Women in science, medicine, and global health: call for papers

Volume 390, No. 10111, p2423–2424, 2 December 2017 Comment lancet/article/PIIS0140-6736(17)32903-3/fulltext Jocalyn ClarkEmail the author Jocalyn Clark , Elizabeth Zuccala , Richard Horton Published: 02 December 2017 PlumX Metrics DOI: https://doi.org/10.1016/S0140-6736(17)32903-3 | s Women are rising. Recent reports of sexual harassment and assault of women by men in powerful positions have regalvanised solidarity around women's rights, and remind us that disadvantage, discrimination, and sexism are a regular part of the lived experience of many women. These reflect broader and unjustified inequalities between men and women that have persisted across time, culture, and geography. That disadvantages exist for women in science, medicine, and global health is thus unsurprising—and yet wholly unacceptable. The renewed visibility of women in these areas, such as the Twitter campaign #allmalepanel, offer hope for change. As part of this movement we are dedicating a special theme issue to women in science, medicine, and global health in late 2018 or early 2019. The reasons for shining light on women and inequalities are clear. Women earn less for the same types of work and are vastly under-represented in senior-level positions across occupational sectors.1 In science and medicine, the glass ceiling is still intact. According to a 2015 UNESCO report, for example, women undergraduates outnumber men but 72% of the global scientific workforce is male.2 In Europe, only 36% of mid-ranking professors and 18% of full professors were women in 2013,3 and just 13% of advanced grants went to women.4 In south Asia, a mere 17% of researchers are women2 and women in China comprise only 25% of the country's scientists and engineers.5 In health, where women make up most of the global workforce, they hold a small fraction of leadership positions.6 Just one of 18 global health organisations has gender parity on its governing board,7 and only two UN agencies have a female head.8 The situation is worse if taking into account the representation of women of colour or of women across ethnicity, class, sexuality, or other categories. Sadly, recent statistics affirm past trends of a leaky pipeline that show women's education and potential are being lost, at great cost to science and society: a waste of intellectual capital, lack of diversity in agenda setting, and the restriction of women's goals and rights.1, 9 This gender gap challenges the Sustainable Development Goal 5 to achieve gender equality and empower all women and girls by 2030. Poor career progression and low representation of senior women leaders in science, medicine, and global health are due to a combination of factors,2, 3, 6, 7, 8, 9, 10, 11, 12, 13 including penalties for motherhood, unconducive graduate research environments, lack of recognition, lack of support for leadership bids, fewer promotions and resources, and exclusion of women from the “old boys' club” cultures of science and medicine that nurture the fraternity, networking, and promotion of men. Women can also find it more difficult to travel for conferences and fieldwork.8, 14 A report on women scientists in Africa identified further barriers such as gender-based violence, higher rates of HIV and tuberculosis, and the burdens of unpaid work.14 Many solutions have been recommended including gender-positive imagery, mentoring, quotas on hiring and review committees, and anti-harassment and diversity training in workplaces. Better enabling maternity leave is a commonly advocated strategy but on its own does not disrupt the system imbued with gender bias: performance standards that require women to work harder than men to prove themselves, cultural norms that expect women to assume most domestic duties in addition to growing professional ones, and rigid expectations of masculinity that also constrain men's choices and contributions. These are not only women's issues—they require the full participation of everyone in deeper explanations and solutions. Gender bias is powerful and insidious. It is an expression of unequal distribution of power within societies and of the low value placed on women's work and contributions to public life. A host of evidence shows women are viewed as less competent and less valuable than men—from creativity to entrepreneurial skills to leadership—and these biases are exhibited by both male and female raters.11, 15 This bias can translate into discrimination in the workplace. In the UK, female doctors earn 40% less than their male counterparts.16 In the USA, 30% of women clinical researchers report experiencing sexual assault versus 4% of men.17 And despite achieving better patient outcomes, a recent analysis showed that female academic physicians were less likely to be full professors, received far less funding, and were paid less than men.12 Clearly, fundamental societal change is required alongside stronger institutional policies and commitments within the areas of science, medicine, and global health. What can a journal do? The Lancet prides itself on our focus on health equity, justice, and action. Here we commit to a specific project to uncover and highlight the representation, experience, and promotion of women in science, medicine, and global health. We call for papers reporting original research, analysis, and commentary to help create a set of transformative explanations and actions (panel). Panel How to submit your paper • Submissions to the women in science, medicine, and global health theme issue should be marked as such and submitted to The Lancet's electronic submission system. • The deadline is March 1, 2018. • All submissions will undergo normal peer review. We are assembling a group of advisers to assist with review of submissions and development of the theme issue. • We invite readers to join our Twitter Chat on Dec 5, 2017, at 1700 h GMT/1200 h EST to share your ideas on how we can make this theme issue most relevant, impactful, and action-oriented. Use #LancetWomen to join the conversation and post your questions. Our focus is on looking forwards. We are not interested in descriptive pieces that cover known ground or describe the problem, but instead papers that extend understandings and best practices for science, medicine, and global health. If we recognise gender bias as a root cause, for example, how can we create change? What interventions, programmes, and incentives work? How do broader issues of inclusivity, intersectionality, social justice, and cultural norms of masculinity and femininity influence the place of women and their advancement, and how can they be harnessed for change? What are the best ways for men to promote gender equity? We recognise relevant best practices can lie in areas such as business, government, and the social sciences, and we also welcome submissions that use the lens of critical and feminist theories to impart new understandings and practices for advancing all women in science, medicine, and global health. Appreciating the wealth of valuable work done to date, we must also recognise that the rate of change is too slow and, in many areas, has stalled. Therefore, above all, we encourage submissions proposing new explanations and solutions that are bold, creative, and disruptive. Although we acknowledge that some issues will be different across the sciences (including the life sciences), medicine (academic and clinical), and global health areas, we expect many to cross-cut. We also recognise that barriers and solutions manifest at many levels—individual, social, institutional, cultural—and hope to receive multidisciplinary work that explicates and interrogates how gender bias is embedded. Recognising that women's experiences are not universal and to broaden the conversation that has favoured the experience of white women and elite organisations, we explicitly seek work that shows the diversity of women's lives and experience, and explores how gender intersects with race, class, sexuality, disability, and other categories of disadvantage.18 Alongside issuing this call for papers, we assert our own commitment to examining the representation of women within the processes and practices of The Lancet, including women's inclusion in peer review and authorship, and the barriers preventing inclusion, building on previous work that shows gender bias in peer review and publishing.19, 20 The Lancet has a long-standing dedication to supporting work that contributes to the ability of women and girls around the world to live safer, healthier, and more empowered lives. We look forward to your submissions. We declare no competing interests. References UNFPA. Worlds apart: reproductive health and rights in an age of inequality. ((accessed Nov 15, 2017).) http://www.unfpa.org/swop Date: 2017 View in Article | Google Scholar UNESCO. UNESCO science report: towards 2030. ((accessed Nov 15, 2017).) https://en.unesco.org/unesco_science_report Date: 2015 View in Article | Google Scholar Vernos, I. Quotas are questionable. Nature. 2013; 495: 39 View in Article | Crossref | PubMed | Scopus (7) | Google Scholar European Research Council. Gender statistics. ((accessed Nov 15, 2017).) http://erc.europa.eu/sites/default/files/document/fileGender_statistics_Dec_2016.pdf Date: 2016 View in Article | Google Scholar Xie, Y, Zhang, C, and Lai, Q. China's rise as a major contributor to science and technology. Proc Natl Acad Sci USA. 2014; 111: 9437–9442 View in Article | Crossref | PubMed | Scopus (32) | Google Scholar Dhatt, R, Kickbusch, I, and Thompson, K. Act now: a call to action for gender equality in global health. Lancet. 2017; 389: 602 View in Article | Summary | Full Text | Full Text PDF | PubMed | Scopus (3) | Google Scholar Hawkes, S, Buse, K, and Kapilashrami, A. Gender blind? An analysis of global public-private partnerships for health. Glob Health. 2017; 13: 26 View in Article | Crossref | PubMed | Scopus (1) | Google Scholar Schwalbe, N. Global health: generation men. Lancet. 2017; 390: 733 View in Article | Summary | Full Text | Full Text PDF | PubMed | Scopus (1) | Google Scholar Edmunds, LD, Ovseiko, PV, Shepperd, S et al. Why do women choose or reject careers in academic medicine? A narrative review of empirical evidence. Lancet. 2016; 388: 2948–2958 View in Article | Summary | Full Text | Full Text PDF | PubMed | Scopus (17) | Google Scholar Nature. Science for all. Nature. 2013; 495: 5 View in Article | Crossref | PubMed | Scopus (11) | Google Scholar Raymond, J. Most of us are biased. Nature. 2013; 495: 33–34 View in Article | Crossref | PubMed | Scopus (20) | Google Scholar Parks, A and Redberg, R. Women in medicine and patient outcomes: equal rights for equal work?. JAMA Intern Med. 2017; 177: 161 View in Article | Crossref | PubMed | Scopus (2) | Google Scholar Double jeopardy: Gender bias against women of color in science. ((accessed Nov 15, 2017).) http://worklifelaw.org/publication/double-jeopardy-gender-bias-against-women-of-color-in-science/ Date: 2015 View in Article | Google Scholar Hafkin, NJ. National Assessments on Gender and Science, Technology and Innovation. ((accessed Nov 15, 2017).) https://owsd.net/sites/default/files/NH4EastAfricaGEKS.pdf Date: 2016 View in Article | Google Scholar Institute for Gender and the Economy. Gender and the economy research briefs. ((accessed Nov 15, 2017).) https://www.gendereconomy.org/research-briefs/ Date: 2017 View in Article | Google Scholar Rimmer, A. Five facts about the gender pay gap in UK medicine. BMJ. 2016; 354: i3878 View in Article | Crossref | PubMed | Scopus (1) | Google Scholar Jagsi, R, Griffith, KA, Jones, R, Perumalswami, CR, Ubel, P, and Stewart, A. Sexual harassment and discrimination: experiences of academic medical faculty. JAMA. 2016; 315: 2120–2121 View in Article | Crossref | PubMed | Google Scholar Hankivsky, O, Reid, C, Cormier, R et al. Exploring the promises of intersectionality for advancing women's health research. Int J Equity Health. 2010; 9: 5 View in Article | Crossref | PubMed | Scopus (82) | Google Scholar Nature. Gender imbalance in science journals is still pervasive. Nature. 2017; 541: 435–436 View in Article | Google Scholar Elsevier Research Intelligence. Gender in a global research landscape. ((accessed Nov 15, 2017).) https://www.elsevier.com/research-intelligence/campaigns/gender-17 Date: 2017 View in Article | Google Scholar

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Choosing ‘between groceries and rent’: Low wages, no security for hundreds of UBC professors

https://www.ubyssey.ca/features/choosing-between-rent-and-groceries-sessional-lecturers-struggle/ Hundreds of professors at UBC are struggling simply to pay their bills. By Jack Hauen and Zak Vescera Feb. 27, 2018 · 16 min read Professor Colin Green has been teaching in UBC’s history department for 15 years — but at least once a year, he has to re-apply for his job. “I teach the same teaching load as regular faculty in my department,” said Green. “I teach 12 credits and for those 12 credits, I get paid around $32,000. The lowest paid assistant professor in our department makes $90,000.” Green is a sessional lecturer, one of 437 at UBC who are hired on short-term contracts. While sessionals often teach the same number of courses as permanent faculty, their pay and treatment are far from equal. Sessionals like Green often report feeling stuck — unable to progress in a competitive academic environment they believe places little value on employees who are, at the end of the day, expendable. With no job security and low pay in one of the most expensive cities in North America, hundreds of employees at a world-class university are struggling to simply pay their bills. Choosing ‘between groceries and rent’ Facing tighter and tighter budgets, the appeal of replacing retiring faculty with flexible, inexpensive contract workers is too much to resist for Canadian universities. The Canadian Association of University Teachers estimates that contract faculty numbers have tripled since 1999, while regular faculty have only seen a 14 per cent increase. According to CBC, more than half of Canadian undergraduates are now taught by professors on short-term contracts. While permanent professors have fixed salaries, sessionals are paid by the course and at UBC, pay for sessional lecturers is based on subject and seniority. A senior law professor can be paid $11,000 or more per course, while a less established engineering professor could get as little as $4,000 for the same number of credits. “For probably the larger number of people, it’s a very tough way to have a satisfying career.” — Dr. Eric Eich, UBC vice provost and associate vice president academic affairs UBC Faculty Association Contract Faculty Committee Chair Sarika Bose said the nature of this pay scale means many of her peers aren’t financially secure. “Some sessional faculty are in a position where they have to choose between heat and rent, or groceries and rent,” said Bose, who is herself a sessional lecturer in the English department. A senior sessional professor in the faculty of arts can make as much as $55,000 a year, but the number of courses they teach is decided by the department, so there’s no guarantee of work. Sessional lecturers are significantly less-likely to believe that their pay is on-par with other comparable institutions. Sessional lecturers are significantly less-likely to believe that their pay is on-par with other comparable institutions. UBC 2009 Workplace Experience Survey “If you are a single parent or a single person, it can be really difficult,” said Bose. “When you’re teaching, you can feel distracted — ‘Will I be able to pay the rent in May because my contract ends in April?’” UBC Vice Provost and Associate Vice President Academic Affairs Eric Eich — who has been a sessional lecturer in the past — said some enjoy the position because they’re able to focus solely on teaching, as opposed to the research and administrative responsibilities that come with a permanent position. “Sometimes if you have a person and they’re teaching in a very specialized area, then they just maybe want to teach that one course,” he said, though he recognized that those are the minority. “For probably the larger number of people, it’s a very tough way to have a satisfying career,” he said. “You’re going to lack the certainty that would come with a tenured position, for instance, or a lot of the other benefits that would come with a full-time faculty position, so it's not easy.” Many sessional faculty take on multiple jobs just to make ends meet. Green, for example, is also a full-time instructor at another university, a position he balances with a full-time course load at UBC. “I have to teach [extra] courses [there] just to get within spitting distance of UBC salaries,” he said. As Bose explained, this solution comes with its own drawbacks. “If you are not paid at a wage that works in this city ... you have to take on the extra work,” she said. “Where do you find the time to do all that extra research to keep up with the pedagogy?” Eich said the university is working to replace sessionals with 12-month “lecturer” contracts that will run for up to three years at a time. Those contracts will be renewable indefinitely “upon evidence that they’re doing a really good job, really excellent teaching,” he said. Eich expects the number of sessionals to “drop dramatically” in the coming years. “It would be a real step forward because in those cases [a professor is] not splitting their time [between] different departments, different universities, even,” he said. “Instead they would have a home ... and they’d be part of the faculty, part of the sinew of that department. And I think that’s a lot more rewarding.” Compared to most sessional salaries, lecturer positions are well paid. A lecturer in the arts department makes around $62,000 a year, compared to $55,000 for someone at the top of the sessional pay scale. But while sessionally contracted faculty aren’t generally expected to do work beyond teaching, faculty in lecturer positions can be tasked with course preparation and service requirements that aren’t explicitly outlined in their contracts. That means that a teacher on a 12-month lectureship could potentially do more work relative to their salary than a sessional teacher. ‘When do you do your grading? On the bus?’ Often forced to work extended hours and multiple jobs to make ends meet, many sessionals find it difficult to fulfill their responsibilities with the limited support they’re given. Sometimes, it’s as simple as trying to get a loan. Because contracts are typically no longer than two school terms, sessional lecturers don’t have guaranteed long-term employment. In one of Canada’s most expensive real estate markets, that makes getting a mortgage difficult. “When you go to the bank, it’ll show that you are employed for eight months,” said Bose. “And you don’t know if you’ll be employed for the next eight months after that.” The solution for many sessionals is to take on a full-time job at other colleges around Vancouver in addition to their work at UBC — but that carries its own hardships. According to the university’s 2009 Workplace Experience Survey, obtained by The Ubyssey through a freedom of information request, almost two-thirds of contract lecturers said they struggled to find a balance between work and life. (In the 2011 and 2014 surveys, sessionals’ answers were no longer grouped together). “I have several colleagues who are teaching a class at UBC in the morning and having to bus it to Kwantlen in the evening, and in between are going to teach a class at Langara in the afternoon,” said Bose. “In practical terms, when do you do your grading? On the bus?” While sessionals are paid on contract, Bose noted that many of them work beyond in-class hours to prepare for courses, meet with students and keep up with research. At similar levels to their full-time colleagues, sessional lecturers have difficulty finding a work-life balance. At similar levels to their full-time colleagues, sessional lecturers have difficulty finding a work-life balance. UBC 2009 Workplace Experience Survey “When you’re not working, you’re actually preparing,” she said. “It creates a lot of stress.” Eich said he could empathize. “If someone was looking for certainty and reliability, a sessional position … isn’t going to provide that, and that would provide a lot of uncertainty in your life, which is not pleasant,” he said. “Hence, the primary reason to try to move to the full-time lecturer position in response to that.” ‘Second-class citizens within the academy’ While sessional lecturers often have the same credentials as full-time faculty, their temporary nature — and lack of contractual protection — means that they can feel underrepresented and unheard within the university. “[Sessional lecturers are] often treated as second-class citizens within the academy.” — Dr. Sarika Bose, UBC Faculty Association contract faculty committee chair According to the 2009 survey, sessional faculty are consistently the least content employment group at UBC. When asked if their workplace was healthy and sustainable, only 44 per cent of sessional faculty agreed, compared to an overall average of 70 per cent — lower than any other measured group. “‘Sessional’ has become a word that’s fairly derogatory within the faculty,” said Bose. “They’re often treated as second-class citizens within the academy.” Bose emphasized that this phenomenon isn’t specific to UBC. Across schools, sessional teachers often feel the nature of their contract affects how they’re treated by peers and evaluators. Much more than full-time faculty, sessional lecturers feel they don't have a voice in decision-making. Much more than full-time faculty, sessional lecturers feel they don't have a voice in decision-making. UBC 2009 Workplace Experience Survey “They feel what is recognized is what they’ve done wrong rather than what they’ve done right,” she said. The 2009 survey noted that only 22 per cent of sessional faculty felt they were recognized for accomplishments at work, while a dismal 5 per cent believed promotions, transfers and appointments are made fairly at UBC. Bose said the stigma around contract faculty can even impact their credibility with university officials, even with something as simple as a letter of recommendation for a student. “We have that stigma of quality from tenured faculty often in admissions committees,” she said. “If it’s a letter written by a sessional faculty member, it doesn’t count as much.” Eich reiterated that while permanent faculty have more research and administrative duties, he understands the appeal of advancing one’s career and finding a “home” within a department. “On one level, that’s all additional work, but it also makes you part of the whole social environment of being in a particular department, whatever it may be,” he said. “If you’re just teaching, say, one or two courses a year ... you’re going to miss that. You don’t feel like you’re part of a larger community.” Sessionals seem to agree — just 10 per cent surveyed in 2009 felt they had sufficient opportunity for advancement in their careers at UBC. No end in sight And UBC is far from alone. Frustration over precarious working conditions boiled over last year in Ontario when faculty at dozens of colleges and universities went on strike, citing job security as a main concern. Sessional faculty complained that despite contributing as much as 70 per cent of certain departments, they were underpaid, overworked and faced constant insecurity about whether they’d be guaranteed work. Some sessional lecturers at UBC would like to follow suit — but since the collective agreement dictates resolutions be solved by binding arbitration, they aren’t allowed to strike. Even if they were, the university could easily terminate them at the end of their contracts without legal consequence. “Sessional faculty do not feel that they are secure enough in their jobs to make complaints,” said Bose. “They don’t want to be seen as uncooperative members of the university community. So sometimes even legitimate grievances are blurred out.” Career advancement is seen as much less likely by sessional lecturers at UBC than by full-time faculty. Career advancement is seen as much less likely by sessional lecturers at UBC than by full-time faculty. UBC 2009 Workplace Experience Survey Similar frustrations are apparent at UBC — only 13 per cent believed they could achieve their long-term career objectives at UBC; less than a third would recommend UBC as a place to work and the same number believed their performance was assessed fairly. Most tellingly, only 28 per cent believed the administration would respond to the issues posed in the survey, signalling a crisis of confidence in the institution itself. Under the collective bargaining agreement between UBC Faculty Association and the university, sessional lecturers have to be notified of full-time faculty appointments, but they don’t necessarily get preference over outside candidates. “They’ll allow a sessional to teach for 15 years,” said Green, “But if the decision is made to convert those courses into a teaching stream position, they’ll throw the candidature out.” Working ‘in the shadows’ In addition to precarious pay, sessional lecturers are often cut out of benefits guaranteed to other staff. According to the collective agreement, staff are guaranteed pension benefits if they work for UBC for four consecutive months. This means sessionals working on a term-by-term basis don’t get benefits during the summer — even though they’re teaching the same amount of credits. “If you teach six credits for the winter, you’re eligible for the full range of benefits including pension,” said Green. “If you teach no courses January to April and then teach six credits in the summer, you would get zero pension.” Green said that after he raised a complaint, a mediator found that two back-to-back sessional contracts should be read as one continuous pay period, making summertime sessionals eligible for full benefits. “There are the regular faculty who have their own issues, and the sessionals who work in the shadows and live a completely different existence.” — Dr. Colin Green, sessional lecturer at UBC Afterwards, he said, UBC began to issue contracts that purposely put a few days of leave between the end of a sessional lecturer’s spring contract and the beginning of their summer one. Instead of viewing it as one continuous employment period from January to August, he said, it was broken in two — meaning sessionals don’t collect benefits in the summer term. “If I teach exactly the same six courses in the summer, I get nothing — or I only get half of what I would normally get for pension contributions,” said Green. “It can create lack of continuity in some of your benefit payments, your pension especially,” said Bose. “[My colleagues] feel that perhaps it’s another way in which they feel marginalized.” Again, Eich can empathize. “That’s another reason for going to the lecturer position, where then it’s seamless,” he said. “That would be irritating to lose your benefits.” Bose noted that sessional lecturers can still collect some pension benefits while working in the summer, but to do so, they have to write post-dated cheques back to UBC, taking the needed amount out of their paycheques manually. The survey data indicates that many sessionals might not even know that was an option: only 34 per cent reported being aware of UBC’s provisions and benefits to support their personal needs. For many sessionals, the inconsistent benefits are just another example of how they feel marginalized within the faculty association. According to the 2009 survey, nearly four-fifths of sessional staff felt uninvolved in decisions that affected them. “It’s two solitudes,” said Green. “There are the regular faculty who have their own issues, and the sessionals who work in the shadows and live a completely different existence.” No simple solution So why do sessionals continue to teach at UBC? Many have family in the region, some are drawn to UBC’s marginally-better pay for contract faculty compared to other institutions and many are ultimately proud to be a part of the school. “We’re proud of the job we do, we care deeply about the job that we do,” said Bose. “There are just these very practical barriers to doing it.” Eich emphasized that sessionals hadn’t fallen off UBC’s radar, mentioning the lectureship model again as a path forward. “We don’t have a simple, easy solution to these things,” he said. “Going ahead with the lecturer position is clearly aimed toward this. We’re cognizant, and we’re not just turning a blind eye to it.” At the end of the day, Bose maintained her goal is to help her students — even when that’s easier said than done. “I think one of the really difficult challenges for people in this position can be that they are in a position in which they want to inspire hope,” she said, “but they are hopeless themselves.”

Murdoch Mysteries continues its crazy feminist science storyline in murdoch-schmurdoch

Sometimes masculinity is explored separately in Murdoch Mysteries like when Bat Masterson pretended to be hunting famous outlaws in Glory Days; when Brackenreid wanted to revive his military career and in most of the Spy vs Spy episodes with Terrence Myers becoming more of a flawed middle aged man than a caricature. James Pendrick is becoming more like James Bond with him hiring more exotic women as scientists to help him with his inventions, and seeming to care less about his inventions as he ages. murdoch-schmurdoch does gender roles for both genders. Bobby Brackenreid plays the "sweet" young man who tries to ask a bad singer out after consulting with some of the older men in the office about it. His Dad tells him "lady of the theatre, excellent choice."... "She is older than you though... experience is a great attribute especially in a woman." So Daddy Brackenreid apparently thinks of "the lady of the theatre" [I don't remember him calling the opera singer that] in one dimension - as experience for his son. In a parallel sub plot, Marilyn Clark [crazy man-hating feminist scientist] reduces Murdoch to one attribute. She comes into the morgue carrying a young male rabbit which a previously infertile doe had produced after receiving the hormone treatment that Dr. Ogden also took to become pregnant. Murdoch tells Miss Clarke "we are most grateful to you". Marilyn brushes him off stating that it is only the work that is important. Murdoch continues "as a potential father, I can't help but tell you..." Miss Clark interupts him and says "if a baby is born, you will merely have been its donor", and she walks away. Julia laughs and reassures Murdoch.

Food as Medicine: Burdock (Arcitum lappa, Asteraceae)

HerbalEGram: Volume 15, Issue 1, January 2018 Editor’s Note: Each month, HerbalEGram highlights a conventional food and briefly explores its history, traditional uses, nutritional profile, and modern medicinal research. We also feature a nutritious recipe for an easy-to-prepare dish with each article to encourage readers to experience the extensive benefits of these whole foods. With this series, we hope our readers will gain a new appreciation for the foods they see at the supermarket and frequently include in their diets. The basic materials for this series were compiled by dietetic interns from Texas State University in San Marcos and the University of Texas at Austin through the American Botanical Council’s (ABC’s) Dietetic Internship Program, led by ABC Education Coordinator Jenny Perez. We would like to acknowledge Perez, ABC Special Projects Director Gayle Engels, and ABC Chief Science Officer Stefan Gafner, PhD, for their contributions to this project. By Hannah Baumana and Bethany Diazb a HerbalGram Associate Editor b ABC Dietetics Intern (Texas State University, 2017) Overview Burdock (Arctium lappa, Asteraceae), also known as great burdock, is a biennial plant in the sunflower family that grows well in full or partial sun and flourishes in undisturbed areas.1 Wild burdock can be found in forests, along roadsides or streams, farmlands, and waste areas. Native to Eurasia, burdock has been naturalized across the world and has a wide history of use in many countries as food and/or medicine.2 This weed-like plant grows well from coast to coast across the northern part of the United States and southern Canada.1 One of the distinct features of burdock is its sturdy stalk that can grow from two to six feet in height and its large, coarse, heart-shaped green leaves that extend out from alternating stems.3 Burdock blooms from mid-summer to early fall starting in its second year of maturity, and produces purple-pink flowers atop the globular bristle heads that are often called burrs.2 The root can reach a depth of approximately two feet and contains the greatest amount of nutrients during the plant’s first year. The root is long, hard, and slender with a carrot-like shape. When the brown outer layer is peeled away, the inside of the root is white and has an earthy, mildly bitter taste. Phytochemicals and Constituents Burdock root is a nutrient-dense food that is low in calories and fat. The root is a good source of protein, calcium, phosphorus, potassium, and folate.4,5 Each of these nutrients plays an important part in human metabolism, growth, and development. Potassium is necessary for electrolyte and pH balance, while folate is involved in amino acid metabolism, red blood cell formation, and DNA synthesis.6 In addition, burdock root is also a great source of fiber in the form of prebiotic inulin, which supports gastrointestinal health. Inulin has also been associated with the anti-diabetic properties of burdock root. Like most root vegetables, burdock is predominantly composed of complex carbohydrates. However, in burdock root, fructose is the dominant monosaccharide in the plant and contains repeating units of fructose and glucose, which contribute to the high oligosaccharide and polysaccharide content known as fructo-oligosaccharides (FOSs).7,8 Inulin is a water-soluble form of fiber that has been studied for its physiological effects on the gut microbiome. Inulin acts as a prebiotic, which allows the beneficial microorganisms to flourish in the gut and generate useful short-chain fatty acids. It also lowers the pH of the intestines, which helps prevent the establishment and growth of pathogenic bacteria.8 Research suggests that the diversity of beneficial gut bacteria and the ratio of beneficial microorganisms to pathogenic microorganisms significantly contribute to healthy weight management, support the immune system through the regulation and enhancement of white blood cell activity, and reduce blood triglyceride and cholesterol levels. Burdock root contains numerous phytochemicals, such as lignans, triterpenoids, and polyacetylenes.3,9 A variety of these constituents have been shown to promote blood circulation and are linked to antidiabetic medicinal properties, such as increasing insulin uptake, which improves glucose tolerance.10 Burdock root also contains caffeic acid and its derivatives chlorogenic acid and cynarin, as well as the flavonoids quercetin, luteolin, and the lignans arctiin and arctigenin, which have demonstrated cytotoxic, anti-inflammatory, and free radical scavenging properties.11-13 Arctigenin is one of the most-studied bioactive compounds in burdock root and has been investigated both in vitro and in animals for its anti-inflammatory benefits and potential anti-tumor properties. Arctigenin has been shown to decrease inflammation in humans by inhibiting the gene expression of proteins that regulate white blood cell activity and T-lymphocytes.14 A 2017 mouse study examined arctigenin’s effects on prostate cancer and reported that when given 50 mg/kg of arctigenin daily prior to tumor implantation, the mice experienced anti-tumor effects including a reduction in tumor growth factors, which suppressed overall tumor growth. This suggests that arctigenin, and thus the use of burdock root, may have a place in preventive medicine and dietary therapy.15 Historical and Commercial Uses When burdock became naturalized in North America, it became a dietary and medicinal ingredient for indigenous tribes.16 Numerous tribes, including the Iroquois, Cherokee, and Delaware, used burdock root to treat rheumatism and as a blood cleanser.17 Some tribes also used burdock root to treat skin disturbances. Another common use of burdock root among tribes was for the treatment of venereal diseases. The Iroquois ate burdock root as a vegetable, drying and storing the root for colder months. Burdock has been used for its medicinal properties for thousands of years in many parts of Europe, China, and Japan. In Japan, burdock root (called gobo) is a common food and is used as a remedy in a traditional herbal medicine practice known as Kampo.2 As a traditional medicine, burdock is used as a diuretic and also as a so-called “blood purifier,” or alterative.2,18,19 As a diuretic, burdock root can increase urination and is used to flush out the urinary tract system and decrease the occurrence of minor liver- and kidney-related complications.17 As an alterative, burdock root is used to enhance the body’s natural detoxification processes and has a 100-year history of use in folk and indigenous medicine as a cancer treatment. In the 1920s, burdock root was an important herbal component of two folk medicine cancer treatment formulas known as the Hoxsey and Essiac formulas.18 In modern times, burdock is used by Western herbalists as a nutritive prebiotic that supports healthy skin, moves lymph, and enhances detoxification and elimination functions.18 Burdock root is indicated for skin conditions such as acne, psoriasis, atopic dermatitis, and cystitis. The root is preferred for chronic skin conditions, while the seed is preferred for treating acute skin eruptions such as boils and sties.2,18 Other therapeutic conditions for burdock include gout, rheumatoid arthritis, and anorexia nervosa.9 In addition, burdock root’s bittersweet flavor can stimulate appetite and improve bowel function.20 As an herbal medicine, burdock root is most often prepared as a tea, but can also be made into extracts and tinctures, or powdered and encapsulated. The first-year root of burdock is the most commonly consumed plant part, though the young leaves are often eaten in salads or lightly steamed.3,21 Similar to carrots, a biennial plant grown as an annual root crop, burdock is cultivated in Japan as an annual root vegetable and is frequently included in soups, stews, salads, and pickles. Although it is a common vegetable in Japan, and occasionally used in some culinary practices in parts of Europe, burdock is little known outside these cultures.2,3 However, it is growing in popularity as both a food and medicine. Modern Research While clinical evidence on the use of burdock root is limited, much of the research focuses on inflammatory markers and response pathways. Chronic skin conditions like eczema and psoriasis, gastrointestinal diseases, rheumatoid arthritis, and gout can be linked to persistent inflammation in the body. A placebo-controlled clinical study demonstrated a significant reduction in osteoarthritis pain in participants who consumed burdock root tea three times daily for six weeks.22 In addition, those in the treatment group also experienced significantly increased Knee Injury & Osteoarthritis Outcome scores and decreased Timed Up and Go scores compared to control. These results indicate that those in the burdock tea group had reduced arthritis symptoms, pain, and fall risk and increased mobility and quality of life. Another clinical study on burdock root and osteoarthritis reported anti-inflammatory and antioxidative results. Patients with osteoarthritis were given six grams of burdock root, delivered as a tea, daily for 42 days. At the end of the experiment, blood samples and biochemical analyses showed a significant reductions in the clinical inflammatory markers interleukin-6 (IL6) and C-reactive protein (CRP) compared to baseline.23 It is important to note that all patients in this study were given acetaminophen and glucosamine as part of their “drug” regimen (glucosamine is technically not a drug, but a dietary supplement, i.e., depending on the regulatory regime in which it is sold and used). Other clinical studies provide evidence that burdock can significantly improve dry skin and wrinkles.24,25 However, these studies used the fruit rather than the root or did not disclose which part of the plant was used. Rat studies have demonstrated the gastroprotective properties of burdock root, seed, and leaf extracts, including healing gastric ulcers, a dose-dependent response for the healing of gastric mucosa,26 inhibiting gastric ulcer formation,27 and decreasing the inflammatory response associated with colitis.28 An in vitro study on the anti-inflammatory response related to atopic dermatitis found that burdock root extract had stimulatory effects on immune cells and inhibited the antigen-induced mRNA expression and production of cytokines related to allergic and atopic reactions.29 Extracts of burdock root with concentrations of 10 µg/mL and 100 µg/mL enhanced proliferation of splenocyte cells that were induced with T-cell immunogenicity. A down-regulation of IL-4 and IL-5 was exhibited with the 100 µg/mL extract, supporting the anti-allergic and anti-inflammatory effects of burdock root. Burdock root extracts have also exhibited antioxidant and cytotoxic effects. One study that experimented with eight different burdock root extracts reported that the hydroethanolic mixture (594 grams of fresh milled burdock root, 1:5 ratio with 70% ethanol) had high amounts of phenolic compounds and the greatest free radical scavenging activity. The study also reported that the dichloromethane extract (276 grams of fresh milled roots, 1:5 ratio) showed cytotoxic properties against specific cancer cell lines.13 Preliminary studies also suggest that burdock root has the ability to benefit patients with type 2 diabetes. In an animal study, daily supplementation with burdock root extract not only increased the levels of insulin produced, but also helped control body weight and facilitated favorable changes in blood lipid profiles such as reducing triglyceride and very low-density lipoprotein (VLDL) cholesterol levels and increasing high-density lipoprotein (HDL) cholesterol levels.30 In addition, when compared to the control group, the treatment group exhibited an increase in liver enzymes and a decrease in leptin levels. This study also had two groups of healthy rats that were not induced with diabetes but were given the same amount of burdock root extract as their diabetic counterparts. These two groups of rats also saw significant changes in lipid profiles and insulin levels, which suggest that burdock root may also be beneficial to patients who are pre-diabetic or have metabolic syndrome. A two-part study reported that burdock root extract in vitro caused an increase in glucose uptake with insulin present and decreased liver glucose production by inhibiting the liver enzyme glucose-6 phosphatase. The in vivo phase, conducted with rats, demonstrated a decrease in blood glucose as well as a decrease in the amount of insulin secreted for the animals that were given 50 or 100 µg /mL of dried burdock root extract.10 This indicates that burdock root extract may be a promising natural remedy for patients with uncomplicated type 2 diabetes. Obesity is a risk factor for many disease states including type 2 diabetes and heart disease. A rat study found that daily supplementation with burdock root for four weeks lead to a reduction in body weight.31 Rats that were fed 500 mg/kg or 1,000 mg/kg of burdock root a day weighed less than the rats in the control group that did not consume any burdock. This study also investigated the mechanisms behind the weight management properties and reported that lipid synthesis was suppressed by downregulating or inhibiting various enzymes that are part of lipid metabolism and decreased overall cellular lipid content. This study provides introductory evidence for an alternative method to weight management in humans. Burdock root may also prevent liver damage from environmental toxicity. Rats with liver injuries ingested 900 mg/kg of burdock root for one day or consumed 300 mg/kg of burdock three times a day for seven days. Both experimental groups showed a decrease in serum levels of the liver enzymes SGOT and SGPT and an increase in glutathione levels.32 Furthermore, additional reviews have found that the root of burdock helps to decrease lipid deposits into the liver caused by alcohol or high-fat diets as well as initiate hepatoprotective mechanisms that increase antioxidant activity.2,8 Consumer Considerations Burdock root is well-tolerated by most individuals, though those with a sensitivity to foods high in the prebiotic inulin, such as Jerusalem artichokes (Helianthus tuberosus, Asteraceae), artichokes (Cynara scolymus, Asteraceae), asparagus (Asparagus officinalis, Asparagaceae), or leeks (Allium ampeloprasum, Amaryllidaceae), may experience temporary gas or bloating post-consumption.18 No significant adverse effects have been reported with burdock root apart from rare cases of anaphylactic shock; however, patients should discontinue use and notify their health care provider if they suspect an allergic reaction.20 Burdock root has not been reported to have any negative interactions with other herbs or medications. However, since burdock root has been used traditionally to increase urine output, taking additional diuretics while using burdock is not recommended.33 Patients should ensure adequate hydration while taking burdock medicinally due to its diuretic effect. Nutrient Profile5 Macronutrient Profile: (Per 1 cup of peeled root [approx. 118 grams]) 85 calories 1.8 g protein 20.5 g carbohydrate 0.2 g fat Secondary Metabolites: (Per 1 cup of peeled root [approx. 118 grams]) Excellent source of: Potassium: 363 mg (7.7% DV) Dietary Fiber: 3.9 g (13% DV) Vitamin C: 3.5 mg (3.9% DV) Calcium: 48 mg (3.7% DV) Very good source of: Iron: 0.9 mg (5% DV) Vitamin E: 0.5 mg (3.3% DV) Vitamin K: 1.9 mcg (1.6% DV) Good source of: Thiamin: 0.01 mg (0.9% DV) Riboflavin: 0.04 mg (3.1% DV) Niacin: 0.4 mg (2.5% DV) Vitamin B6: 0.3 mg (17.6% DV) Folate: 27 mcg (6.8% DV) Also provides: Phosphorus: 60 mg (4.8% DV) Magnesium: 45 mg (10.7% DV) Manganese: 0.3 mg (13.0% DV) DV = Daily Value as established by the US Food and Drug Administration, based on a 2,000-calorie diet. Recipe: Burdock Kinpira Courtesy of Chichi Wang34 When shopping for burdock, choose plump, crisp roots, gently scrub to remove dirt, and briefly soak in acidulated water (one teaspoon lemon juice or vinegar to one liter water) to prevent browning or oxidation. To store, wrap in a damp paper towel, refrigerate, and use within a week. Ingredients: 2 burdock roots approximately one foot in length 1 tablespoon vegetable oil 2 tablespoons soy sauce 1 tablespoon sake or mirin 2 tablespoons sugar Directions: Wash and peel burdock root. Cut the root into four-inch segments, the quarter lengthwise. Place the prepared root in acidulated water to prevent discoloration. Place a sauté pan over medium heat and add the oil. Sauté root for four to six minutes until lightly browned. Add soy sauce, sake, and sugar to pan. Simmer for five minutes, until the root is cooked through but still crunchy. Serve at room temperature or cold. References Doll J, Doll J. Common Burdock. University of Wisconsin Weed Science Cooperative Extension website. November 2, 1997. Available at: https://fyi.uwex.edu/weedsci/1997/11/02/common-burdock/. Accessed December 20, 2017. El-Darier SM, Salama SG. Arctium lappa L. (Asteraceae); a new invasive highly specific medicinal plant growing in Egypt. Pyrex J Plant Agric Res. 2016;2(2):44-53. van Wyk B. Food Plants of the World. Portland, OR: Timber Press; 2006. Wood R. The New Whole Foods Encyclopedia. New York, NY: Penguin Books; 1999. Basic Report: 11104, Burdock root, raw. US Department of Agriculture Agricultural Research Service website. Available at: https://ndb.nal.usda.gov/ndb/foods/show/2883. Accessed December 20, 2017. Gropper SAS, Smith JL, Carr TP. Advanced Nutrition and Human Metabolism. Australia: Cengage Learning; 2018. Liu W, Wang J, Zhang Z, et al. In vitro and in vivo antioxidant activity of a fructan from the roots of Arctium lappa L. Int J Biol Macromol. 2014;65:446-453. doi:10.1016/j.ijbiomac.2014.01.062. Wang H, Wu W. Studies on the physiological functions of burdock inulin. Medicinal Plant. 2013;4(11/12):58-60. Barnes J, Anderson LA, Phillipson JD. Herbal Medicines. 3rd ed. London, UK: Pharmaceutical Press; 2007. Tousch D, Bidel LPR, Cazals G, et al. Chemical analysis and antihyperglycemic activity of an original extract from burdock root (Arctium lappa). J Agric Food Chem. 2014;62(31):7738-7745. Ferracane R, Graziani G, Gallo M, Fogliano V, Ritieni A. Metabolic profile of the bioactive compounds of burdock (Arctium lappa) seeds, roots and leaves. J Pharm Biomed Anal. 2010;51(2):399-404. doi:10.1016/j.jpba.2009.03.018. Liu J, Cai YZ, Wong RN, et al. Comparative analysis of caffeoylquinic acids and lignans in roots and seeds among various burdock (Arctium lappa) genotypes with high antioxidant activity. J Agric Food Chem. 2012;60(16):4067-4075. Predes FS, Ruiz ALTG, Carvalho JE, Foglio MA, Dolder H. Antioxidative and in vitro antiproliferative activity of Arctium lappa root extracts. BMC Complem Alt Med. 2011;11(25):1-5. Tsai W, Chang C, Wang G, Lee T, Chang S, Lu S. Arctigenin from Arctium lappa inhibits interleukin-2 and interferon gene expression in primary human T lymphocytes. Chinese Medicine. 2011;6(12):1-8. Wang P, Solorzano W, Diaz T, Magyar CE, Henning SM, Vadgama JV. Arctigenin inhibits prostate tumor cell growth in vitro and in vivo. Clin Nutr Exp. 2017;13:1-11. doi:10.1016/j.yclnex.2017.04.001. Duke JA, Duke P. Common burdock: Arctium minus (Hill) Bernh; Family Asteraceae. HerbalGram. 1997;39:87. Moerman D. Native American Ethnobotany. Portland, OR: Timber Press; 1998. de la Forêt, R. Burdock benefits. Herbs with Rosalee website. 2017. Available at: www.herbalremediesadvice.org/burdock-benefits.html. Accessed December 21, 2017. Bebeau GD. Lesser (Common) Burdock, Great Burdock: Arctium minus Bernh., Arctium lappa L. Friends of the Wildflower Garden, Inc. website. 2014. Available at: /www.friendsofthewildflowergarden.org/pages/plants/burdock.html. Accessed December 20, 2017. Community herbal monograph on Arctium lappa L ., radix. European Medicines Agency. 2010;44(September 2010):2-7. Arctium lappa. NDHealthFacts website. March 18, 2014. Available at: www.ndhealthfacts.org/wiki/Arctium_lappa. Accessed December 20, 2017. Alipoor B, Norouzabad LM, Abed R, Oskouei MAE, Sadat BE, Jafarabadi MA. Effect of Arctium lappa L. (Burdock) root tea on clinical signs and symptoms in patients with knee osteoarthritis. Curr Top Nutraceutical Res. 2014;12(4):149-154. Maghsoumi-Norouzabad L, Alipoor B, Abed R, Eftekhar B. Effects of Arctium lappa L. (Burdock) root tea on inflammatory status and oxidative stress in patients with knee osteoarthritis. International Journal of Rheumatic Diseases. 2016;19(3):255-261. Lee DH, Seo ES, Hong JT, et al. The efficacy and safety of a proposed herbal moisturising cream for dry skin and itch relief: a randomised, double-blind, placebo-controlled trial- study protocol. BMC Complement Altern Med. 2013;13(1):330. doi:10.1186/1472-6882-13-330. Knott A, Reuschlein K, Mielke H, et al. Natural Arctium lappa fruit extract improves the clinical signs of aging skin. J Cosmet Dermatol. 2008;7(4):281-289. doi:10.1111/j.1473-2165.2008.00407.x. da Silva LM, Allemand A, Mendes DAGB, et al. Ethanolic extract of roots from Arctium lappa L. accelerates the healing of acetic acid-induced gastric ulcer in rats: Involvement of the antioxidant system. Food Chem Toxicol. 2013;51:179-187. doi:10.1016/j.fct.2012.09.026. Li XM, Miao Y, Su QY, Yao JC, Li HH, Zhang GM. Gastroprotective effects of arctigenin of Arctium lappa L . on a rat model of gastric ulcers. Biomedical Reports. 2016;5:589-594. doi:10.3892/br.2016.770. de Almeida ABA, Sánchez-Hidalgo M, Martín AR, et al. Anti-inflammatory intestinal activity of Arctium lappa L. (Asteraceae) in TNBS colitis model. J Ethnopharmacol. 2013;146(1):300-310. doi:10.1016/j.jep.2012.12.048. Sohn E, Jang S, Joo H, et al. Anti-allergic and anti-inflammatory effects of butanol extract from Arctium lappa L. Clinical and Molecular Allergy. 2011:9(4)1-12. Ahangarpour A, Heidari H, Oroojan AA, Mirzavandi F, Nasr Esfehani K, Dehghan Mohammadi Z. Antidiabetic, hypolipidemic and hepatoprotective effects of Arctium lappa root’s hydro-alcoholic extract on nicotinamide-streptozotocin induced type 2 model of diabetes in male mice. Avicenna J Phytomedicine. 2017;7(2):169-179. Kuo D, Hung M, Hung C, et al. Body weight management effect of burdock (Arctium lappa L.) root is associated with the activation of AMP-activated protein kinase in human HepG2 cells. Food Chem. 2012;134(3):1320-1326. doi:10.1016/j.foodchem.2012.03.023. Lin S-C, Lin C-H, Lin C-C, et al. Hepatoprotective effects of Arctium lappa Linne on liver injuries induced by chronic ethanol consumption and potentiated by carbon tetrachloride. J Biomed Sci. 2002;9(5):401-409. doi:10.1007/BF02256533. Burdock. University of Maryland Medical Center website. June 22, 2015. Available at: www.umm.edu/health/medical/altmed/herb/burdock. Accessed September 1, 2017. Wang C. Seriously Asian: Burdock Root Recipe. Serious Eats website. May 2010. Available at: www.seriouseats.com/recipes/2010/05/seriously-asian-stir-fried-burdock-root-kinpira-pickled-burdock-recipe.html. Accessed January 3, 2018.

Re: Meta-analysis Finds Black Cumin Beneficial for Glucose Homeostasis and Serum Lipids; Confirms Potential as Adjunct Therapy for Type 2 Diabetes

PDF (Download) Black Cumin (Nigella sativa, Ranunculaceae) Type 2 Diabetes Systematic Review/Meta-analysis Date: 02-15-2018 HC# 011841-586 Daryabeygi-Khotbehsara R, Golzarand M, Ghaffari MP, Djafarian K. Nigella sativa improves glucose homeostasis and serum lipids in type 2 diabetes: a systematic review and meta-analysis. Complement Ther Med. December 2017;35:6-13. Black cumin (BC; Nigella sativa, Ranunculaceae) seed, a food and traditional medicine native to South and Southwest Asia and widely cultivated in the Middle East and North Africa, has drawn strong research interest. An appetite stimulant, bronchodilator, diuretic, antibacterial, liver tonic, and analgesic, it is used for type 2 diabetes (T2D), liver and kidney problems, hypertension, cardiovascular diseases, digestive ailments, diarrhea and dysentery, cancer, skin ailments, infections, rheumatism, headaches, and asthma and bronchitis. Human trials have investigated its seed oil or powder in T2D, rheumatoid arthritis, and hypertension. Animal studies report hypoglycemic and hypolipidemic effects in T2D models. Systematic reviews and meta-analyses have reported promising results on metabolic parameters, but none have previously assessed its pooled effects on glycemia and serum lipids. This lack of evidence precludes the American Diabetes Association from listing BC as a primary option (Level A) for T2D management. The authors conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A database search for human trials of BC's effects on glycemia and serum lipids up to February 2017 located 292 non-duplicate reports. Titles and abstracts were screened for relevance; 275 were excluded. To meet criteria, trials had to be of interventions using BC seed oil or powder in patients with T2D, report relevant outcome measures of glycemia (fasting blood sugar [FBS], glycated hemoglobin [HbA1c], etc.) and/or serum lipids profile (triglycerides [TG], cholesterol, etc.), and compare BC with placebo or standard treatment. Excluded were animal studies, those studies lacking an interventional approach, those lacking pre- and post-intervention desired outcomes, and any duplicates. Of 17 full-text articles considered, eight were not trials and two were in languages other than English or Persian. Their exclusion left seven for review and analysis. These included 255 patients in active arms; 250 in controls. Three studies were conducted in Iran; three, Saudi Arabia; and one, India. Duration was two to 12 months. Four investigated BC seed powder at dosages from 0.5-2.0 g/day; three used seed oil at doses from 1-5 mL/d. All used a parallel design. Risk of publication bias for each outcome was assessed via Egger's test. No significant risk was found for FBS, total cholesterol (TC), TG, high-density lipoprotein cholesterol (HDL-c), or low-density lipoprotein cholesterol (LDL-c). However, there was significant publication bias risk for HbA1c (P = 0.01). Pooled effects of trials reporting outcomes of interest are shown in forest plots. For glycemic results, five trials saw significant reductions in FBS with BC powder or oil (weighted mean difference [WMD], −17.84 mg/dL; 95% confidence interval [CI], −21.19 to −14.49; P < 0.001). No heterogeneity was found (I2 = 28.5%; P = 0.23). Five studies had pooled decreases in HbA1c with either form of BC (WMD, −0.71%; 95% CI, −1.04 to −0.39; P < 0.001). There was significant evidence of heterogeneity (I2 = 89.3%; P < 0.001). For FBS and HbA1c, sensitivity analysis found that omitting one study significantly changed pooled effect size. Excluding it left a WMD for FBS of −16.89 mg/dL (95% CI, −22.42 to −11.33; P < 0.001); for HbA1c, WMD was −0.61% (95% CI, −0.93 to −0.29; P < 0.001). Mechanisms of action for BC's significant benefits on glycemia in T2D are posited to include amelioration of pancreatic β-cells and the resultant increased insulin secretion, reduced liver gluconeogenesis, and induced insulin sensitivity in peripheral tissue. BC compounds thymoquinone, dithymoquinone, linoleic acid, and oleic acid are credited, although research in this area is limited. Both BC powder and oil were seen to maintain significant decreases in FBS and HbA1c for more than a year. This meta-analysis found BC's effects on HbA1c equal to those of dipeptidyl peptidase-4 (DPP-4) inhibitors. Four studies reported significant decreases in TC from baseline with BC (WMD, −22.99 mg/dL; 95% CI, −32.16 to −13.83; P < 0.001). Heterogeneity was not seen (I2 = 31.9%; P = 0.22). Subgroup analyses found greater reductions in TC with oil over powder, but studies with oil showed moderate heterogeneity. Five studies assessed BC's effect on plasma TG. WMD was −6.80 mg/dL (95% CI, −33.59 to 19.99; P = 0.61). Heterogeneity was significant (I2 = 89.5%; P < 0.001). Subgroup analyses showed that BC oil significantly reduced TG (WMD, −14.8 mg/dL; 95% CI, −23.1 to −6.5; P < 0.001), but BC powder significantly raised it (WMD, 29.4 mg/dL; 95% CI, 16.9-42.0; P < 0.001). There was significant heterogeneity in powder studies (I2 = 71.2%; P = 0.06) but not in those using oil (I2 = 0.0%; P = 0.48). Pooled effects of five studies reporting HDL-c were nonsignificant (WMD, 0.37 mg/dL; 95% CI, −1.59 to 2.33; P = 0.71), with no heterogeneity (I2 = 0.0%; P = 0.52). For LDL-c, five trials showed a significant drop (WMD, −22.38 mg/dL; 95% CI, −33.60 to −11.15; P < 0.001). Heterogeneity was seen (I2 = 80.0%; P < 0.01). Subgroup analyses found that both forms of BC reduced LDL-c, but studies of each type were heterogeneous (oil, I2 = 76.7%, P = 0.01; powder, I2 = 91.1%, P = 0.001). Sensitivity analysis found that no single study significantly affected pooled effects on TC, TG, HDL-c, or LDL-c. BC's effects on lipid levels are thought to be due to its antioxidant activity. An agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ), it reduces lipid peroxidation, promotes hepatic uptake of LDL-c, and inhibits cholesterol synthesis. Lipid profiles in healthy people also have been found in meta-analyses to improve with BC supplementation. The lack of BC powder effect on TG levels in this meta-analysis may be due to insufficient dosage, since patients with T2D tend to have significantly higher TG than healthy people. This does not explain the observed different effects of oil vs. powder on TG, perhaps related to preparation processes. While standard statin doses reduce LDL-c more than BC, evidence suggests that further reductions in LDL-c after statin therapy reduce all-cause mortality among patients with T2D, pointing to a complementary role for BC. Mild, "barely reported" adverse events (there is some reporting of mild gastrointestinal problems) make BC even more promising in managing T2D. —Mariann Garner-Wizard

Re: Review of the Cardioprotective Effects of Resveratrol Reveals Inconsistent Findings in Clinical Trials, with Positive Results in Preclinical Trials

Resveratrol Cardiovascular Disease Date: 02-15-2018 HC# 061737-586 Cho S, Namkoong K, Shin M, et al. Cardiovascular protective effects and clinical applications of resveratrol. J Med Food. 2017;20(4):323-334. Cardiovascular diseases (CVDs) are the most common cause of death worldwide. These authors reviewed the potential effects of resveratrol, a natural compound found in red grapes (Vitis vinifera, Vitaceae) and other fruits, in the development of CVDs and described the evidence on the mechanisms of those effects. Five beneficial effects of resveratrol are reviewed, namely, antiatherogenic, anti-inflammatory, antihypertensive, cardioprotective, and metabolic modulation. Inflammation of the arterial wall, or atherosclerosis, is caused by endothelial damage induced by cytokines responding to hemodynamic and redox stress conditions. Macrophages, a type of white blood cell, play a key role in the development of atherosclerosis. Resveratrol affects many of the chemical compounds involved in macrophage lipid metabolism; it activates endothelial nitric oxide synthase (eNOS), increases high-density lipoprotein efflux, and downregulates endothelin 1 gene—actions that are linked to its antiatherogenic effects. Low-grade inflammation associated with age increases the incidence of both stroke and coronary artery disease. Nitric oxide (NO) helps maintain endothelial cell function. Endothelium-derived NO protects the cardiovascular system during aging, as shown in a study in which mice deficient for the eNOS gene displayed premature cardiac aging and early mortality. Hypertension increases the risk for CVDs. Researchers suggest that resveratrol reduces blood pressure through vasodilatation, antioxidative processes, and neovascularization, with various molecules responsible for each of these processes. Cardioprotective effects of resveratrol have been reported in animal studies. Its protective effects against cardiac hypertrophy are explained by several mechanisms. It protects cardiac muscle cells by decreasing oxidative stress, autophagy, apoptosis, and cardiac fibrosis. The authors caution that "despite the encouraging results in animal models, clinical trials that provide support for the beneficial effects of resveratrol in human subjects are rare to date." Affecting almost one-fourth of the world's population, metabolic syndrome is associated with the risk for CVD and diabetes mellitus. The complex pathophysiology of metabolic syndrome has been only partly explained, with insulin thought to play an important role in the syndrome. Because low potency and stability limit the use of resveratrol, various derivatives have been synthesized to increase its efficiency and stability. In a previous study, the authors described the derivative HS-1793 as a strong cardioprotective drug with enhanced stability and efficiency.1 Human clinical studies have reported on the effects of resveratrol on CVDs. These authors reviewed 20 clinical trials, with 909 subjects, investigating the cardiovascular protective effects of resveratrol. Dosages ranged from 8 mg/kg to 2,000 mg/kg daily. The antiatherosclerotic effect of resveratrol is supported by large clinical trials. Among the studies reporting a beneficial effect is a trial of 75 patients who were undergoing primary prevention of CVDs with statin treatment and who were treated with resveratrol (350 mg daily of resveratrol-enriched grape extract containing 8 mg resveratrol). The investigators reported a 20% decrease in oxidized low-density lipoprotein (LDL) and a 4.5% decrease of LDL cholesterol in those patients.2 In a study of 24 healthy obese men treated with 500 mg resveratrol daily for 28 days, no effects were seen on blood pressure or lipid profile.3 Because other studies found no effect on the lipid profile and some found beneficial effects, the authors write, "[C]linical trials investigating the effect of resveratrol on plasma lipid profile in human subjects remain unclear … ." Clinical studies on the effect of resveratrol on blood pressure reported that doses of resveratrol at 150 mg or more daily significantly reduced systolic blood pressure but did not affect diastolic blood pressure in healthy subjects. Furthermore, one study found that lower doses of resveratrol had no effect on blood pressure. The authors suggest that the antihypertensive effects of resveratrol might be more effective in patients with high blood pressure. In 40 patients with stable coronary artery disease after myocardial infarction, one study reported improved cardiac function after supplementation of 10 mg resveratrol daily for 90 days4; resveratrol helped reduce LDL and improved flow-mediated dilatation and left ventricle diastolic function. In another clinical study of 166 patients with stable angina pectoris, the administration of 20 mg/d resveratrol, calcium fructoborate, and their combination for 60 days improved several markers of coronary artery disease.5 Among the clinical trials investigating the effects of resveratrol on metabolic syndrome are studies in which treatments of resveratrol at doses of 150 mg daily in 11 healthy obese men and 500 mg daily in 50 healthy adult smokers6 reduced plasma triglyceride levels. In the study of the 11 healthy obese men, resveratrol also elevated intramyocellular lipid levels and decreased intrahepatic lipid content, glucose, triglycerides, alanine aminotransferase, and inflammation markers. In healthy, nonobese subjects, however, resveratrol along with other dietary supplements did not affect cardiometabolic risk factors.7 The authors conclude that findings from clinical studies on the cardioprotective effects of resveratrol "are either inconsistent or not as promising as the preclinical findings," suggesting that "conflicting findings between different clinical trials are due to major differences in research protocols, because the relationships between dosage, bioavailability, and physiological response may result in different conclusions in resveratrol effects." This study was supported by grants from the Priority Research Centers Program of the National Research Foundation of Korea, which is funded by the Ministry of Education, Science and Technology of the Republic of Korea. ―Shari Henson References 1Jeong SH, Hanh TM, Kim HK, et al. HS-1793, a recently developed resveratrol analogue protects rat heart against hypoxia/reoxygenation injury via attenuating mitochondrial damage. Bioorg Med Chem Lett. 2013;23(14):4225-4229. 2Tomé-Carneiro J, Gonzálvez M, Larrosa M, et al. Consumption of a grape extract supplement containing resveratrol decreases oxidized LDL and ApoB in patients undergoing primary prevention of cardiovascular disease: a triple-blind, 6-month follow-up, placebo-controlled, randomized trial. Mol Nutr Food Res. 2012;56(5):810-821. 3Poulsen MM, Vestergaard PF, Clasen BF, et al. High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes. 2013;62(4):1186-1195. 4Magyar K, Halmosi R, Palfi A, et al. Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc. 2012;50(3):179-187. 5Militaru C, Donoiu I, Craciun A, Scorei ID, Bulearca AM, Scorei RI. Oral resveratrol and calcium fructoborate supplementation in subjects with stable angina pectoris: effects on lipid profiles, inflammation markers, and quality of life. Nutrition. 2013;29(1):178-183. 6Bo S, Ciccone G, Castiglione A, et al. Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial. Curr Med Chem. 2013;20(10):1323-1331. 7Soare A, Weiss EP, Holloszy JO, Fontana L. Multiple dietary supplements do not affect metabolic and cardiovascular health. Aging (Albany NY). 2014;6(2):149-157.

The Potential of Phytomelatonin as a Nutraceutical

Molecules. 2018 Jan 22;23(1). pii: E238. doi: 10.3390/molecules23010238. . Arnao MB1, Hernández-Ruiz J2. Author information 1 Department of Plant Biology (Plant Physiology), Faculty of Biology, University of Murcia, 30100 Murcia, Spain. marino@um.es. 2 Department of Plant Biology (Plant Physiology), Faculty of Biology, University of Murcia, 30100 Murcia, Spain. jhruiz@um.es. Abstract Phytomelatonin (plant melatonin) is chemically related to the amino acid tryptophan and has many diverse properties. Phytomelatonin is an interesting compound due to its outstanding actions at the cellular and physiological level, especially its protective effect in plants exposed to diverse stress situations, while its vegetable origin offers many opportunities because it is a natural compound. We present an overview of its origin, its action in plants in general (particularly in plant species with high levels of phytomelatonin), and its possibilities for use as a nutraceutical with particular attention paid to the beneficial effects that it may have in human health. The differences between synthetic melatonin and phytomelatonin, according to its origin and purity, are presented. Finally, the current market for phytomelatonin and its limits and potentials are discussed. KEYWORDS: antioxidant; cancer; circadian rhythm; dietary/food supplements; free radicals; fruits; medicinal plants; melatonin; neurological diseases; nutraceutical; phytomelatonin; plant foodstuffs; sleep disorders PMID: 29361780 DOI: 10.3390/molecules23010238 Free full text The Potential of Phytomelatonin as a Nutraceutical

Halophytic herbs of the Mediterranean basin: An alternative approach to health

Food Chem Toxicol. 2018 Feb 15;114:155-169. doi: 10.1016/j.fct.2018.02.031. [Epub ahead of print] Petropoulos SA1, Karkanis A2, Martins N3, Ferreira ICFR4. Author information 1 Department of Agriculture Crop Production and Rural Environment, University of Thessaly, Fytokou Str, 38446 Nea Ionia, Magnesia, Greece. Electronic address: spetropoulos@uth.gr. 2 Department of Agriculture Crop Production and Rural Environment, University of Thessaly, Fytokou Str, 38446 Nea Ionia, Magnesia, Greece. 3 Mountain Research Centre (CIMO), ESA, Polytechnic Institute of Bragança, Campus de Santa Apolónia, 1172, 5301-855 Bragança, Portugal. 4 Mountain Research Centre (CIMO), ESA, Polytechnic Institute of Bragança, Campus de Santa Apolónia, 1172, 5301-855 Bragança, Portugal. Electronic address: iferreira@ipb.pt. Abstract Wild native species are usually grown under severe and stressful conditions, while a special category includes halophytic species that are tolerant to high salinity levels. Native halophytes are valuable sources of bioactive molecules whose content is higher in saline than normal conditions, since the adaptation to salinity mechanisms involve apart from changes in physiological functions the biosynthesis of protectant molecules. These compounds include secondary metabolites with several beneficial health effects which have been known since ancient times and used for medicinal purposes. Recent trends in pharmaceutical industry suggest the use of natural compounds as alternative to synthetic ones, with native herbs being strong candidates for this purpose due to their increased and variable content in health promoting compounds. In this review, an introductory section about the importance of native herbs and halophyte species for traditional and modern medicine will be presented. A list of the most important halophytes of the Mediterranean basin will follow, with special focus on their chemical composition and their reported by clinical and ethnopharmacological studies health effects. The review concludes by suggesting future requirements and perspectives for further exploitation of these valuable species within the context of sustainability and climate change. KEYWORDS: Bioactive compounds; Halophytes; Health effects; Native herbs; Salinity; Secondary metabolites PMID: 29454868 DOI: 10.1016/j.fct.2018.02.031

The Effect of Some Natural Essential Oils Against Bovine Mastitis Caused by Prototheca zopfii Isolates In Vitro.

Mycopathologia. 2018 Jan 27. doi: 10.1007/s11046-018-0246-9. [Epub ahead of print] Grzesiak B1, Kołodziej B2, Głowacka A3, Krukowski H4. Author information 1 Department of Environmental Biology, Medical University of Lodz, Żeligowskiego 7/9, 90-572, Lodz, Poland. barbara.grzesiak@umed.lodz.pl. 2 Department of Industrial and Medicinal Plants, University of Life Sciences in Lublin, Akademicka 15, 20-950, Lublin, Poland. 3 Department of Environmental Biology, Medical University of Lodz, Żeligowskiego 7/9, 90-572, Lodz, Poland. 4 Department of Animal and Environmental Hygiene, University of Life Sciences in Lublin, Akademicka 13, 20-950, Lublin, Poland. Abstract The aim of the study was to evaluate the effect of essential oils obtained from Thymus vulgaris L., Origanum vulgare L., Origanum majerana L., Mentha × piperita L. and Allium ursinum L. against Prototheca zopfii strains that cause inflammation of the udder (mastitis) in cows. The study was conducted on ten strains derived from milk samples. The microdilution method was used to determine the sensitivity of P. zopfii strains to the studied essential oils, and the disk diffusion method was used to determine the sensitivity to antifungal chemotherapeutics. The plates were incubated for 48 h at 37 °C under aerobic conditions. All strains of algae were sensitive to the essential oils marjoram, thyme and oregano and resistant to mint and garlic oils. MIC values ranged from 0.25 to 1 μl/ml. Marjoram oil demonstrated the greatest activity, and oregano oil the weakest. Among the antifungal agents tested, 90% of strains showed sensitivity to nystatin. One of the tested strains (71/IV) was resistant to all investigated antifungal agents. The tested essential oils are known to have anti-algae activity and can be used as natural agents for prophylaxis in animals, particularly in mastitis-affected cows. KEYWORDS: Cow’s milk; Essential oils; Inhibitory effect; Mastitis; Prototheca PMID: 29380186 DOI: 10.1007/s11046-018-0246-9

HPTLC determination of diosgenin in fenugreek seeds.

Acta Pharm. 2018 Mar 1;68(1):97-107. doi: 10.2478/acph-2018-0002. Król-Kogus B1, Lamine KM2, Migas P1, Boudjeniba M2, Krauze-Baranowska M1. Author information 1 1Department of Pharmacognosy with Medicinal Plants Garden Medical University of Gdańsk 80-416 Gdańsk, Poland. 2 2Laboratoire d'Ethnobotanique et Substances Naturelles Ecole Normale Supérieure de Kouba B.P 92 Kouba, 16050 Algerie. Abstract A new HPTLC-densitometric method for diosgenin determination in fenugreek seeds was established after optimization of the conditions for efficient saponin extraction and acid hydrolysis. Several procedures were tested, the best of which was a three-step Soxhlet extraction, followed by hydrolysis of the obtained methanolic extract with 2 mol L-1 H2SO4. Best diosgenin separation from other hydrolysis products was obtained on HPTLC Si60F254 plates u sing a mixture of n-heptane/ethyl acetate (7:3, V/V) and modified anisaldehyde as a spraying reagent. The method was preliminarily validated and the determined amounts of diosgenin in fenugreek seeds of Polish and African origin were found to be similar and ranged from 0.12-0.18 %. KEYWORDS: HPTLC; diosgenin; fenugreek (Trigonella foenum-graecum); quantitative analysis PMID: 29453912 DOI: 10.2478/acph-2018-0002

Use of non-conventional medicine two years after cancer diagnosis in France: evidence from the VICAN survey.

J Cancer Surviv. 2017 Aug;11(4):421-430. doi: 10.1007/s11764-017-0599-y. Epub 2017 Feb 1. Sarradon-Eck A1,2, Bouhnik AD3, Rey D3,4, Bendiane MK3,4, Huiart L3,5,6, Peretti-Watel P3,4. Author information 1 Aix Marseille Univ, INSERM, IRD, SESSTIM, "Economics & Social Sciences Applied to Health & Analysis of Medical Information", Marseille, France. aline.sarradon@inserm.fr. 2 Inst Paoli Calmettes, SESSTIM, Marseille, France. aline.sarradon@inserm.fr. 3 Aix Marseille Univ, INSERM, IRD, SESSTIM, "Economics & Social Sciences Applied to Health & Analysis of Medical Information", Marseille, France. 4 ORS PACA, Southeastern Health Regional Observatory, Marseille, France. 5 CHU de la Réunion, Unité de Soutien Méthodologique, Saint Denis, France. 6 CHU de la Réunion, INSERM, CIC 1410, Saint-Pierre, France. Abstract PURPOSE: The purpose of this study was to assess the use of non-conventional medicine (NCM) in a representative sample of French patients 2 years after cancer diagnosis. METHODS: The study was based on data obtained in the VICAN survey (2012) on a representative sample of 4349 patients 2 years after cancer diagnosis. Self-reported data were collected at telephone interviews with patients. The questionnaire addressed the various types of non-conventional treatments used at the time of the survey. RESULTS: Among the participants, 16.4% reported that they used NCM, and 45.3% of this group had not used NCM before cancer diagnosis (new NCM users). Commonly, NCMs used were homeopathy (64.0%), acupuncture (22.1%), osteopathy (15.1%), herbal medicine (8.1%), diets (7.3%) and energy therapies (5.8%). NCM use was found to be significantly associated with younger age, female gender and a higher education level. Previous NCM use was significantly associated with having a managerial occupation and an expected 5-year survival rate ≥80% at diagnosis; recent NCM use was associated with cancer progression since diagnosis, impaired quality of life and higher pain reports. CONCLUSION: This is the first study on NCM use 2 years after cancer diagnosis in France. In nearly half of the NCM users, cancer diagnosis was one of the main factors which incited patients to use NCM. Apart from the NCM users' socioeconomic profile, the present results show that impaired health was a decisive factor: opting for unconventional approaches was therefore a pragmatic response to needs which conventional medicine fails to meet during the course of the disease. IMPLICATIONS FOR CANCER SURVIVORS: Better information of patients and caregivers is needed to allow access to these therapies to a larger population of survivors. KEYWORDS: Cancer survivors; Cohort study; Complementary and alternative medicine; Coping; France; Integrative medicine PMID: 28150122 DOI: 10.1007/s11764-017-0599-y [Indexed for MEDLINE]

[Effectiveness of preventive treatment by Influenzinum in the winter period against the onset of influenza-like illnesses].

Therapie. 2017 Sep;72(4):465-474. doi: 10.1016/j.therap.2016.12.011. Epub 2017 Feb 17. [Article in French] Marinone C1, Bastard M1, Bonnet PA1, Gentile G1, Casanova L2. Author information 1 Département de médecine générale, Aix-Marseille université, 27, boulevard Jean-Moulin, 13385 Marseille cedex 05, France. 2 Département de médecine générale, Aix-Marseille université, 27, boulevard Jean-Moulin, 13385 Marseille cedex 05, France. Electronic address: ludovic.casanova@inserm.fr. Abstract AIM: In vitro Influenzinum induce a cellular change. We present the results of the first study examining the effectiveness of Influenzinum against influenza-like illnesses. METHOD: Retrospective cohort study during winter 2014-2015. After influenza epidemic, a self-assessment questionnaire was offered to patients presenting for a consultation. The primary endpoint was the declaration of an influenza-like illness. The exposed patients (treated by Influenzinum) were matched to two non-exposed patients (untreated) with a propensity score. A conditional logistic model expressed influenza-like illness risk reduction provided by the Influenzinum. RESULTS: The cohort included 3514 patients recruited from 46 general practitioners. After matching, the treated group (n=2041) and the untreated group (n=482) did not differ on variables collected. Influenzinum preventive therapy does not significantly alter the likelihood of influenza-like illness (adjusted odds ratio=0,91 [0,62 to 1,35], p=0,64). CONCLUSION: Influenzinum preventive therapy did not appear effective in preventing influenza-like illness. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved. KEYWORDS: Active immunization; Ambulatory care; Grippe humaine; Homeopathy; Homéopathie; Human influenza; Influenzinum; Médecine ambulatoire; Propensity score; Score de propension; Vaccination

Introduction: Novel hybrid combinations containing synthetic or antibiotic drugs with plant-derived phenolic or terpenoid compounds

Phytomedicine. 2017 Dec 15;37:1-3. doi: 10.1016/j.phymed.2017.10.020. Epub 2017 Nov 2. Wagner H1, Efferth T2. Author information 1 Department Pharmacy, Center for Pharma Research, Butenandtstr. 5, House B, 81377 Munich, Germany. Electronic address: Wagner.Breitbrunn@t-online.de. 2 Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany. Abstract BACKGROUND: There is a paradigm shift in chemotherapy from mono-drug therapy towards multidrug combination regimens. Natural products from medicinal plants may play an important role for the design of novel combination therapy protocols. HYPOTHESIS: We introduce the novel term "hybrid combination" for the therapeutic combination of chemically defined plant-derived constituents (e.g. phenolic or terpenoid compounds with synthetic or antibiotic drugs to increase pharmacological activity and simultaneously toxic side effects. STUDY DESIGN: Several literature databases were screened on the combination of phenolic/terpenoid compounds with synthetic/antibiotic drugs. RESULTS: Phenolic compounds are water soluble and interact with target proteins due to their OH-groups. They reveal antioxident, antiinflammatory and sometimes apoptotic activities whereas the terpenoids possess due to their lipophilic nature together with the phenolics amphiphilic properties and thereby good cell-penetrating features. They reveal antioxidant properties, anti-inflammatory and sometimes apoptotic activities as well as cell-penetrating features due to their amphiphilicity. Synergistic or antagonistic interactions with synthetic or antibiotic drugs have to be demonstrated by using suitable methods (e.g. isobologram analysis). The molecular modes of action may be elucidated by approaches of network pharmacology (e.g. protein-protein interaction networks). CONCLUSION: There is convincing evidence for the improvement of pharmacological activity at reduced side effects by hybrid combinations. Future efforts should focus on clinical trials with hybrid combinations to treat a broad range of diverse diseases such as cardiometabolic and neurotropic syndromes, drug resistance phenotypes, and so-called neglected infectious diseases. Copyright © 2017. Published by Elsevier GmbH. KEYWORDS: Antibiotics; Natural products; Network pharmacology; Phytochemicals; Synergism PMID: 29174652 DOI: 10.1016/j.phymed.2017.10.020

Constructing Scientific Communities Midland Medical Miscellany (1881-95)

Posted: 23 Feb 2018 01:00 AM PST MMM One of the pleasures of working with a physical collection of journals is serendipity. Scholars of periodical literature frequently cite chance encounters with interesting material as the chief advantage of engaging with original, hard-copy sources. My PhD research drew extensively on a collection of journals in the Royal College of Surgeons of England’s library. It was while I was wandering around their underground stacks that I came across the Midland Medical Miscellany. I was initially attracted by its playfully alliterative title and its beautiful frontispiece. However, I soon became absorbed by its insight into provincial medical identities and its in-depth discussions of ‘problem’ patients. This was not an irreverent ‘light entertainment’ magazine but a serious periodical catering for beleaguered practitioners outside the metropolis. Medical Miscellany A periodical for the provinces The Miscellany was a general medical monthly which launched in 1881 as a Leicester-based publication. It was originally edited by Kenneth W. Millican, a general practitioner in the village of Kineton (Warwickshire) and later a specialist in throat diseases in London. In a future blog post I’ll be profiling Millican, showing how he presented himself as a spokesperson for provincial practitioners but ended up leading a relatively cosmopolitan career. In 1885, editorship passed to Thomas Michael Dolan, a doctor based in Halifax. The periodical was renamed the Provincial Medical Journal, a title it retained until it folded in 1895. The inaugural issue of the Miscellany featured a long opening address, which set out the journal’s intended readership. While noting that its ‘careful selection of information’ would not ‘be uninteresting to those in what are commonly considered to be the higher ranks of the profession’, it asserted that it was designed to be of ‘especial value to the hardworking and leisureless General Practitioner’. In particular, it felt that its condensed reports of new research would be ideally suited to the ‘overworked’ medical man.[1] This editorial engaged with common tropes about the toils of provincial and country general practice. As its later title implies, the journal proudly asserted its provincial character, while criticising the metropolitan elite. In 1882, the Miscellany reprinted comments made by its future editor. Dolan had characterised England’s major medical journals – the Lancet and the British Medical Journal (BMJ) – as essentially ‘London publication[s]’. He suggested that: the literary activities of the provincial general practitioners were increasing each year – the London Practitioner alone could produce enough material to fill the Lancet and Medical Journal – therefore, if they desired not to be beaten out of the field, they must look for a new vehicle for the conveyance of their thoughts. The Miscellany styled itself as this ‘new vehicle’. It modestly suggested that it did not lay claim to be ‘at present in a position adequately to represent the General Medical Practitioners of the Country’, but emphasised that it was ‘compiled in [their] interests’.[2] The journal suggested that there was an opening in the market for a new type of publication, implying that provincial GPs felt underrepresented by mainstream metropolitan journals. It positioned itself as better suited to these readers’ interests and lifestyle. By insinuating that the BMJ privileged metropolitan practitioners, Dolan implied that it had alienated its traditional readership. The BMJ began life in 1840 as the Provincial Medical and Surgical Journal (PMSJ), the defacto periodical of the Provincial Medical and Surgical Association. Both were rebranded in the 1850s, becoming the BMJ and British Medical Association respectively. These changes were controversial; some Association members expressed fears that the interests of the metropolis were being prioritised over those of the provinces.[3] Under Dolan’s editorship, the Miscellany was later renamed the Provincial Medical Journal. This was presumably a marketing tactic designed to increase the journal’s appeal outside the Midlands; by this time, it was also published in London, Edinburgh, and Dublin. Further, by framing itself as a journal for provincial medical practitioners, it effectively positioned itself in the space once occupied by the PMSJ. Perhaps this was a bid to claim the BMJ’s disaffected readers, though it came several decades after the controversy surrounding that journal. Scholars have discussed the diminishing popularity of the ‘provincial’ as a template for national identity.[4] However, the journal’s use of the term as late as the 1880s and 90s indicates a desire to reclaim provincialism and assert it as a broader identity. The journal addressed itself to all those who practised outside of the metropolis. pmj.jpg Engaging with ‘problem’ patients Upon its launch, the Miscellany asserted that among its chief interests were ‘Ethics and Etiquette, the relations of members of the profession with the public’.[5] The journal did not adopt a romanticised perspective of the doctor-patient relationship, but rather discussed what it saw as the challenges of general practice. In 1882, it featured a lengthy article on ‘The Question of Patients’, which focused on the difficulties encountered in ‘diagnostic interrogation’. The article demonstrated remarkable snobbery towards ‘the badly educated classes’, remarking on the ‘sheer inability […] of persons who have led unintelligent lives, to grasp the meaning and importance of questions that are put to them’.[6] The writer implied that patients were to blame for unsatisfactory medical interactions. Two months later, the journal published a feature on ‘A Practitioner’s Grievances’, many of which related specifically to country practice, particularly the demands made on ‘the Doctor’s time’. It complained that, ‘in country districts, especially, it is almost impossible to induce patients to send their messages to the doctor in decent time’. It described the practitioner arriving home after a long day, ‘weary and hungry’, only to ‘find a message awaiting him’ to return to a village he had visited earlier that day. This frustration is compounded by the fact he ‘finds that the patient has been ill for a week, and that to-morrow morning would have done just as well’.[7] Complaints about patients requesting attendance at inconvenient times were not unusual, though together these articles seem particularly critical of patients. The journal was also concerned about medical men’s interactions with women. In these instances it was the practitioner (rather than the patient) who was supposed to alter his behaviour. An article on ‘The Relation of Medical Men to their Patients’ (1885) counselled ‘[y]oung medical practitioners [to] bear in mind a few general truths in their dealings especially with female patients’. It recommended that ‘[c]onfidential relations with ladies of a household’ were to be ‘absolutely declined’ and that ‘examinations of female patients should always be made in presence of a third person’.[8] Such warnings were common in medical writing. Jukes de Styrap’s The Young Practitioner (1890) – an advice guide for aspiring medical men – counselled its readers to be ‘extremely cautious […] in having married women or young females to consult you secretly’.[9] Practitioners were taught that their encounters with female patients should be conducted with propriety. Medical men in rural or small-town practices were thought to be particularly susceptible to rumour, innuendo and scandal. In 1883, the Miscellany reprinted a poem entitled ‘The Doctor’s Dream’, which originally appeared in Punch.[10] The poem’s speaker is a village practitioner, who reminisces about his life and career. One of the challenges he recalls is having ‘[t]o face and brave the gossip and stuff that travels about through a country town;/ To be thrown in the way of hysterical girls, and live all terrible scandal down’. Though humorous in tone, the Miscellany suggested that the poem was ‘worthy of preservation in medical literature’ and likely to ‘strike a chord in every medical man’s heart’.[11] The Miscellany’s later incarnation, the PMJ, featured an article on ‘Doctors and Lady Patients’ (1887) which warned of the dangers surrounding long visits to women. It noted that, ‘[i]n London possibly they might escape, for a time, from the eye of Mrs Grundy […] In provincial towns medical men who are too attentive, very soon fall under her ken and then – Nemesis!’[12] These pieces show how communities might police the practitioner’s professional conduct. The Miscellany/PMJ framed itself as a riposte to the dominance of the London periodical press and capitalised on the provincial medical man’s perceived resentment towards his metropolitan counterparts. It grappled with the supposed challenges of general practice and proudly asserted its provincialism. While it enjoyed almost fifteen years in circulation, the fact it eventually folded perhaps indicates that its approach was not particular popular with medical readers. The journals that it attacked – the Lancet and BMJ – remained the most widley read titles. [1] ‘Introduction’, Midland Medical Miscellany, January 1881, pp. 1-2 (p. 1). [2] ‘A Journal for the General Practitioner’, Midland Medical Miscellany, April 1882, p. 55. [3] For an overview, see Peter W.J. Bartrip, Mirror of Medicine: The BMJ, 1840-1990 (Oxford: Oxford University Press, 1990) [4] Robin Gilmour, ‘Regional and Provincial in Victorian Literature’, in The Literature of Region and Nation, ed. by R.P. Draper (Basingstoke: Macmillan, 1989), pp. 51-60 (p. 52). [5] ‘Introduction’, pp. 1-2. [6] ‘The Question of Patients’, Midland Medical Miscellany, February 1882, pp. 21-4 (p. 22). [7] ‘A Practitioner’s Grievances’, Midland Medical Miscellany, April 1882, pp. 51-2 (p. 51). [8] ‘The Relation of Medical Men to their Patients’, Midland Medical Miscellany, 1 January 1885, p. 23. [9] Jukes de Styrap, The Young Practitioner (London: H.K. Lewis, 1890), p. 110. This book was based on Daniel Webster Cathell’s popular US manual, Book on the Physician Himself (1881), which exercised similar caution. [10] ‘The Doctor’s Dream’, Punch, 20 January 1883, p. 35. [11] ‘The Doctor’s Dream’, Midland Medical Miscellany, February 1883, pp. 63-4 (p. 63). [12] ‘Annotations: Doctors and Lady Patients’, Provincial Medical Journal, 1 January 1887, p. 35.

Inclusion of Yucca schidigera extract in diets with different protein levels for dogs

Authors Jéssica S. Dos Reis, Márcio G. Zangerônimo, Rosana C. S. Ogoshi, Janine França, Adriano C. Costa, Thomás N. Almeida, João P. F. Dos Santos, Carolina P. Pires, Ana F. Chizzotti, Carlos A. L. Leite, Flávia M. O. B. Saad First published: 21 January 2016Full publication history DOI: 10.1111/asj.12535 View/save citation Cited by (CrossRef): 0 articles Check for updates Citation tools Abstract This study evaluated the effects of inclusion of Yucca schidigera extract (YSE) in two diets with different levels of crude protein (CP) for dogs on facal odour, nutrient digestibility, ammonia concentration in feces and hematological and serum biochemical profiles. Twenty adults Beagles were used, distributed in a randomized block design in a 2 × 4 factorial design (two diets, 25% and 34% CP, and four YSE levels: 0, 250, 500 and 750 mg/kg) with five replicates, obtained during two experimental periods. The fecal odour reduced (P < 0.05) when 500 mg/kg of YSE was used in diets with higher CP. The inclusion of YSE reduced (P < 0.05) fecal ammonia, and the inclusion of 250 and 500 mg/kg YSE reduced intestinal gas. The inclusion of 750 mg/kg YSE increased the mean corpuscular hemoglobin (MCH), alanine aminotransferase (ALT) activity and tended to increase the serum cholesterol concentration, regardless of the protein level of the diets. There was no effect on the digestibility of nutrients, fecal consistency, nitrogen balance and thickness of the intestinal wall. The inclusion of 500 mg/kg YSE is effective in reducing fecal odour in dogs receiving diets with 34% of CP. Regardless of the protein content, YSE reduces fecal ammonia, but may cause adverse effects if included at higher doses.

Neurologically Potent Molecules from Crataegus oxyacantha; Isolation, Anticholinesterase Inhibition, and Molecular Docking.

Neurologically Potent Molecules from Crataegus oxyacantha; Isolation, Anticholinesterase Inhibition, and Molecular Docking Mumtaz Ali1*, Sultan Muhammad1, Muhammad R. Shah2, Ajmal Khan3,4*, Umer Rashid3, Umar Farooq3, Farhat Ullah5, Abdul Sadiq5, Muhammad Ayaz5, Majid Ali3, Manzoor Ahmad1 and Abdul Latif1* 1Department of Chemistry, University of Malakand, Chakdara, Pakistan 2International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan 3COMSATS Institute of Information Technology, Abbottabad, Pakistan 4UoN Chair of Oman Medicinal Plants and Marine Products, University of Nizwa, Nizwa, Oman 5Department of Pharmacy, University of Malakand, Chakdara, Pakistan Crataegus oxyacantha is an important herbal supplement and famous for its antioxidant potential. The antioxidant in combination with anticholinesterase activity can be considered as an important target in the management of Alzheimer’s disease. The compounds isolated from C. oxyacantha were evaluated for cholinesterases inhibitory activity using Ellman’s assay with Galantamine as standard drug. Total of nine (1–9) compounds were isolated. Compounds 1 and 2 were isolated for the first time from natural source. Important natural products like β-Sitosterol-3-O-β-D-Glucopyranoside (3), lupeol (4), β-sitosterol (5), betulin (6), betulinic acid (7), oleanolic acid (8), and chrysin (9) have also been isolated from C. oxyacantha. Overall, all the compounds exhibited an overwhelming acetylcholinesterase (AChE) inhibition potential in the range 5.22–44.47 μM. The compound 3 was prominent AChE inhibitor with IC50 value of 5.22 μM. Likewise, all the compounds were also potent in butyrylcholinesterase (BChE) inhibitions with IC50s of up to 0.55–15.36 μM. All the compounds, except 3, were selective toward BChE. Mechanism of the inhibition of both the enzymes were further studied by docking procedures using Genetic Optimization for Ligand Docking suit v5.4.1. Furthermore, computational blood brain barrier prediction of the isolated compounds suggest that these are BBB+. Introduction Neurodegenerative disorders affecting a huge number of elder population worldwide (Novakovic et al., 2013). The etiology of neuronal death in these diseases remains inexplicable (Beal, 1995). The onset of these diseases is quite dangerous with gradual progression (Howes et al., 2003). The disorders include Alzheimer’s disease (AD), Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and cerebellar degenerations (Beal, 1995). Of these, AD is a chronic neurodegenerative disorder and is the most common type of dementia (Yoshita et al., 2001). AD is supposed to be account for 50–60% of dementia cases in elderly patients (Francis et al., 1999). Major symptoms associated with AD are memory loss, behavioral turbulence and mood disturbance in routine life (Kumar et al., 1998). Several biochemical pathways are followed for the management of AD but one of the most established approach is the inhibition of acetylcholinesterase (AChE) (Zeb et al., 2014; Ahmad et al., 2015; Kamal et al., 2015; Sadiq et al., 2015). The AChE is found in excitable tissues in most erythrocytes and in the placental tissues while butyrylcholinesterase (BChE) is present in nervous system, liver and plasma (Massoulié et al., 1993). In cholinergic synapse, a vital neurotransmitter acetylcholine (ACh) is break down into acetyl group and choline by AChE and BChE (Voet and Voet, 1995). The reduction of ACh concentrations in the hippocampus and cortex of brain can bring a vital biochemical change in AD patients (Jaén et al., 1996). Therefore, a key target in the management of AD is the inhibition of AChE and BChE (Schneider, 1995). Several cholinesterase inhibitors from natural and synthetic sources are available like galantamine, donepezil, rivastigmine, and tacrine (Schulz, 2003). Numerous researchers have also shown that oxidative stress is an early pathogenic event in AD (Sadiq et al., 2015). Therefore, they supplement their anticholinesterase with antioxidants as free radicals scavengers. A constant research is going in the field of AD, which brought several reports from natural product sources and synthetic origin (Ayaz et al., 2014; Sadiq et al., 2015). However, most of these remedies are associated with severe side effects, low efficacy or availability. Therefore, the researchers working on AD are in constant search of novel, safe, effective, and economical origin of drugs. Recently, galantamine isolated from several species of Amaryllidaceae family including Galanthus species, Leucojum species, and Narcissus species was effectively marketed for the symptomatic relief of AD (Parys, 1998). Galantamine mediate its therapeutic effect via reversible inhibition of acetyl cholinesterase (AChE) and allosterically mediate the action of nicotinic cholinergic receptors (nAChRs). Its selectivity against cholinesterase of different origin is variable. For instance the galantamine selectivity against human erythrocytes (RBCs) based AChE is fifty three times greater than plasma based BChE. Furthermore, galantamine exhibited 10 times lower potency against human brain based AChE as compared to RBCs variant (Harvey, 1995). Crataegus oxyacantha, a flowering shrub of Rosaceae family is medicinally used as cardiovascular tonic, anti-hypertensive and agent to induce blood lipid profile (Weihmayr and Ernst, 1996). This plant, also known as hawthorn is an economical and rich source of triterpenic acids, ursolic acid, oleanolic acid, polyphenols like procyanidins, epicatechin, hyperoside, isoquercitrin, chlorogenic acid, and other important organic molecules (Cui et al., 2006). In this piece of research work, we have isolated bioactive compounds from the aerial parts of C. oxyacantha. Furthermore, the purified compounds after structure confirmations were subjected to anticholinesterase inhibition assay. In the current study we have isolated two new (1 and 2) and seven (3–9) reported compounds from the C. oxyacantha. C. oxyacantha is herbal supplement and is mainly known for its antioxidant, antimicrobial, anti-inflammatory, gastroprotective, and anti-arrhythmic potentials (Tankanow et al., 2003; Tadic‘ı et al., 2008; Kashyap et al., 2012; Kostić et al., 2012). The compound 3 isolated from C. oxyacantha, also called β-sitosterol-3-O- β -D-glucopyranoside is majorly reported with antitumor (Guevara et al., 1999), antiprotozoal (Alanís et al., 2003), antimicrobial (Kuete et al., 2007), and as DNA polymerase inhibitor (Mizushina et al., 2006). Lupeol a naturally occurring triterpenoid is recently identified and quantified by HPLC analysis in the hawthorn ethanolic extract (Rezaei-Golmisheh et al., 2015). Lupeol (4) has been studied for its possible use in hepatoprotective (Sunitha et al., 2001), anti-inflammatory (Fernández et al., 2001), anticancer (Saleem et al., 2001, 2004), and in inhibition of protein tyrosine phosphatase (Na et al., 2009). An important phytosterol, i.e., β-sitosterol (5) was also isolated from C. oxyacantha. β-Sitosterol mostly found in vegetable oil, nuts, and avocados has also been reported with clinical trial for it possible use in the management of benign prostatic hyperplasia (Berges et al., 1995). Betulin (6) can be easily converted to its structure analog betulinic acid (7) and those compounds are reported with identical activities like antimalarial (Alakurtti et al., 2006), anti-inflammatory (Alakurtti et al., 2006), anticancer (Alakurtti et al., 2006), antiviral (Pavlova et al., 2003), and as anti-AIDS (Sun et al., 1998). The oleanolic (8) and ursolic acids are famous for their reported activities like hepatoprotective, anti-inflammatory, antihyperlipidemic, antioxidant, and antitumor effects (Liu, 1995). C. oxyacantha is a rich source of flavonoids (Li et al., 2009). Chrysin (9), naturally occurring flavonoid is majorly reported for its possible use in the management of cancer (Zheng et al., 2003), anxiety (Brown et al., 2007), inflammation (Woo et al., 2005), and in behavioral effects (Zanoli et al., 2000). Based on the literature survey it can be obviously scrutinized that there is no report available on the acetyl or BChE inhibitions of the compounds isolated from C. oxyacantha. Materials And Methods General Information Column Chromatography was used to purify the compounds using silica gel (E. Merck, 70–300 mesh) and flash silica gel (E. Merck, 230–400 mesh). Thin-layer chromatography (TLC) was carried out pre-coated aluminum sheets (60 F254, E. Merck). Purity of the compounds was also checked on the same pre-coated plates visualized under UV light (254 and 366 nm). UV spectra were obtained on Optima SP3000 plus (Japan) using chloroform and methanol as solvent. IR spectra were analyzed on an Elmer Fourier-Transform spectrometer, using KBr plates. 1H, 13C NMR, and 2D-NMR (HMQC, HMBC, NOSEY, and COSEY) spectra were recorded on a JEOLl ECA 600 (United States) and Bruker AV 500 (Germany) spectrometers. Tetramethylsilane (TMS) was used as an internal standard and Chemical shifts (δ) were expressed in ppm relative to TMS. Plant Material Crataegus oxyacantha was collected from local area of Pashtonai (72° 18′ 36″ E, 35° 03′18′ N), KP, Pakistan in June 2013 during flowering season. Plant was identified by Prof. Mahboob Ur Rehman, Govt. Jehanzeb College Swat. Voucher specimen (C-124) was retained for verification purpose in herbarium of the College. Extraction and Isolation Plant twigs were shade dried at room temperature and chopped. Dry powdered plant (22 Kg) was extracted with methanol (3 L × 30 L) at room temperature. The methanolic extract was concentrated under reduced pressure at 50°C using rotary evaporator (R-301, Bucchi) and obtained a gummy extract (1 Kg). The extract was suspended in water and successively partitioned to hexane, dichloromethane, ethyl acetate, and butanol fractions. DCM soluble fraction was subjected to column chromatography over silica gel using n-hexane: ethyl acetate and ethyl acetate: methanol as eluting solvent system which yielded nine daughter fractions (S1–S9). On repeated column chromatography of these nine resulted in two new (1–2) seven (3–9) known compounds. [2-(3, 4-Dimethoxyphenyl)-2-Methoxyethanol] (1) Slightly greenish in color, IR (KBr) max: 3425, 1570, 3450, and 1245 cm-1; EI-MS m/z: 212 [M+] (calcd. 212.1049 for C11H16O4); 1H-NMR (DMSO, 300 MHz) δ: 6.87 (1H, s, H-2), 6.71 (1H, m, H-5), 6.71 (1H, m, H-6), 4.60 (1H, d, J = 3.9Hz, H-7), 4.12 (2H, t, J = 2.9Hz, H-8), 3.71 (3H, s, Me-9), 3.70 (3H, s, Me-10), 3.01 (3H, s, Me-11). 3-Hydroxy-1-(4-Hydroxy-3-Methoxyphenyl) Propan-1-One (2) Amorphous solid compound; IR (KBr) max: 3420, 1685, 1580, 3460, and 1240 cm-1; EI-MS m/z: 194 [M+] (calcd. 194.0943 for C11H14O3); 1H-NMR (DMSO, 300 MHz) δ: 3.04 (2H, t, J = 6.3Hz, H-2), 3.74 (2H. t, J = 6.3Hz, H-3), 3.81 (3H, s, Me-4), 7.43 (1H, d, J = 1.2Hz, H-2′), 6.85 (1H, d, J = 8.1, H-5′), 7.50 (1H, dd, J = 8.1, 1.2Hz, H-6′). β-Sitosterol-3-O-β-D-Glucopyranoside (3) White amorphous solid; IR νmax (KBr): 3452, 1648, 1379 and 1065 cm-1; EI-MS: m/z 414.0000 (calcd. for [C29H450O]+); 1H-NMR (DMSO, 300 MHz) δ: 1.20 (2H, m, H-1), 1.66 (2H, s, H-20), 3.51 (1H, m, H-3), 2.21 (2H, m, H-4), 5.35 (1H, m, H-6), 1.40 (2H, m, H-7), 1.44 (1H, m, H-8), 1.56 (1H, m H-9), 1.40 (2H, s, H-11), 1.41 (2H, s, H-12), 1.40 (1H, m, H-14)1.42 (2H, m, H-15), 1.86 (2H, s, H-16), 1.48 (2H, m, H-17), 0.64 (3H, s, Me-18), 1.0 (3H, m, Me-19), 1.66 (1H, m, H-20), 0.92 (3H, d, Me-21), 1.68 (2H, s, H-22), 0.83 (2H, s, H-23), 0.82 (1H, s, H-24), 1.2 (1H, m, H-25), 0.82 (3H, d, J = 6.51 Hz, Me-26), 0.81 (3H, d, J = 6.51 Hz, Me-27), 1.34 (2H, m, H-28), 0.84 (3H, t, J = 6.91 Hz, Me-29), 4.57 (1H, d, J = 7.51 Hz, H-1′), 3.14 (1H, m, H-2′), 3.21 (1H, m, H-3′), 3.24 (1H, m, H-4′), 3.35 (1H, m, H-5′), 3.85 (2H, dd, J = 11.8 Hz, H-6′). Lupeol (4) White powder; FT-IR (neat) max: 3406, 1645, 1495, 1381, 1183, 1104, 1039, 985, 940 cm-1. Molecular formula: C30H50O; EI-MS m/z: 426 [M+] (calcd. 426.0000 for C30H50O); EI-MS m/z (rel. int.) (%): 426 (55.45), 393 (3.71), 315 (13.57), 257 (10.04), 234 (18.16), 189 (68.11), 161 (30.98), 135 (63.03); 1H-NMR (CDCl3, 300 MHz) δ: 1.69 (2H, dd, J = 6.12Hz, H-1), 1.37 (2H, m, H-2), 3.16 (1H, dd, J = 11.46 Hz, 4.8 Hz, H-3), 0.66 (1H, m, H-5), 1.37 (2H, m, H-6), 1.37 (2H, m, H-7), 1.24, 1.27 (1H, m, H-9), 1.55, 1.59 (2H, m, H-11), 1.66 (2H, m, H-12), 0.89, 1.69 (1H, m, H-13), 1.55 (2H, d, H-15), 1.37 (2H, m, H-16), 1.32 (1H, d, H-18), 2.37 (1H, m, H-19), 1.24 (2H, q, H-21), 1.18 (2H, m, H-22), 0.95 (3H, s, Me-23), 0.81 (2H, s, H-24), 1.01 (3H, s, Me-25), 0.74 (3H, s, Me-26), 0.93(3H, s, Me-27), 0.77 (3H, s, Me-28), 4.46 (2H, m, H-29), 1.66 (3H, s, Me-30). β-Sitosterol (5) White powder; IR (KBr) max: 3406, 2905, and 1640 cm-1; Molecular formula C29H50O; EI-MS: m/z 414 [M+] (calcd. 414.0000 for C29H50O); 1H-NMR (DMSO, 300 MHz) δ: 1.07 (2H, dd, J = 6.12 Hz, H-1), 1.23, 1.48 (2H, m, H-2), 3.52 (2H, m, H-3), 1.98 (2H, t, H-4), 5.33 (1H, d, H-6), 1.44 (2H, m, H-7), 1.42 (1H, m, H-8), 0.84 (1H, m, H-9), 1.49, 1.47 (1H, m, H-11), 2.19 (2H, d, J = 2.1, H-12), 0.96 (1H, m, H-14), 1.56 (2H, m, H-15), 1.23 (3H, m, Me-16), 1.07 (1H, d, J = 7.8, H-17), 0.66 (3H, s, Me-18), 0.99 (3H, s, Me-19), 1.35 (1H, m, H-20), 0.90 (3H, d, J = 5.26Hz, Me-21), 1.27 (2H, m, H-22), 1.14 (2H, m, H-23), 0.92 (1H, m, H-24), 1.26 (1H, m, H-25), 0.79 (3H, d, J = 6.8 Hz, Me-26), 0.81 (3H, d, J = 5.58 Hz, Me-27), 1.22 (2H, m, H-28), 0.82 (3H, t, J = 7.5 Hz, Me-3). 3β, 28-Dihydroxylup-20(29)-ene (Betulin) (6) White amorphous powder; IR (KBr) ýmax: 3400, 1603.4 cm-1; EI-MS m/z 442 [calcd. 442.0000 for M+, C30H50O2]; 1H-NMR (MeOD, 300 MHz) δ: 1.44 (2H, m, H-1), 1.44 (2H, m, H-2), 4.01 (1H, dd, J = 10.8 Hz, H-3), 1.40 (1H, m, H-5), 1.42 (2H, m, H-6), 1.44 (2H, m, H-7), 1.39 (1H, m, H-9), 1.42 (2H, m, H-11), 1.42 (2H, m, H-12), 1.40 (1H, m, H-13), 1.44 (2H, m, H-15), 1.44 (2H, m, H-16), 1.42 (1H, m, H-18), 2.39 (1H, m, H-19), 1.39 (2H, m, H-21), 1.30 (2H, m, H-22), 0.94 (3H, s, Me-23), 0.80 (3H, s, Me-24), 0.74 (3H, s, Me-25), 1.06 (3H, s, Me-26), 1.00 (3H, s, Me-27), 3.40 (2H, m, H-28), 4.66 (3H, s, Me-29), 1.66 (3H, s, Me-30). 3β-Dihydroxylup-20(29)-ene-28-oic Acid (Betulinic Acid) (7) White amorphous powder; IR (KBr) ýmax: 3500, 1700, 1625 cm-1; EI-MS m/z 442 [M+, C30H48O3]; 1H-NMR (DMSO, 300 MHz) δ: 1.44 (2H, m, H-1), 1.44 (2H, m, H-2), 3.47 (1H, dd, J = 10.2 Hz, H-3), 1.39 (1H, m, H-5), 1.41 (2H, m, H-6), 1.44 (2H, m, H-7), 1.40 (1H, m, H-9), 1.41 (2H, m, H-11), 1.41 (2H, m, H-12), 1.40 (1H, m, H-13), 1.44 (2H, m, H-15), 1.87 (2H, m, H-16), 1.71 (1H, m, H-18), 3.0 (1H, t, J = 10.2, 5,5 Hz, H-19), 1.47 (2H, m, H-21), 1.72 (2H, m, H-22), 0.82 (3H, s, Me-23), 0.95 (3H, s, Me-24), 0.81 (3H, s, Me-25), 0.95 (3H, s, Me-26), 0.93 (3H, s, Me-27), 4.66 (3H, s, Me-29), 1.68 (3H, s, Me-30). 3β-Hydroxyurs-12-en-28-oic Acid (Oleanolic Acid) (8) Colorless crystals (CHCl3–MeOH); IR (KBr) ýmax: 3450 cm-1, 1700 cm-1; EI-MS m/z 456 [M+, C30H48O3]; 1H-NMR (DMSO, 300 MHz) δ: 1.43 (2H, m, H-1), 1.61 (2H, m, H-2), 3.44 (1H, dd, J = 11.2, 5.5 Hz, H-3), 1.37 (1H, m, H-5), 1.38 (2H, m, H-6), 1.43 (2H, m, H-7), 1.44 (1H, m, H-9), 1.90 (2H, m, H-11), 5.50 (2H, Brs, H-12), 1.24 (2H, m, H-15), 1.47 (2H, m, H-16), 2.53 (1H, d, J = 12.0 Hz, H-18), 1.34 (2H, m, H-19), 1.43 (2H, m, H-21), 1.87 (2H, m, H-22), 1.24 (3H, s, Me-23), 1.01 (3H, s, Me-24), 0.88 (3H, s, Me-25), 1.03 (3H, s, Me-26), 1.30 (3H, s, Me-27), 0.94 (3H, d, J = 6.2 Hz, Me-29), 1.02 (3H, s, Me-30). 5,7-Dihydroxyflavone (Chrysin) (9) Slightly yellow Crystals; IR νmax (KBr): 3406, 1656, 3090, 1600, 1571, 1500 cm-1; EI-MS: m/z 254 [calcd. 254.0579 for C15H10O4]; 1H-NMR (DMSO, 300 MHz) δ: 6.76 (1H, s, H-3), 6.28 (1H, d, J = 1.9 Hz, H-6), 6.57 (1H, d, J = 1.9 Hz, H-8), 8.05 (1H, dd, J = 8.1 Hz, H-2′), 7.58 (1H, m, H-3′), 7.60 (1H, m, H-4′), 7.58 (1H, m, H-5′), 8.05 (1H, dd, J = 8.1 Hz, H-6′). In Vitro Cholinesterase Inhibitory Assays In vitro cholinesterase inhibitory potentials of our test compounds were evaluated using Ellmans assay (Ellman et al., 1961; Ayaz et al., 2015). Basic principle of this procedure is reliant on catalytic degradation of substrates including acetylthiocholine iodide and butyrylthiocholine iodide by the respective enzymes AChE and BChE to form 5-thio-2-nitrobenzoate anion which is subsequently complexed with DTNB to form a yellow color compound. This yellow compound is UV detectable and is quantified with the passage of time with and without the impact of inhibitor agent. Briefly, from each enzyme solution, 5 μl were added to wells of micro plate and 5 μl DTNB was added to it. The resultant mixture was incubated for 15 min at 30°C in water bath followed by addition of 5 μl substrate solution. Finally, absorbance was measured at 412 nm using micro plate reader. Control contains all solutions except inhibitor. Change in absorbance was recorded along with reaction time. At the end, Enzymes and enzymes inhibitory activities by control and our test samples were calculated from the rate of absorption with change in time as (V = Δ Abs /Δ t) and Enzyme inhibition as; Percent Enzyme activity = 100 × V/VMax. Where, VMax is enzyme activity in the absence of inhibitor agent. Molecular Modeling The molecular construction of isolated compounds were performed using ChemBioDraw Ultra 14 suite (PerkinElmer Inc.) and converted into 3D conformations by ChemBio3D (Mills, 2006). Molecular docking simulations of isolated compounds were carried out using GOLD (Genetic Optimization for Ligand Docking) (version 5.4.1) (Verdonk et al., 2003) software, with goldscore_p450_csd template. Goldscore was selected as a fitness function. Docking search area was sphere of radius 6 Å. Crystal structures of the enzymes, AChE (PDB: 1EVE) and BChE (PDB: PDB Code 1P0I) used for protein–ligand interactions, were retrieved from Protein Data Bank (PDB). The target proteins were prepared by the addition of hydrogen, removal of water and the removal of cocrystallized ligands. All other parameters were used with the default settings. The ligand-bound sites of the enzymes were used as possible binding sites to analyze the potential binding of isolated compounds. Co-crystallized ligands (reference ligands) were also re-docked to compare the results for accuracy. 3D images were taken using UCSF Chimera 1.11 software (Pettersen et al., 2004), while 2D images were taken using (Biovia, 2016). Results The C. oxyacantha was collected from the district Swat of Pakistan. The crude extract of the plant was obtained using its aerial parts. Based on the initial screening, TLC analysis and quantity of the dichloromethane fraction (80 g), this fraction was selected for isolation of bioactive among other solvent fractions. Initially, the TLC analyzed DCM fraction was subjected to a major chromatography which resulted in semi-purified organic molecules. Then by using a small scale column chromatography for all of individual samples resulted in isolation of nine organic molecules (compounds 1–9, Figure 1). To the best of our literature survey we claim that compounds 1 [2-(3, 4-dimethoxyphenyl)-2-methoxyethanol] and 2 [3-hydroxy-1-(4-hydroxy-3-methoxyphenyl) propan-1-one] were obtained for the first time from the natural sources. The remaining seven compounds are pre-existing important natural products including β-Sitosterol-3-O-β-D-Glucopyranoside (3), lupeol (4), β-sitosterol (5), betulin (6), betulinic acid (7), oleanolic acid (8), and chrysin (9). All the isolated compounds are very important moieties in natural products. FIGURE 1 www.frontiersin.org FIGURE 1. Isolated organic molecules from dichloromethane fraction of aerial parts of Crataegus oxyacantha. In Vitro Pharmacology Initially, we evaluated the dichloromethane fraction for its possible potential of inhibition the acetyl and BChE s. After getting encouraging results from the initial screening/extract, pure compounds (1–9) were subjected to the acetyl and BChE e inhibitions as shown in Table 1. TABLE 1 www.frontiersin.org TABLE 1. Results of in vitro cholinesterase inhibitory assays on the isolated compounds. In AChE inhibition assay, almost all of the compounds exhibited considerable results with IC50 values of greater potency as shown in Table 1. In AChE inhibitory assays, Compounds 1, 6, 3, 7, 8 exhibited highest AChE inhibitory activities displaying 97.32 ± 1.06, 96.13 ± 0.20, 95.70 ± 1.60, 95.70 ± 1.60, and 95.05 ± 0.75% inhibitions at 250 μg/ml, respectively. The AChE inhibitory activities of these samples were very much comparable with the galantamine at the same concentrations Table 2. In BChE inhibition assay, 2, 3, 6, and 7 showed highest inhibitory activity with inhibitions of 95.76 ± 0.71, 94.84 ± 0.30, 95.85 ± 2.25, 94.10 ± 0.60, respectively. Percent inhibitions of our test compounds were more against AChE in comparison to BChE. Among the entire compound 3 showed the most prominent inhibition with IC50 value of 5.22 μM. At the same three concentrations the standard drug Galantamine was observed with IC50 = 8.0 μM. Newly isolated compounds 1, 2 displayed moderate activities with IC50 values of 23.2 and 25.90 μM, respectively. The order of potency of the remaining compounds was 5 > 6 > 9 > 8 > 7 (Table 1). TABLE 2 www.frontiersin.org TABLE 2. Physico-chemical descriptors of the isolated compounds (1–9). A summary of the BChE inhibitions of compounds 1–9 is also shown in Table 1. In BChE assay all the compounds achieve lower IC50 values than that of the standard drug Galantamine. With exception of compounds 3 and 6, all the other isolated compounds exhibited excellent selectivity toward BChE (Table 1). Compounds 5 and 9 have shown the BChE inhibition in nano-molar range (IC50 = 0.55 and 0.63 μM, respectively). Compound 6 exhibited very little activity (IC50 = 25.63 μM). In the current study galantamine selectivity was definitely greater for AChE (56%) more than BChE as given in Table 1. Molecular Modeling Studies To gain insight into the mechanism of AChE and BChE inhibition, binding modes of the isolated compounds were explored by GOLD suit v5.4.1. There are a plenty of X-ray crystal structures of AChE in PDB like Drosophila melanogaster, Electrophorus electricus (eel), Torpedo californica (TcAChE), human (hAChE) and mouse in apo or with co-crystallized ligand. These crystal structures can be used for the designing of new AchE inhibitors. In the current study, we tried to present the possible mechanism of action of the isolated compounds. For this purpose, X-ray crystal structure of TcAChE and hAChE also studied. The X-ray crystallographic structure of TcAChE (PDB Code 1EVE) and hAChE (PDB Code 4EY6) in complex with donepezil and galantamine were used as enzyme structures. Superposition of the docked poses of the most active compound 3 into the binding pockets of TcAChE and hAChE is shown in Figure 2A. The binding mode analysis of isolated compound 3-TcAChE and 3-hAChE complex shows that the compound 3 have same binding orientation in binding pocket of TcAChE and hAChE. FIGURE 2 www.frontiersin.org FIGURE 2. Superimposed ribbon diagram of the top-scoring docking pose for isolated compound 3-TcAChE (PDB ID 1EVE, red ribbons) and 3-hAChE complex (PDB ID 4EY6, green ribbon). Visual inspection of all the best docked pose of the most active compound 3 in the active site of 1EVE revealed that hydrocarbon chain is embedded into the hydrophobic slot formed by Trp279 and Leu282. Tetrahydropyran ring formed five conventional hydrogen bonding interactions with Gln69, Trp84, Tyr121, Ser122, and Gly123. Tetracyclic ring structure is sandwiched between bottleneck residue Phe330 and Tyr334 (Figure 3). Isolated compound 3 showed highest Gold fitness score (79.9353). To understand the mechanism, we also docked compound 3 into the binding hAChE co-crystallized with galantamine. Figure 4, reveals that it is embedded into the binding site of galantamine. FIGURE 3 www.frontiersin.org FIGURE 3. (A) Stereoview of the docking pose of β-Sitosterol-3-O-β-D-Glucopyranoside (3), (blue color stick model) in the binding pocket of AChE (1EVE). (B) Two dimensional (2D) interactions of β-Sitosterol-3-O-β-D-Glucopyranoside (3). Conventional hydrogen bonding interactions are depicted in green and hydrophobic interactions in light pink (Prepared by using Discovery Studio Visualizer). FIGURE 4 www.frontiersin.org FIGURE 4. Putative binding mode of 3 in the binding cavity of human AchE (PDB Code 4EY6). The structure reveals that compound 3 is embedded in the binding pocket of galantamine. The binding mode of the compound 7 (Betulinic acid), the least active compound with IC50 value of 44.47 μM, was also analyzed. The carboxylic group of compound 7 formed conventional hydrogen bonding interactions with the catalytic triad residue (His440) and oxyanion hole residue (Gly118). It also established with the acidic residue Glu199 near the base of the gorge (Figure 5). The Gold fitness score for 7 is 47.8194. FIGURE 5 www.frontiersin.org FIGURE 5. (A) Stereoview of the docking pose of Betulinic acid (7, blue color stick model) in the binding pocket of AChE (1EVE). (B) 2D interactions of betulinic acid (7). For gaining insight into the mechanism of BChE inhibition, the X-ray crystallographic structure of human BChE (PDB Code 1P0I) was used as enzyme structure. The environment of the active site BChE gorge is hydrophobic due to presence of aromatic and aliphatic amino acid residues. This hydrophobic patch consists of Trp82, Tyr128, Ala328, and Phe329. The acyl pocket contains leu286 and Val288. The amino acid residues in wall of the gorge are Trp114, Trp231, Tyr332, Trp430 and Tyr440. Structural analysis has revealed that all the isolated compounds (1–9) contain both hydrophobic alkyl chains as well as hydrophilic features. The most active BChE inhibitor compound 5 (β-sitosterol) is a hydrophobic molecule as indicated by its logP value (9.29, Table 2). Docked binding pose of β-sitosterol in the binding pocket of BChE is shown in Figures 6a,b. β-Sitosterol (5) is located in hydrophobic patch and forms mainly hydrophobic interactions with Trp82, Trp231, Leu286, Val288, Ala328, Phe329, and Tyr332 (Figure 6c). β-Sitosterol-BChE complex also stabilized by the formation of hydrogen bonding interactions between one of the residue of catalytic triad (His438) and hydroxyl group of β-sitosterol at the distance of 1.6 Å. FIGURE 6 www.frontiersin.org FIGURE 6. Docked binding pose of the most active isolated compound β-sitosterol (5) in the binding pocket of BChE (magenta color stick model); Surface diagram (a) and Ribbon (b) as rendered by Chimera 1.11.2rc. (c) 2D interactions of (5). Conventional hydrogen bonding interactions are depicted in green and hydrophobic interactions in red (Prepared by using Discovery Studio Visualizer). Preliminary In Silico Pharmacokinetics Poor pharmacokinetic properties are the main cause of failure of the drugs or lead compounds to enter the market. Prediction of in silico ADMET studies (prediction of the in vivo pharmacokinetics) as early as possible in the drug discovery process has now become imperative to develop drugs with improve oral bioavailability, reduced toxicity, and adverse side effects. Lipinsiki criteria for oral absorption was computed by using Molinspiration online software. The analysis of the Lipinsiki’s descriptors tabulated in Table 2 indicated compound 3 have molecular weight >500. Isolated compounds 3–8 violated the Lipinski’s Ro5 due to their logP value > 5 (Table 2, highlighted in red). Compound 3 is predicted to be the most lipophilic compound due to its high value of logP. Polar surface area is another important criteria for the determination of BBB penetration. According to Waterbeemd the cutoff value is 90 Å2 or less []. Compound 3 violates the criteria for cutoff value of tPSA (99.38). Number of rotatable bonds (nROT) is an additional property that measures the flexibility of the molecule. It can also be used as a filter in the ADME predictions. The drugs that penetrate BBB usually reported to have fewer nROT counts. Discussion This study was designed to further validate the medicinal uses of C. oxyacantha based on anticholinesterase activity and computational studies of pure principles from the plant. In terms of enzyme ihibition, dichloromethane soluble fraction with highest activity was separated into nine compounds (1–9). This work is a first report on enzyme inhibitory potential of C. oxyacantha. As shown in Figure 1, the isolated compounds (1–9) contain both hydrophobic alkyl chains as well as hydrophilic features. In AChE activity, we have demonstrated that compound 3 is the most active one with IC50 value of 5.22 μM in comparison to the standard drug Galantamine with IC50 = 8.0 μM. From molecular docking point of view, for the most active compound 3 (Gold fitness score = 79.9353), the hydrocarbon side chain and sugar moiety are the best features needed for the enzyme activity (Figure 2). For compound 7 which is the least active (IC50 = 44.47 μM), binding modes have been recorded for carboxylic acid group (Figure 3). Amongst the compounds, β-sitosterol (5) was found highly active in BChE inhibition with IC50 value of 0.56 μM. This activity can be attributed to the docking positions of side chain and hydroxyl group in compound 5 (Figure 4). We assessed the in silico pharmacokinetic profile of the isolated natural products. Although most of these isolated compounds are reported in literature, the aim of this study is to predict their blood brain barrier (BBB) penetration by detailed understanding of physicochemical descriptors (Table 2). Targeting the central nervous system is a challenge for drug designing chemists due to the tight junctions of the BBB epithelial cells (Pajouhesh and Lenz, 2005). Therefore, BBB penetration is required by the drug candidates targeting AChE. For this purpose, online software admetSAR was used to predict whether the isolated compounds can cross blood brain barrier (BBB+) or not (BBB). However, with exception of compound 3, all isolated compounds are predicted to cross blood brain barrier (i.e., BBB+). Conclusion Herein, we claim that C. oxyacantha is a rich source of neurologically potent organic molecules. The isolated compounds from C. oxyacantha are evaluated for the first time for its possible use in acetyl and BChE inhibitions. All the isolated compounds showed an overwhelming acetyl and BChE inhibitions. There is good agreement found between in vitro experimental results and the docking scores. 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The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Mumtaz Ali, mumtazphd@gmail.com; mumtazali@uom.edu.pk Abdul Latif, dralatif2016@gmail.com; ajmalchemist@yahoo.com Ajmal Khan, ajmalkhan@ciit.net.pk