oxidative stress and incidence as well as severity of CVD is a possible unifying factor in the progression of CVD. 5. Therapeutic strategies to overcome oxidative stress induced metabolic abnormalities The best strategies to get rid of unhealthy oxidative stress are to restore the body's redox balance. The goal may include to restore healthy BMI by physical activity and consuming low-fat low-carbohydrate diet containing a plenty of antioxidants. A clinical study has shown that cardiovascular risk associated with obesity can be improved through weight reduction which subsequently decreases markers of oxidative stress and increased antioxidant system . The diet regimen containing natural fruits, green vegetables, whole grains, legumes, fish, olive oil, and probiotics which are rich in monounsaturated fatty acids (MUFA) and Ω-3 polyunsaturated fatty acids (Ω-3 PUFA), vitamin C, vitamin E and phytochemicals, help in good weight management and decrease the chances of developing metabolic diseases [129–131] through a number of potential mechanisms including cell signalling, altered gene expression, and decreased oxidative stress, inflammatory molecules and lipid accumulation [132, 133]. However, in human clinical studies use of purified individual nutritional molecule has not been successful and failed to reverse obesity or related pathologies [134, 135]. Therefore, treatment with multiple natural product combinations may result in a synergistic activity which may increase their bioavailability and act on multiple molecular targets, may offer advantages over pure chemical formulation . Physical activity and exercise improve antioxidant system of the body which helps manage the oxidative stress by scavenging harmful free radicals and modifies cell-signalling pathways which activate detoxification enzymes, ameliorate inflammation, preserve normal cell cycle, inhibit proliferation, induce apoptosis and inhibit tumour invasion and angiogenesis [137, 138]. Oxidative and anti-oxidative regimes may successfully suppress carcinogenesis. Cancer cells seem to depend more on the redox-buffering system for the maintenance of redox homeostasis as compared to normal cells. This has been exploited to target cancer cells via further increasing the cellular ROS level and oxidative stress to intolerable level resulting in their death . Grape seed extract has been shown to target mitochondrial electron transport chain complex III, inhibit the glycolytic and oxidative phosphorylation rate, and induce strong oxidative and metabolic stress in head and neck squamous cancer cells leading to autophagy and apoptotic death . Similarly, novel combination strategies have been adopted that include targeting glycolysis (via targeting PKM2 or pyruvate dehydrogenase kinase) and promoting oxidative phosphorylation, resulting in higher oxidative stress in cancer cells . Rysman et al.  showed that targeting the de novo lipogenesis in prostate cancer cells by soraphen A (an inhibitor of acetyl Co-carboxylase) can result in an increased level of polyunsaturated fatty acids, strong oxidative stress, and cancer cells could be further sensitized to chemotherapeutic drugs . Overall, oxidative stress is an integral component of carcinogenesis as well as cancer cell metabolism, and offers unique therapeutic opportunities. The prevention strategy in obesity-associated colon cancer has been suggested to use phytochemicals such as green tea component epigallocatechin-3 gallate and turmeric component curcumin, which have been demonstrated to decrease obesity-associated polyp formation in animal models by inhibiting PI3K/Akt and MAPK signal pathways . A series of epidemiological studies have also shown a decrease in cancer incidence among metformin-treated diabetic patients [144–146]. Metformin activates AMPK (AMP-activated protein kinase) pathway, a major sensor of cellular energy status that inhibits mTOR-mediated biosynthesis . A recent study suggested that use of metformin in pancreatic cancer stem cells (CSCs) which are dependent upon oxidative metabolism and limited metabolic plasticity can cause mitochondrial inhibition leading to energy crisis and induction of apoptosis of CSCs . Metformin is now being tested both in the laboratories and clinic for its effectiveness against several cancers including pancreatic cancer, breast cancer, prostate cancer, head and neck cancer [149–151]. The current strategies designed for therapeutics are to target either metabolic diseases or associated abnormalities. It is therefore imperative that targeting a common node such as redox imbalance between these multifactorial disorders could be beneficial in developing strategies for novel therapeutics. Based on animal studies, anti-oxidative therapies have been found effective in treatment [152, 153]. Besides assisting in treatment of such disorders, it is important to develop therapeutics which could prevent the progression of disease as such or at least block the progression from one clinical stage to the other. It is however a tough challenge to design such a therapeutic intervention with the meagre mechanistic information available that can link such disorders. Additionally, it becomes difficult to control events of adverse effects and toxicity which further delays the progress in this field. To take into account the increasing population of obese, diabetic and heart patients, there is an urgent need to develop safer and less toxic therapy for long-term relief. Considering the disadvantages associated with synthetic drugs, plant-based therapies are found to be less toxic and their marked effects in the prevention of oxidative stress have been well documented [152–154]. Recently, there is a growing interest in identifying natural source of antioxidants that have therapeutic role in global healthcare and in this context, anti-oxidant natural substances including herbal medicines may prevent these metabolic disorders. Herbal formulations have taken preference due to low cost and lesser side effects and also contain free radical-scavenging and reducing potential that protect cells against oxidative stress-induced anomalies and have multiple biological effects under varied stress conditions . Plants contain bioactive compounds known as phytochemicals that work along with essential nutrients and dietary fibre to protect against diseases . Such treatments help maintain glycaemic control, assist in healthy weight loss and improve insulin action, and therefore may be beneficial in metabolic syndrome associated pathologies and exert a positive effect on human health. 6. Conclusion and future prospects Life-style and diet-related chronic non-communicable diseases have already become a major burden on global health care. A multi-pronged strategy of dealing with this epidemic must be rapidly evolved and implemented to stem the rising tide of diseases of metabolic syndrome. Along with advocating the adoption of healthy life style, a massive influx of funding for research in the area of metabolic syndrome is the need of the hour. Since oxidative stress has emerged as a central player in chronic metabolic diseases such as diabetes, obesity, cancer and CVDs, it is imperative to explore the mechanisms that disrupt the normal equilibrium between oxidative and anti-oxidative processes. As discussed above excessive release of ROS and RNS (from endogenous as well as exogenous sources) leads to oxidation of all important macromolecules of life including lipid, proteins and nucleic acids. The persistent oxidative stress-induced DNA damage may not only lead to genomic instability but also activate transcription factors and induce expression of proto-oncogenes. It has further been shown that insulin's pro-tumorigenic potential is exhibited by excess generation of ROS, subsequently leading to DNA damage, genomic instability and consequently carcinogenesis. Further, the damaged macro-biomolecules disrupt the normal cellular physiology leading to metabolic disorders-related diseases. In order to prevent the development of or to clinically intervene in these health anomalies novel therapeutic strategies are being investigated including the use of plant-based natural anti-oxidative medicines. One of the emerging areas of research is the effect of oxidative stress and chronic inflammation on stem cells. The effect of ROS on stem cells is especially significant as it may disturb their ability to self-renew and replenish various types of body cells for the life span of the organism. It has been demonstrated that ROS production in cancer stem cells is dysregulated, which may present a therapeutic opportunity as the cancer stem cells are the most problematic to deal with in the current cancer therapy regimes and are responsible for relapse in many cases. In light of catastrophic consequences of oxidative stress and chronic inflammation in metabolic syndrome, it is imperative to identify molecular targets that may help re-establish the oxidative balance for a better health. Future research should focus to understand the disease mechanisms and to detect common targets to prevent or treat oxidative stress-induced pathologies in people with metabolic disorders. Conflict of interest All the authors declare that there is no conflict of interest regarding the publication of this paper. Acknowledgements Award of Ramanujan Fellowship from Department of Science and Technology (DST), Government of India SR/S2/RJN-102/2012 (UCSY); fund support from Department of Biotechnology (DBT), Government of IndiaBT/PR3978/17/766/2011 (VR) and Abraham A. Mitchell Cancer Research Scholar Endowment Grant (KP) are acknowledged. Assistance of Drs. Chinnadurai Mani and Neha Atale for assisting with preparation of the manuscript is also acknowledged. 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