Category Archives: Longevity Medicine

Immortality is the gift we might secretly desire but know would be an abominable curse to receive. To truly live forever would mean watching our loved ones die, generations at a time around us, and looking on while the natural world we value withers and falls into decay.

But while eternal life may be a fantasy, the prospect of us living longer lives than our predecessors is very real. The global Covid-19 pandemic might have interrupted proceedings, but the evidence clearly shows that over the long term the longevity of the worlds populations is unstoppably on the rise.

Even over relatively recent periods, the statistics are striking. In 1960, for example, the average life expectancy for men was 50.7 years, according to data from the World Bank, and for women it was 54.6.

Fast forward six decades to 2019, and World Bank figures show that the average life expectancy for men had grown to 70.6 years, and for women had edged past 75 years.

Looking into the future, the Hamburg, Germany-based market and consumer data firm Statista projects that, by 2050, the average life expectancy globally will reach 76.7 years and, by 2100, an impressive 81.7 years.

Given that these figures are averaged out across societies worldwide with wildly differing economic fortunes, that must surely mean that some people will be living considerably longer still.

Therein, of course, lies part of the explanation. The worlds populations are becoming wealthier, bringing with it improvements in diet and lifestyle and more advanced medical treatments and healthcare provision.

It seems hardly surprising that, according to World Bank figures, the 2019 average life expectancy of someone on a low income was 66 years, while for an upper-middle-income earner, it was a full 13 years longer, at 79.

The pace of developments in technology and in the provision of infrastructure such as roads, rail, schools and hospitals also means that as the worlds populations grow they are also urbanising more quickly. In short, our lives are better, from the moment we are born often in sanitised maternity units at the hands of trained experts to the moment we die, perhaps in a quality long-term care home.

Part of the deal, unfortunately, is that as we age, we tend to become more infirm and more vulnerable to diseases including conditions such as cancer, diabetes and heart disease.

Health and longevity make up one of the six themes that we have identified within the social and demographic change megatrend. And the more than 1,340 companies captured by the Fix the Future database strongly reflect some of the factors that are fuelling our longer lifespans.

By business line, they range from diagnostics and research firms to drug manufacturers, medical device makers, healthcare information providers and pharmaceuticals retailers.

The history of drug research and discovery is littered with casualties in the form of companies that believed theyd found a blockbuster treatment only to crash and burn in late-stage trials or founder when their medicine reached the market.

But there are plenty of established players, many of which have the backing of the worlds most skilled fund managers and are included in the Fix the Future database.

Among them is Novo Nordisk, a Denmark-based multinational that researches, develops and produces treatments for people with serious chronic diseases, including diabetes, obesity and rare blood and endocrine problems. (The endocrine system essentially regulates all of the bodys biological processes, including metabolism and blood sugar.)

Novo Nordisk is listed on the Nasdaq Copenhagen stock exchange with a market value of DKK 1.2tn (138bn). It produces half of the worlds supply of insulin for people with diabetes and says its aim is to prevent more than 100 million people from getting type 2 diabetes (often diet-related) by 2045. The company also carries out clinical trials in more than 50 countries.

From an investment perspective, this means that not only does Novo Nordisk have established, recurring and resilient sales, but it is also locked into long-term developments in demographics and growing healthcare needs.

There are numerous other routes into health and longevity as an investment theme, however. There are the manufacturers of medical equipment, for example, including Smith & Nephew, the UK-listed group most well known for its hip and knee replacements.

Listed on the London Stock Exchange with a market value of 10.6bn, Smith & Nephew also makes products to help stabilise fractures and correct bone deformities and has sports medicine and ear, nose and throat divisions, along with a unit that specialises in advanced wound management.

Crucially, the group describes itself as a medical technology company, signposting that it has its eye on the need to keep pace with modern treatments. In practice, that has meant building up its capabilities in robotics and digital surgery, and increasing its investment in research and development from 4.7% of sales in 2017 to more than 6% in 2021. With sales of just over $5.2bn (4bn) last year, that equates to about $312m.

Hospital operators such as HCA Healthcare provide the bricks and mortar of healthcare. This is a US business listed on the New York Stock Exchange, valued at just under $79bn, and which runs private hospitals and other centres in 20 American states as well as in the UK.

All told, HCA Healthcare manages more than 2,000 facilities, including hospitals and surgeries, emergency rooms and urgent care centres, as well as diagnostic and imaging units and walk-in physician clinics.

For an investor, that means HCA Healthcare is exposed to the structural growth of the private provision of healthcare and the harsh reality that well need more medical treatment in our old age.

And, of course, there are the insurers and sellers of healthcare plans, whose policies help cover medical bills and, in turn, help to underwrite the growth of private provision. Just one example is Fairfax Financial, a Canada-based business that also operates in parts of Asia, Europe and the Americas and is the owner of Brit Insurance in the UK.

Fairfax Financial is listed on the Toronto Stock Exchange and has a market value of just under C$14.6bn.

The company sells life cover and health insurance, among other financial services, so in this regard is positively plugged into the dynamics of ageing populations and their medical needs. However, it is also in the business of expanding opportunistically in regions where insurance penetration is low, which adds to its potential interest and ability to increase revenues.

Fairfax Financial has a solid foothold in high-growth Asian markets such as Indonesia, Thailand and Vietnam, where the populations are growing rapidly, wealth is on the up, and the safety nets of a welfare state are all but non-existent.

Like the rest of us, no company is immortal, but some of the smartest investors are working on the assumption that these and other businesses will be with us for some time to come.

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The companies leading the drive for longer, healthier lives - citywireselector.com

Human wellbeing is increasingly viewed as a multidimensional phenomenon, of which income is only one facet (Stiglitz et al. 2009, OECD 2011, Proto and Rustichini 2014). However, economists continue to rely on GDP to gauge wellbeing (Oulton 2012). A way to assess GDP as a comprehensive measure of wellbeing is by looking beyond per capita income. In a recent paper, I focus on life expectancy at birth a synthetic measure of health and its relationship with per capita income over the past 150 years (Prados de la Escosura 2022).

An important caveat is that, when assessing life expectancy over time and across countries, we need to bear in mind that original values of life expectancy are bounded and that life quality improves with the quantity of years lived (Prados de la Escosura 2021). A solution is provided by Kakwanis (1993) non-linear transformation in which an increase in life expectancy at birth at a higher level implies a greater achievement than would have been the case had it occurred at a lower level.

Life expectancy (expressed as a Kakwani index) exhibits slightly faster long-run growth than per capita GDP. A closer look, however, reveals an apparent development puzzle: economic growth and life expectancy gains do not match each other (Table 1). During the globalisation backlash between 1914 and 1950, real per capita GDP growth slowed down as world commodity and factor markets disintegrated, while life expectancy experienced major gains across the board. But, from 1950 onwards, life expectancy achieved, on average, smaller gains to GDP per head. Thus, world average life expectancy exhibited a major advance across the board before 1950, earlier than usually presumed and at odds with the view that that global health only improved after WWII, when new drugs from the West reached the rest of the world (Acemoglu and Johnson 2007, Klasing and Milionis 2020).

Table 1 Trends in life expectancy and real per capita GDP

Notes: Kakwani Index (growth rates %)Sources: Foundation Rafael del Pino

Moreover, the evolution of life expectancy and per capita incomes international distribution is at odds. Life expectancy inequality rose from 1870 to the mid-1920s, fell until the early 1980s, and experienced a partial rebound over 19902010. In the case of per capita income, inequality rose up to the mid-1970s, stabilised, and then declined sharply since 1990.

Figure 1 International inequality in life expectancy and real per capita income, 1870-2015

Notes: Kakwani Index, population-weighted mean log deviation (MLD)

The annual cumulative growth rate by percentiles, from bottom to top (the growth incidence curve) also shows differences. In the case of life expectancy, the middle of the distribution experienced the main relative gains in the long run, followed by the lower-middle ventiles, and the smallest gains accrued to those at the top (Figure 2). As for per capita income, the bottom ventile achieved the lowest relative gains while the middle and the top of the distribution experienced the main relative gains

Figure 2 Growth incidence curves for life expectancy and real per capita income, 1870-2015 (%)

Source: Kakwani Index. See the text for further details.

What explains the different pace and breadth of life expectancy gains? It is commonly assumed that economic progress largely does. By raising average incomes, modern economic growth facilitates better nutrition, which strengthens the immune system and reduces morbidity (McKeown 1976, Fogel 2004). The increase in the public provision of health is another effect of higher average incomes (Loudon 2000, Cutler and Miller 2005). However, health improved across the board during the past 100 years, including in countries in which social spending did not expand and during phases of sluggish economic growth (Riley 2001, Sunde and Cervellati 2012).

Samuel Preston (1975) investigated the connections between life expectancy at birth and per capita GDP and concluded that increases in per capita income only explained a minor proportion of the rise in the lifespan, which was mainly attributable to the diffusion of medical advances resulting from the empirical validation of the germ theory of disease.

I tested Prestons association for a sample of 112 countries over 1870-2015, but instead of the original values, I used the Kakwani index of life expectancy and the natural logarithm of real per capita GDP at different cross-sections. The resulting relationship is convex, rather than concave as Preston observed. This suggests that advances in medical knowledge led to more-than-proportional gains in health as income rose. Moreover, the exercise confirms the existence of sustained outward shifts in the relationship over time, as put forward by Preston. Figure 3 shows a clear outward shift over time, but it does not proceed at the same pace between each pair of cross-sections. Thus, intense outward shifts between 1913 and 1950 and between 1970 and 2015 contrast with mild ones during 1870-1913 and 1950-1970.

Figure 3 Revisited Preston curve, 1870-2015

Over the past one and a half centuries, economic growth and medical advances appear to have contributed alike to longevity gains, but their contributions vary over time. Modern economic growth accounted for over 60% of the increase in the Kakwani index of life expectancy over 1870-1913 and, again, during the last period, 1970-2015. However, during the first half of the 20th century, three-fourths of the Kakwani index gains accrued to advances in medical knowledge. This finding matches Prestons lower bound estimates. Conversely, during the Golden Age (1950-1970) the increase in per capita income accounted for the entire improvement in the Kakwani index of life expectancy.

Life expectancy improvements can be depicted in terms of a health function (Easterlin 1999). Movements along the function represent gains attributable to economic growth and outward shifts of the health function result from improvements in medical knowledge. The strong outward shift in the health function during the first half of the 20th century arose from the diffusion of epidemiological transition. Triggered by the germ theory of disease, the epidemiological transition initiated in western Europe in the late 19th century and only started spreading worldwide from the 1920s (Riley 2001). Persistent gains in lower mortality and higher survival rates were achieved as infectious disease gave way to chronic disease as a major cause of death (Omran 1971). Two main consequences resulted from the diffusion of the germ theory of disease. On the one hand, medical technological progress resulted in new drugs to cure infectious diseases and spread the health transition (Easterlin 1999, Jayachandran et al. 2010, Lindgren 2016). On the other hand, and most decisively, low-cost improvements in public health derived from the diffusion of preventive methods of disease transmission and knowledge dissemination often through school education. This second channel of diffusion helps explain why the epidemiological transition spread in developing countries since the early 20th century, despite the fact that many of them were still under colonial rule and the new drugs were largely unaffordable.

Another significant outward shift of the health function took place in the late 20th century. This was the outcome of what may be depicted as a second health transition in which mortality and morbidity fall among the elderly as a result of new medical knowledge that allows better treatment of respiratory and cardiovascular disease (Cutler et al. 2006, Chernew et al. 2016, Eggleston and Fuchs 2012).

The substantial increases in longevity during the epidemiological transition were unevenly distributed throughout the world. Lack of economic means and basic scientific knowledge prevented a fast and wide diffusion of new medical technology and health practice across countries. In the late 19th and early 20th centuries, the increase in life expectancy inequality was due to the fact that the first health transition was initially restricted to advanced western countries. The gradual international diffusion of the health transition favoured the reduction in life expectancy inequality between the late 1920s and 1980. By 1970 the diffusion of the epidemiological transition was largely exhausted. The second health transition has been restricted so far to advanced countries due to its higher cost and this helps explain why inequality rebounded at the turn of the century.

Unlike the conventional wisdom, life expectancy at birth and real per capita GDP behaved differently in terms of trends and distribution during the past 150 years. Long-run improvements in life expectancy depended on advances of medical knowledge as much as on economic growth that facilitated better nutrition and the provision of health services. Thus, focusing only on movements along the health function, which derive from increases in average incomes, ignores the important shifts in the function that are closely connected to the diffusion of new medical knowledge.

Acemoglu, D and S Johnson (2007), Disease and Development: The Effects of Life Expectancy on Economic Growth, Journal of Political Economy 115: 925-985.

Chernew, M, D M Cutler, K Gosh and M B Landrum (2016), Understanding the Improvement in Disability Free Life Expectancy in the U.S. Elderly Population, NBER Working Paper 22306.

Cutler, D and G Miller (2005), The role of public health improvements in health advance: The twentieth century United States, Demography 42(1): 1-22.

Cutler, D M, A Deaton and A Lleras-Muney (2006), The Determinants of Mortality, Journal of Economic Perspectives 20: 97-120.

Easterlin, R (1999), How Beneficient is the Market? A Look at the Modern History of Mortality, European Review of Economic History 3(3): 257-294.

Eggleston, K N and V Fuchs (2012), The New Demographic Transition: Most Gains in Life Expectancy Now Realized Late in Life, Journal of Economic Perspectives 26: 137-156.

Fogel, R W (2004), The Escape from Hunger and Premature Death, 17002010. Europe, American and the Third World, New York: Cambridge University Press.

Jayachandran, S, A Lleras-Muney and K V Smith (2010), Modern Medicine and the Twentieth Century Decline in Mortality: Evidence on the Impact of Sulfa Drugs, American Economic Journal: Applied Economics 2: 118-146.

Kakwani, N (1993), Performance in Living Standards. An International Comparison, Journal of Development Economics 41: 307-336.

Klasing, M J and P Milionis (2020), The International Epidemiological Transition and the Education Gender Gap, Journal of Economic Growth 25: 3786.

Lindgren, B (2016), The Rise in Life Expectancy, Health Trends among the Elderly, and the Demand for Care. A Selected Literature Review, NBER Working Paper 22521.

Loudon, I (2000), Maternal Mortality in the Past and its Relevance to Developing Countries Today, American Journal of Clinical Nutrition 72(1) (supplement): 241S-246S.

McKeown, T (1976), The Modern Rise of Population, New York: Academic Press.

OECD (2011), Hows Life. Measuring Wellbeing, Paris: OECD Publishing.

Omran, A R (1971), The Epidemiological Transition: A Theory of Epidemiology of Population Change, Milbank Memorial Fund Quarterly 49(4): 509-538.

Oulton, N (2012), Hooray for GDP! GDP as a measure of wellbeing, VoxEU.org, 22 December.

Prados de la Escosura, L (2021), Augmented Human Development in the Age of Globalisation, Economic History Review 74(4): 946-975.

Prados de la Escosura, L (2022), Health, Income, and the Preston Curve: A Long View, CEPR Discussion Paper 17151.

Preston, S H (1975), The Changing Relationship between Mortality and the Level of Economic Development, Population Studies 29(2): 231-248.

Proto, E and A Rustichini (2014), GDP and life satisfaction: New evidence, VoxEU.org, 11 January.

Riley, J C (2001), Rising Life Expectancy. A Global History, New York: Cambridge University Press.

Stiglitz, J E, A Sen, and J P Fitoussi (2009), Report by the Commission on the Measurement of Economic Performance and Social Progress.

Sunde, U and M Cervellati (2012), Diseases and development: Does life expectancy increase income growth?, VoxEU.org, 6 January.

Excerpt from:
Health, income, and the Preston curve | VOX, CEPR Policy Portal - voxeu.org

Kyle Kasperbauer on Calling it a Career: Retirement here we come - Morning Chalk Up

Photo Credit: Kyle Kasperbauer

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Kyle Kasperbauer still remembers his first workout. It was 2009 and Joe Westerlin, the co-owner of CrossFit Omaha along with Ricky Frausto talked him into coming into a class. Kasperbauer said hed already been working out consistently for three years after his college football career with some free weights, focusing primarily on strength training and accessory movements.

Then he was introduced to Helen, which is a three rounds for time workout with a 400 meter run, 21 kettlebell swings and 12 pull-ups.

It was eye opening, pride crushing, and almost humiliating. I loved it, said Kasperpauer. I had gotten beat by the majority of the class, which in my eyes at that time should not have happened, but it did because they were more fit than I was. That was a big piece of humble pie, and I embraced that. Anything that exposed my lack of fitness that effectively was the real deal. I jumped all the way in immediately.

Kasperbauers long history with the CrossFit Games also started in 2009 when he came in 37th. The 39-year-old, who has officially announced his retirement from the sport, got on the podium in 2012, and has now taken stock on a career that saw him go to the Games 10 times in total as both an individual, team and masters athlete.

CrossFit has changed drastically over the years for me as an individual, he said, looking back on his 14 years in the sport. It started as a way to compete and fulfill my desire for competition. Competing has been life for me since I was five years old, and CrossFit allowed me to continue competing. So I dug into the process and got to work. However, aside from competing, I do still respect my body and have a desire to maintain health and fitness as I age.

He said one of the most important things hes learned over the years is how to prime his body, and recover, which includes everything from warmup and coaching to hydration, nutrition and sleep. But no coffee, as Kasperbauer said hes never indulged to help his training.

CrossFit was actually a great resource for physical and mental longevity. Not only a physical workout, but a very effective mental stress reliever. It gave me the drive to get better. It gave me things to think about as I am performing the movement. Technique, technique, technique. Overall, in my opinion, CrossFit hasnt changed, but it has changed my life.

Kasperbauer holds a bachelors degree in Exercise Science and a Masters in Athletic Training Sports Medicine. He is the founder and co-owner of CrossFit Kinesis/Kinesis Fitness with Nissa Cohen, and the co-owner of Integrative Psychiatry with Macy Kasperbauer. He was born and raised in Nebraska, where he still lives to this day and runs his businesses.

Kasperbauers career has spanned almost everything CrossFit has seen. Rich Froning and Mat Frasers dynasty runs, a leadership change, and what many people are hoping is a new route for the sport and company coming out of the pandemic.

But he said at the core, CrossFit, in essence, never really changed at all.

The methodology hasnt changed. The movements are still the same. The definition is clear and concise. However, I have changed. My season in life has changed. So CrossFit within my life cycle has changed. People may have changed. Gyms may have evolved. Different people may be working for HQ. But at its core, CrossFit is what each gym and individual make it, and how much they want from it. The more you put into CrossFit, the more you will get back from CrossFit.

Kasperbauer said after a long and fortuitous career, he is more than ready for retirement, and calling it a career on competing in CrossFit.

Retirement here we come. After much thought, many prayers and multiple conversations with Macy, its time for a change. This would have been my 14th year in the sport. Time for the next chapter in my life. More time to focus on my faith, family, business and life, .in that order.

For a daily digest of all things CrossFit. Community, Competitions, Athletes, Tips, Recipes, Deals and more.

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Kyle Kasperbauer on Calling it a Career: Retirement here we come - Morning Chalk Up

The Pediatric ICU at Doernbecher Childrens Hospital is loud. Alarms go off all the time, and residents and nurses rush to a room. Monitors shout their data. When the IV drip runs out, the machine beeps. When oxygen levels drop, the pulse oximeter screeches.

When my son was an infant, he was on ECMO, or extracorporeal membrane oxygenation, an extreme form of life support that bypasses the heart and lungs. It was invented for open heart surgeries, but now is sometimes used for respiratory failure in babies.

ECMO meant that my son had a nurse in his room day and night. They had to monitor the lines that looped his blood out of the carotid artery in his neck, oxygenated it, and fed it back to his body. Clots were likely, so someone had to sit there and bang on the machine with a closed fist every once in a while to loosen the lines. In addition to his assigned nurse, there were X-ray techs coming to get photos of his lungs, surgeons checking his incisions, residents on pediatric rotation, respiratory therapists who specialized in ventilators, paramedicsthe only people skilled enough to get IVs into tiny infant veinsand a palliative care team who worked with my husband and me to determine what would happen if he didnt make it, and if he did, what quality of life he would have.

It was so busy, and I had never felt more alone. All my attention was focused on the little body that had been severed from me, that was nearly severed from itself. The beeps of the morphine dispensing, the antibiotics, the anticoagulants. Bubbles of oxygen seeping out the tube; the EKG showing the terribly dull brain waves; the bright ruby sheen of his blood; the smell of him so fresh and soft and enticing despite all the antiseptic. My own body, aching where they had cut him out of me. Aching with the absence of him.

But around the room was this strange arising energy, a centrifugal whirling. People were coming together to save a days-old infant, lending their expertise and kindness in whatever doses they could. I sat at the center of this benevolent hurricane. They let me sit and grieve and they whirled around me. It was a spontaneous, transient storm, formed not of old bonds but a common and urgent purpose. While that common energy didnt stop my loneliness, it held me together, like fingertips pressing a shattered china teacup back into shape.

The view from Doernbecher is beautiful: the Willamette snaking beneath Portlands bridges, all those cars streaming away in silver lines. Sometimes you can see Mount Hood, sharp-edged and white in the distance.

Its a lonely view. Anyone who has spent time receiving medical care in a hospital knows that the windows feel like escape hatches but also like taunts. The viewof trees, of rain, of people going about their daily livesfeels both comforting and grossly unfair.

Joshua Bells window looked down onto the parking lot. The sixteen-year-old was back for another treatment in the pediatric oncology ward. With COVID-19 restrictions in place, he could only have two visitors total, one at a time. That meant his parents, Mark and Sara, were his only contacts when he was undergoing chemotherapy. He missed his brother. He missed his friends.

One day, Joshuas classmates called him on FaceTime. They were grinning and holding signs, and something about where they were standing looked familiar. Joshua went to the window and looked down: there were four teenagers in the parking lot, backs to his window, waving into a tiny screen. He could see himself in the background of their video.

It made it a lot more manageable, says Joshua. Seeing them in person, even if were just communicating over FaceTime...its hard to describe, but its just so different for me.

Medical care like what Joshua is undergoing often requires isolation. To keep their bodies safe, patients step back from daily activities. Their loved ones find themselves in a parallel universe of appointments and medications, strange rooms and masked specialists. Receiving care requires near-total immersion in this new life. Old commitments are set aside and plans abandoned in favor of one goal: healing.

Being removed from daily life takes a strain on our mental and physical health. Those undergoing care can create community within the hospital setting, but care-based relationships are often transient and have some inherent boundaries. Maintaining connections to outside friends and family becomes essential. Through gifts, window visits, letters, and photographs, patients are reminded of the web of care that exists beyond the walls.

In 2022, we are all familiar with isolation. Everyone has, to some degree, learned what it feels like to detach from our normal lives.

Isolation during the pandemic has been both protective and damaging. Quarantining can be seen as an act of community care; to stop the spread of the virus, to defend elders and the immunocompromised, we have gone into our homes and stayed there. Some of us have taken pride in our commitment to protect others, but weve also suffered record rates of mental illness, loneliness, and substance abuse.

For some folks who have remained out in the world working, parenting, or doing other essential tasks, the isolation has manifested in a sort of cognitive dissonance. We are in crowds yet still hunched into masks, hurrying through the necessities to get back to the safety of being alone.

This tension manifests even more strongly for people with medical conditions. Even in non-pandemic times, receiving medical care is often a lonely, confusing process. Now, care often means severing our connections to the outside world. To heal, we cut ourselves off from those we love. But without them, how do we heal?

When she was twenty-five years old, Ericka Sullivans cancer came back. Shed beat it once, and the second diagnosis devastated her. My hope was kind of gone, she recalls. I felt super isolated, not in a physical sense but just lonely. Very alone. I knew my community was there, but I was struggling so hard.

She received a bone marrow transplant, which would kick-start her immune system. The caveat: she had to isolate in her home for one hundred days. For a few weeks, her mom stayed with her. After that, a rotating crew of friends and community members became her caregivers. They took regular shifts, two people per day, five days a week. When caregivers started coming in . . . I felt better. I think I was so grateful to not be physically alone, she says.

Sullivans story makes me think of a long rope, pulled taut from both ends. On one end of the rope are the people who sustain us: best friends, parents, kids, coworkers, the familiar server at our favorite diner. On the other end is the body, struggling to heal and thrive. In the center, like a red flag tied to the rope in a tug-of-war, is the self.

In good times, our loved ones often drag that flag close, for we need community to thrive. Research has shown that having social connections increases longevity, immune system functioning, and overall wellness. Saying that were social creatures is more than a platitude; human beings need each other.

But in times of medical care, the body tugs back. It needs our attention. Sometimes it needs physical isolation. Our community recedes in favor of the bodys immediate demands. And yet we cannot healnot really, not wellwithout them.

People really need the support of their network in order to do well in the hospital, says George Keepers, professor of psychiatry at the OHSU School of Medicine. Family can do practical things for patients, Keepers says, like explain a complex medical history or help patients keep up with appointments and medications. But they can also help prevent conditions that impede healing.

Lack of social support and isolation are a significant risk factor for depression, says Keepers. Depression is well known, actually, to produce poorer outcomes in a number of conditions. In other words, the physical body depends on good mental health, and mental health depends on community.

So what do you do if youre a sixteen-year-old cancer patient in a pandemic? How do you isolate for your physical safety but still stay close to the people you love?

At home, twelve-year-old Matthew Bell walks his dog, Packer. He goes for bike rides by himself. He makes small crafts. When his brother Joshua was home more, they crafted together and made short films for their YouTube channel. Now Matthew calls his brother a few times a day to check in, since he isnt allowed to visit.

I think for the two of them that has been one of the hardest things, says Sara Bell, Joshua and Matthews mom.

COVID-19 has exacerbated isolation not just for patients, but also for their families. Susan Sherwood is the child life specialist for the pediatric oncology ward at Doernbecher. She says many of the families want connection when they arrive for care.

They feel isolated from their normal lives, and they also are struggling to develop a new normal for themselves, she says.

To facilitate that new normal, Sherwood helps provide support for siblings and families, prepares patients for medical procedures, and tries to help young kids figure out whats happening to them in developmentally appropriate ways.

She also tries to make life in the hospital as fun as possible. She organizes bingo nights, art events, movies, music, and catered dinners for families. There is the costume cart with free dress-up clothes delivered by a nonprofit, Chelseas Closet. Kids can walk laps of the floor, adding up their miles to try and get a pair of Nikes. Sherwood says the hallways are usually a place where parents can briefly connect with each other. Its these liminal spacesthe break room, the hallsthat provide transient moments of community, where moms and dads can meet other parents going through the same difficult experience.

However, most of these activities have been restricted throughout the pandemic. Joshuas dad, Mark Bell, laments that the virus has made parents more leery of connecting in person. In general, its scurry on and get back to your kids room, he says.

Thats especially hard when your kid is seriously ill, because it can feel like no one shares your experience. Friends outside might be supportive, but its not the same if youre not talking with someone who knows what this is, says Mark.

Mark and Sara take shifts at the hospital, trying to time their arrivals and departures so that they have a few minutes in the parking lot together each day. Otherwise, they dont see each other for the four or five days of Joshuas hospital stay.

Its robbing families of that precious time, says Sara. When youre going through the most grueling thing that you can imagine, you need one another. Physical touch is huge.

Denied that touch, families have to find other ways to connect. Matthew does crafts at home and sends them with his parents to deliver to Joshua: felt wool dogs, a miniature Indiana Jones board game. Gifts bridge the isolation. Theyre a way to reach across the distance and hand something physical to the person on the other side.

Over the weeks my son was sick, I got to know the nurses well. We chatted about our lives outside. They watched me weep silently over his bed. They forced me to brush my teeth and eat. They helped take his footprints, gave him stuffed animals to prop up his limbs, and cried when he survived the surgery coming off ECMO.

When my son weaned off his last ventilator, we transferred to another ward. I never saw most of those people again, but if I met them in the street, I would get down on my knees and thank them. I would call them family.

Spontaneous care communities form under crisis, but they fade when you leave the hospital. And medical staff are not family. While nurses, doctors, and medical specialists feel deeply about their patients, they need boundaries to maintain both their mental health and the professionalism of the patient-caregiver relationship.

We as staff try to be very mindful of those good boundaries too, because we are there as caregivers, not to be their new friends and their new community outside the hospital, says Sherwood.

And yet. And yet. I had a text chain with many of my sons caregivers for years after his birth. It was probably against several HIPAA guidelines, but none of us cared. We needed each other to heal from what had happened to that little body under our care.

Ericka Sullivans caregivers were also her friends and family. For one hundred days, pre-pandemic, her community knocked on her door. Every time they did, she recalls thinking, Somebody showed up. Her hope returned, along with her sense of self.

Showing up for someone doesnt always mean walking through the door. In COVID times, you often cant. While she was in treatment, Sullivans friends wore special T-shirts and took photos of themselves, filling a blog for her with their travels and good wishes. She says several people who had never met before saw each other on the street wearing her T-shirts and realized they were part of the same care community, people whose lives were whirling around Sullivans recovery.

When we are physically distant from each other, objects become talismans. It could be the rough-knit purple hat that someone left in our PICU room, from a volunteer who made them for babies in critical care. It could be a paper letter from the woman the Bell family met on a ferry in Alaska, or the signs Joshuas classmates make for him. It could be a photo of friends at a Blazers game, grinning and repping your recovery T-shirts for the jumbotron.

Thoughts and prayers are not enough. Nothing is enough when you are very sick or someone you love is sick. Still, on the day that my son had surgery to come off ECMO, we asked friends and family to read a childrens book. People sent videos to my email. They were curled up with their kids reading The Very Hungry Caterpillar and Home for a Bunny and Llama Llama Red Pajama. The kids wore jammies and the parents tucked their small bodies close, in laps and nestled under arms.

I was preoccupied with the surgery and didnt watch the videos until much later. But I did see the names piling up in my inbox. I refreshed and refreshed. Each bold name felt like another hand holding my back, holding my hand, holding me up when I wanted to fall. I stayed upright because people were out there rooting for us, reading with their beloveds. It wasnt enough, and it was everything.

Caitlin Dwyer is a writer, storyteller, poet, and multimedia journalist. She studied journalism at the University of Hong Kong and creative writing at the Rainier Writing Workshop. She teaches at Portland Community College, where she is the 202122 writer-in-residence. When not teaching or writing, she is probably playing with her kids, wandering around in the forest, or lost in a book.

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Dr. Jason Sonners, author of the book, Oxygen Under Pressure: Using Hyperbaric Oxygen to Restore Health, Reduce Inflammation, Reverse Aging and Revolutionize Health Care, started out as a chiropractor. His passion, however, is hyperbaric oxygen therapy (HBOT), which is the focus of his Ph.D. studies at the University of Miami.

While commonly used to speed up stubborn wounds and tissue infections, hyperbaric medicine can also be helpful in the treatment of infectious diseases such as COVID. Its also enormously useful for stroke patients. I cant think of a more effective intervention than to get the stroke patient into a series of hyperbaric treatments as quickly as possible.

Every cell in your body, with the exception of your red blood cells (which have no mitochondria that require oxygen), requires oxygen to create energy. Many chronic diseases of the modern world involve decreased mitochondrial function, increased systemic inflammation, and an inability of cells to generate the required amounts of energy for optimal function.

We use hyperbaric oxygen, traditionally, for these terrible and severe conditions, Sonners says. Unfortunately, its typically a last resort, literally right before an amputation surgery or as a life-saving mechanism for somebody with carbon monoxide poison or air gas embolism.

So, we only think about it, traditionally, to help save the life or limb of somebody in a really severe condition, but the mechanisms that are working for those folks are very similar to the reasons that you and I might consider using hyperbaric oxygen:

For upregulating the oxygen levels inside your body, which will help reduce inflammation, increase mitochondrial function and thereby increasing the energy that those cells are able to generate

Sonners goal is to expand the use of HBOT from the acutely life-threatening issues like gangrene to more chronic conditions, such as autoimmune and neurodegenerative diseases.

My thought process is that the mechanisms of action of hyperbaric are the same whether were talking about gangrene, radiation burns and osteonecrosis, or TBI [traumatic brain injury], concussion, maybe MS [multiple sclerosis] and post-stroke.

If we really get a mastery of the mechanisms of action, we can start to apply those mechanisms across the board. Clinically, weve seen hyperbaric work for so many of these other chronic illnesses

So, if we could really home in on those mechanisms and understand them better, and then get a better feeling for what time and pressure settings we require in order to get those mechanisms to kick in, then we can really, with more confidence, apply this therapy to these other conditions and have more consistent results in doing so.

A lot of the work Im proposing to do is tagging onto some of this work in regenerative medicine, where they were looking at the collagen, fibroblast and stem cell response to hyperbaric. A study came out in 2020 on telomeres, and looking at this potential, upwards of 20% increase in telomere length, especially in certain immune system cells.

I want to build on that knowledge base, so what Im doing is Im creating a study thats going to have a lower-pressure group and a higher-pressure group, and were going to be looking at a whole cytokine panel, so we can understand the mechanisms of the anti-inflammatory side.

Were going to have a methylation panel so that we can start looking at the epigenetic effects of hyperbaric. Were going to have a telomere component, similar to the telomere study that was done a year and a half ago.

And were going to start comparing all of those metrics across roughly a three- to six-month timeframe of treatment, and over two separate pressure settings, to better understand which pressures are getting which effects, and again, what period of time should we be expecting before we get the results that were looking for?

On the low end, Sonners will be using 1.3 atmospheres (4.2 PSI) at 100% oxygen, and on the high end, hell use 2.0 atmospheres (14.7 PSI) at 100% oxygen. All patients will use hard chambers at two different pressures. The lower pressure group will be at 4.2 psi, which is the same as soft chamber pressures.

Theres nowhere near the amount of research in soft chambers as there are in hard chambers, Sonners says. The overwhelming majority of research is done at that 2-atmosphere range, which is why Im choosing that as the upper end of the research that Im doing in the soft chamber research.

There is definitely some [research] on sports recovery. Theres actually some ongoing studies right now on hyperbaric for stem cell use that were waiting for. In some cases, 1.3 [atmospheres] has been used as the sham group, opposed to a treatment arm in the research. Maybe the study team really thought that 1.3 wasnt going to have an effect and its a legitimate sham

Im not sure, but there are some great studies. Theres a study that was done on cerebral palsy (CP) and 1.3 was used as the sham group In this particular study, with 1.3 being the sham group, there was also a control group that got no hyperbaric at all.

Within the sham group, there was significant improvement on the metrics they were measuring. Then they had a 1.5 [atmospheres at] 100% oxygen, which also had a good improvement and then, a 1.75 [atmospheres at] 100% oxygen, which had even a greater improvement.

The issue in the study was that while all three of those groups improved, there was no statistical difference or enough of a statistical difference between the 1.3, the 1.5 and the 1.75. So, the conclusion of the study was therefore that hyperbaric does not work for CP, although all three of those groups had significant improvement.

So, because the sham group was not considered a treatment, that was the conclusion of that study. Now, the natural consequence of that should have been redoing the study and creating a different level of what the sham and the treatment arms ought to be, but that was never redone.

So, as a result, theres this study with results that say hyperbaric does not work for CP. Meanwhile, clearly, what it means is we need more studies. Its just that studies are expensive. Theyre very time consuming and you really have to have a large interest in trying to come up with the right answers to put forth the effort and time and money to get that kind of work done.

If you breathe 100% oxygen under pressure, its intuitively obvious that youre going to deliver more oxygen to your tissues. Thats one clear mechanism, but its not the only or even primary reason for most of the benefits of hyperbaric therapy.

Evidence suggests part of the benefit might be related to the degeneration of a molecule called hypoxia-inducible factor alpha (HIF-1 alpha), which is generated when you lower the pressure. The pressure is high inside the chamber, and is lowered when you exit the chamber and enter the normal atmosphere. That means some of the benefit might actually be occurring when you get out of the chamber. Sonners explains:

We dont have an exact number right now, but roughly half of the treatment is occurring while youre in the chamber, being exposed to the pressure, being exposed to the oxygen and literally accumulating a surplus of oxygen because of the therapy itself.

The other half of the therapy is when you get out of the chamber, as that oxygen can no longer stay in solution. It literally starts trying to bubble out of solution. As that happens, its not inert, its actually very active. So, as its coming out of solution, its interacting with all of our cells.

As a result, its triggering a massive cascade of events, cellular communication that seems to stimulate multiple series of regeneration and anti-inflammatory [events], even within the reactive oxygen species themselves.

When we look at the first part, which is the dosage of oxygen a person is getting, and thats measurable, you could say, Heres a person, they were in a chamber, they were at this pressure, breathing this percentage of oxygen for this amount of time, and you could literally calculate the theoretical dose of oxygen that person was exposed to and should have been able to absorb.

Weve kind of just stayed in that mindset for all these years. [However], there was a great paper out of Israel called The Hypoxia-Hyperoxia Paradox, and what theyre saying is we know that theres amazing benefits of hypoxia actually.

Some of these benefits include the stimulation of HIF-1 alpha, stem cell responses, collagen responses and the angiogenic responses. For these reasons, Sonners views hyperbaric as an anabolic therapy a therapy that stimulates vitally important growth and repair, as growth factors such as VEGF (vascular endothelial growth factor), and BDNF (brain derived neurotropic factor) are both stimulated.

Again, these growth factors are not stimulated by the hyper-oxygenation. Theyre a result from the hypoxic component, the process your body goes through as the oxygen is leaving your body.

The important thing to note is that once youve accumulated all this extra oxygen, your hyper-oxygenation component, as that oxygen is leaving your body, youre never truly hypoxic, Sonners says, but the cell signaling factors that respond to traditional hypoxia are also seemingly responding to this relative hypoxia.

If you look at that paper [The Hypoxia-Hyperoxia Paradox] it seemed to delineate this. With hypoxia alone, you will still get VEGF, which means youll still get a lot of angiogenics, the rebuilding of the endothelial lining, the creation of a new micro-circulation bed, all this capillary regrowth will happen from hypoxia.

Youll get these stem cell releases, this potential for increase in the regenerative nature of cells. Youll get this increase in the HIF-1 alpha. But if youre chronically hypoxic, youre also going to get a downregulation of sirtuins [longevity proteins] and youre going to get a downregulation of mitochondrial function.

Sirtuins could play a great role in things like cell cycle life, getting cells out of cellular senescence kicking them back into active life or apoptosis, killing that cell so that we can replace it with a new stem cell, or even the genetic and epigenetic repair mechanisms. A lot of that has to do with sirtuins, so we dont want to downregulate those. We want to upregulate those.

So, to clarify, with HBOT, you get the benefits of hypoxia with none of the downsides. Rather than inhibiting sirtuins, which are important for health and longevity, you actually get an upregulation of sirtuin activity. It also upregulates mitochondrial function and boosts mitochondrial replication, which the complete opposite to what happens in true hypoxia.

Without any doubt, HBOT is a type of oxidative stress, but it doesnt have the adverse effects youd expect. Sonners explains:

There was a great paper done by Dominic DAgostino and Angela Poff, back in 2017 or 2018, specifically looking at the reactive oxygen species or the free radical component of hyperbaric oxygen. What are the benefits or consequences as we upregulate, as we increase the amount of oxygen into the body?

As the cells and the mitochondria start to uptake that oxygen, producing more energy, there is a natural consequence where this byproduct of free radicals are released as a part of normal cellular respiration. Excess free radicals is obviously consequential to cell membranes, lipid peroxidation and protein degradation.

It could destroy cell membranes, mitochondrial membranes, nuclear membranes, genetic material At the same time, its a normal response to cellular respiration and our bodies have their own intrinsic mechanisms for dealing with some of this excess free radical, things like the superoxide dismutase, catalase and glutathione pathways.

So, there seems to be a distinction that we should make. One is that some of the free radicals our bodies are exposed to come from the outside world in. Radiation, smoking, air pollution, the list goes on and on. So, we need to have a robust, intrinsic ability to tolerate these free radicals with our own antioxidant system.

But in excess, we could be getting too much free radicals and we could be depleting our own systems, in which case supplementation should certainly be considered and used. On the flip side, we look at hyperbaric oxygen as this tool that theoretically has all these great effects, but one of those consequences would also be this increase in free radical exposure.

There seems to be a very big delineation between a body thats exposed to free radicals from the outside world, versus a body that is exposed to free radicals that its creating on its own.

One of those distinctions is that through the use of hyperbaric oxygen, even without supplementation, and the increase in free radical production from mitochondrial ATB production, the body itself assuming it has the right raw materials will actually increase its own superoxide dismutase, catalase and glutathione pathways.

This would No. 1, help make you more resilient to hyperbaric oxygen, but No. 2, would also help make you more resilient to all the other free radicals that youre potentially exposed to in your environment.

So, I would say two things. One, especially with patients who are a little bit more fragile when it comes to oxidative stress, those people, I would tend to not over oxidize to begin with, so I might start at a gentler hyperbaric protocol with them, and Im likely to want to start quickly upregulating their own system, getting the right supplementation for improving their intrinsic antioxidant systems

Then, as their system improves their tolerance for reactive oxygen species, we may not need as much of that, or if were going to be using high dose hyperbaric oxygen for a period of time, we might use things like certain SOD precursors, or molecular hydrogen.

Through conversations with you, it has become one my favorite antioxidants that we use. Between 45 minutes to an hour before [hyperbaric treatment], well start loading people with the molecular hydrogen as a mechanism to reduce the consequences. There are benefits, in other words. Reactive oxygen species on its own also helps stimulate hormone balance and helps stimulate cell repair by themselves. So, there has to be this balance.

We dont want to quelch all the free radicals because free radicals are a very important signaling molecule for so much cellular activity and at the same time, we want to be aware of the fact that hyperbaric does increase that, and we want to make sure that were not over-exposing somebody.

Sonners also reviews the curriculum he developed for the International Board of Undersea Medicine. The IBUM has been certifying people in hyperbaric medicine for 25 years, and the curriculum Sonners created has been taught as a functional medicine hyperbaric course for clinicians for the past year.

A big push for me, and even for the research Im doing, is to help create awareness that gets more doctors excited about [HBOT], that want to actually use it in their practice, Sonners says. So, this has been an attempt to really improve the education so that people arent just going to hyperbaric courses to learn about wound care.

We needed courses to help practitioners like myself or other people interested in the regenerative side to be able to learn how to apply it that way. So, we now have a course that I teach a few times a year to get people on the same page.

The majority of this last year, other than getting through school and writing the thesis, has been developing and promoting that course. I think weve certified about 125 to 150 practitioners and technicians specifically on the functional medicine side of hyperbaric use

At this time, I still see a pretty big mix between soft chamber use and hard chamber use. A lot of those doctors are either Dos, MDs, chiropractors or naturopaths, getting into more of a functional medicine base, just looking for other natural approaches to the things they are treating.

Hyperbaric supplies the body with a fundamental ingredient and its so necessary for cellular performance. It just seems to make sense to start implementing a tool and a modality like that into a setting where youre trying to reduce inflammation, youre trying to improve energy production cellularly.

While the list of potential uses for HBOT is extremely long, in the U.S., the Food and Drug Administration has approved and most insurance will pay for HBOT for the following 14 conditions:1

Air or gas embolism

Carbon monoxide poisoning

Clostridial myositis and myonecrosis (gas gangrene)

Crush injuries, compartment syndrome and other acute traumatic ischemia

Decompression sickness

Arterial insufficiencies, such as central retinal artery occlusion

Severe anemia

Intracranial abscess

Necrotizing soft tissue infections

Osteomyelitis

Delayed radiation injury (soft tissue and bone necrosis)

Compromised grafts and flaps

Acute thermal burn injury

Idiopathic sudden sensorineural hearing loss

In terms of conditions that can benefit from HBOT, I would certainly add stroke, TBI, heart attack, anytime theres post ischemic reperfusion injury, and most neurodegenerative conditions. Internationally, there are about 100 recognized indications. While that might make it sound like a magical cure-all, its important to remember that it doesnt cure anything directly.

The main effect of hyperbaric is really achieved through the cumulative effect and the increasing and decreasing the wave of hyper-oxygenation back to normal oxygen levels creating that hyperoxia-hypoxia type paradox. ~ Jason Sonners

What it does is provide your body with a foundational nutrient, oxygen, that virtually all cells require. HBOT supplies your body oxygen in a surplus, creating an excess reservoir of oxygen to improve that function. Thats why it can help improve such a wide variety of health conditions.

Even autoimmune diseases such as MS, lupus and rheumatoid arthritis, just to name a few, may benefit, Sonners says. A whole other category of potential use would be wellness, longevity and regenerative-type therapies.

Were just applying the tools slightly differently to help match the intensity of the therapy to the severity of the condition. We can utilize the principles of gas exchange in various ways to help so many different types and various types of conditions, Sonners says.

One condition or subclass that we talked about it in the beginning is, from the immune system standpoint, upregulating your ability to fight infection by increasing white blood cell activation through the reactive oxygen species mechanisms. We use it for anaerobic infection, bacterial infections all the time.

One of the main reasons that hyperbaric works in those severe conditions is those bacteria are anaerobic. They dont live in high oxygen environments.

So, we know that putting a patient in a high oxygen environment massively decreases bacterias ability to function, potentially helps to kill that infection, helps to block the toxicity of that infection and helps to break down the biofilms around that infection. So, hyperbaric becomes an amazing tool in the capacity of immune system balancing and/or ability to help fight infection.

As a general guidance, Sonners recommends doing hyperbaric for about two hours a week on a regular basis. Thats his personal routine. In addition to that, three times a year he does a 30- to 40-hour protocol over the course of six to eight weeks. He explains why:

We know that in general three or four sessions is not going to ever cut it. The main effect of hyperbaric is really achieved through the cumulative effect and the increasing and decreasing the wave of hyper-oxygenation back to normal oxygen levels creating that hyperoxia-hypoxia type paradox

When you do a protocol similar to like what I would do for a patient, lets say four to six hours a week for eight weeks, the frequency of those the space in between them, really shrinks and you get far more signaling to occur

If all we cared about was the physical dose, we would stay at 100% oxygen as long as we possibly could, at the highest pressure we could tolerate to get the most oxygen absorption. I dont think that thats where the majority of benefit exists.

Every time your pressure changes or your percentage of oxygen changes, youre stimulating HIF-1 alpha, the reactive oxygen species load, sirtuins, youre signaling a hormetic effect. I picture them as switches. Youre flipping that switch on, off, on, off, on, off. I think its the amount of times that you stimulate that switch that will create the benefits were looking for, more than the physical dose of oxygen over time.

To learn more about HBOT in general, be sure to pick up Sonners book, Oxygen Under Pressure: Using Hyperbaric Oxygen to Restore Health, Reduce Inflammation, Reverse Aging and Revolutionize Health Care.

In the interview, we also discuss how you can incorporate HBOT in your fitness routine, along with fasting, to augment and upregulate cellular performance, recovery and regeneration. So, if thats of interest to you, be sure to listen to the interview in its entirety, or read through the transcript.

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Hyperbaric Therapy A Vastly Underused Treatment Modality - Verve Times

Oxid Med Cell Longev. 2017; 2017: 1259510.

1Institute of Food Security and Sustainable Agriculture, Universiti Malaysia Kelantan, Campus Jeli, 17600 Jeli, Malaysia

2Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, Campus Jeli, 17600 Jeli, Malaysia

2Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, Campus Jeli, 17600 Jeli, Malaysia

2Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, Campus Jeli, 17600 Jeli, Malaysia

3Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, 16150 Kelantan, Malaysia

1Institute of Food Security and Sustainable Agriculture, Universiti Malaysia Kelantan, Campus Jeli, 17600 Jeli, Malaysia

2Faculty of Agro-Based Industry, Universiti Malaysia Kelantan, Campus Jeli, 17600 Jeli, Malaysia

3Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, 16150 Kelantan, Malaysia

Academic Editor: Jasminka Giacometti

Received 2017 Feb 17; Accepted 2017 Apr 9.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

There are several health benefits that honeybee products such as honey, propolis, and royal jelly claim toward various types of diseases in addition to being food.

In this paper, the effects of honey, propolis, and royal jelly on different metabolic diseases, cancers, and other diseases have been reviewed. The modes of actions of these products have also been illustrated for purposes of better understanding.

An overview of honey, propolis, and royal jelly and their biological potentials was highlighted. The potential health benefits of honey, such as microbial inhibition, wound healing, and its effects on other diseases, are described. Propolis has been reported to have various health benefits related to gastrointestinal disorders, allergies, and gynecological, oral, and dermatological problems. Royal jelly is well known for its protective effects on reproductive health, neurodegenerative disorders, wound healing, and aging. Nevertheless, the exact mechanisms of action of honey, propolis, and royal jelly on the abovementioned diseases and activities have not been not fully elucidated, and further research is warranted to explain their exact contributions.

Apiculture is the science and art of prolonging, sustaining, and retaining health by using products obtained from honeybee hives, such as honey, bee bread, bee venom, bee pollen, propolis, and royal jelly. Recent years have seen the fast application of bee products in both traditional and modern medicine. Currently, many studies are targeted toward investigating directed health benefits and pharmacological properties of bee products due to their efficacies, leading to the increasing development of nutraceuticals and functional food from these products. The concept of functional food refers to food that has the ability to promote better physiological or psychological health compared to traditional remediated and nutritional food. These effects positively contribute toward excellent health maintenance, well-being, and reduced chronic illness [1]. The present review focuses on the potential health benefits of bee products, including honey, propolis, and royal jelly.

Honey is a sweet liquid processed by the honey bee. Honey is recognized worldwide due to its high nutritive components that are beneficial for human well-being. It has been traditionally used by Egyptians, Greeks, Romans, and Chinese to heal wounds and diseases of the gut, including gastric ulcers. It has also been used as a remedy for cough, sore throat, and earaches [2]. In India, Lotus honey has been traditionally used to treat eye infections and other diseases. In addition to being used externally, honey is also used internally [3] as a functional food to provide energy and nourishment to enhance vital organs in the body [4]. This has been in practice since ancient times. The active components of honey, such as glucose, fructose, flavonoid, polyphenols, and organic acids, play an important role in its quality [5]. Honey is being produced in many countries all over the world and is recognized as an important medicine as well as energy-providing food due to its functional properties and nutritional values. Additionally, honey is well known for its biological, physiological, and pharmacological activities.

Propolis is generally known as the bee glue, which is a generic name that refers to the resinous substance accumulated by the bees from different types of plants. The word propolis is derived from Greek to mean defense for pro and city or community for polis, or the beehive, in other words [6]. Propolis functions in sealing holes and cracks and for the reconstruction of the beehive. It is also used for smoothing the inner surface of the beehive, retaining the hive's internal temperature (35C), preventing weathering and invasion by predators. Furthermore, propolis hardens the cell wall and contributes to an aseptic internal environment. Propolis generally becomes soft and sticky upon heating [7]. It also possesses a pleasant smell. Propolis and its extracts have numerous applications in treating various diseases due to its antiseptic, anti-inflammatory, antioxidant, antibacterial, antimycotic, antifungal, antiulcer, anticancer, and immunomodulatory properties.

Royal jelly, a white and viscous jelly-like substance, is a form of hypopharyngeal and mandibular gland secretion from the worker bees. It is also known as a superfood that is solely consumed by the queen bee. Royal jelly is also fed to the honeybee larvae upon hatching and helps to nurture the brood [8]. It is the exclusive nutriment offered to the immature young larvae in their first 2-3 days of maturation besides being used as a food specifically for the queen bee throughout her entire life cycle. Royalactin is the main compound in royal jelly that allows the morphological change of a larva into the queen bee [9]. This superfood is the main reason for the longevity of the queen bee compared to the other bees. Royal jelly is widely used as a dietary nutritional complex to help combat various chronic health conditions. Furthermore, it is one of the profitable remedies for human beings in both traditional and modern medicine. Many pharmacological activities such as antibacterial, antitumor, antiallergy, anti-inflammatory, and immunomodulatory effects have also been attributed to it.

Honey is also known as a supersaturated sugar solution. Natural honey is composed of 82.4% carbohydrates, 38.5% fructose, 31% glucose, 12.9% other sugars, 17.1% water, 0.5% protein, organic acids, multiminerals, amino acids, vitamins, phenols, and a myriad of other minor compounds. In addition, honey consists of minor amounts of bioactive components, including phenolic acid, flavonoid, and -tocopherol [10]. Honey constituents with health benefits include phenolic acids, flavonoids, ascorbic acid, proteins, carotenoids, and certain enzymes, such as glucose oxidase and catalase [11].

Propolis is the third most important component of bee products. It is composed mainly of resin (50%), wax (30%), essential oils (10%), pollen (5%), and other organic compounds (5%) [12]. Phenolic compounds, esters, flavonoids, terpenes, beta-steroids, aromatic aldehydes, and alcohols are the important organic compounds present in propolis [13]. Twelve different flavonoids, namely, pinocembrin, acacetin, chrysin, rutin, luteolin, kaempferol, apigenin, myricetin, catechin, naringenin, galangin, and quercetin; two phenolic acids, caffeic acid and cinnamic acid; and one stilbene derivative called resveratrol have been detected in propolis extracts by capillary zone electrophoresis [14]. Propolis also contains important vitamins, such as vitamins B1, B2, B6, C, and E and useful minerals such as magnesium (Mg), calcium (Ca), potassium (K), sodium (Na), copper (Cu), zinc (Zn), manganese (Mn), and iron (Fe). A few enzymes, such as succinic dehydrogenase, glucose-6-phosphatase, adenosine triphosphatase, and acid phosphatase, are also present in propolis [15].

Royal jelly consists of water (50%60%), proteins (18%), carbohydrates (15%), lipids (3%6%), mineral salts (1.5%), and vitamins [16]. Based on modern spectrometric analysis, approximately 185 organic compounds have been detected in royal jelly. Royalactin is the most important protein present in royal jelly. In addition, royal jelly is composed of a significant number of bioactive compounds, including 10-hydroxy-2-decenoic acid (HAD), which has some immunomodulatory properties [17]. Fatty acid, proteins, adenosine monophosphate (AMP) N1 oxide, adenosine, acetylcholine, polyphenols, and hormones such as testosterone, progesterone, prolactin, and estradiol are other useful bioactive components reported to be present in royal jelly [18].

Honey, propolis, and royal jelly are highly rich in bioactive compounds (). Essential and nonessential compounds, such as polyphenols and vitamins occurring naturally as part of food chains, are considered bioactive. These compounds are naturally present in food and confer useful health benefits. Phenolic compounds are bioactive compounds. Phenols are defined as organic compounds with an aromatic ring that is chemically bonded to one or additional hydrogenated substituents in the presence of corresponding functional derivatives [19].

Important bioactive compounds in honey, propolis, and royal jelly.

In honey, propolis, and royal jelly, phenolic compounds are commonly present as flavonoids [20]. Various phenolic compounds contribute to the functional properties of bee products, including their antioxidant, antimicrobial, antiviral, anti-inflammatory, antifungal, wound healing, and cardioprotective activities [21]. summarizes the important biological efficacies of bee products.

Various types of biological activities of honey products.

Honey has traditionally been used to treat wounds, insect bites, burns, skin disorders, sores, and boils. Scientific documentation of the wound-healing capabilities of honey validates its efficacy as a promoter of wound repair and an antimicrobial agent [37]. Honey promotes the activation of dormant plasminogen in the wound matrix, which results in the dynamic expression of the proteolytic enzyme. Plasmin causes blood clot retraction and fibrin destructions. It is an enzyme that breaks down fibrin clots with attached dead tissues in the wound bed [38].

Clinical evidence supporting the effectiveness, specificity, and sensitivity of honey in wound care indicates that the performance of conventional and modern wound care dressing is inferior to that using honey [39]. Certain cases have shown that honey stimulates wound-healing properties even in infected wounds that do not respond to antiseptics or antibiotics and wounds that have been infected with antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) (Natarajan et al. 2001). Honey also aids autolytic debridement and accelerates the growth of healthy granulated wound bed [40].

Malodor is a general attribute of severe wounds caused by anaerobic bacterial species belonging to Bacteroides spp. and Peptostreptococcus spp. [41]. Malodourous compounds, such as ammonia, amines, and sulfur, are produced by bacteria during the metabolism of amino acids from putrefied serum and tissue proteins. These compounds are replaced by lactic acids as honey dispenses a substantial amount of glucose, a substrate metabolized by bacteria in preference to amino acids [42]. The therapeutic effects observed after honey application include fast healing, wound cleansing, clearance of infection, tissue regeneration, minimized inflammation, and increased comfort during dressing due to lower extent of tissue adhesion [43].

Honey also controls skin damage near stomas, such as ileostomy and colostomy, by enhancing epithelialization of the afflicted skin surface [44]. Honey has a beneficial effect on pediatric dermatitis caused by excessive use of napkins and diapers, eczema, and psoriasis. The effect of honey mixed with beeswax and olive oil was investigated on patients with psoriasis or atopic dermatitis condition. A clinical trial showed that a mixture containing honey was extremely well tolerated and caused significant improvements. Honey consists of various nitric oxide metabolites, which reduce the incidence of skin infection in psoriasis [45].

Consumption of honey is a low-cost and effective therapy for the treatment of DFU. DFU is often complicated by microbial infections and slows the healing process. Apart from the infection, symptoms such as pain, swelling, and redness might not be present for diabetic peripheral neuropathy patients due to their reduced immune response, which further complicates the diagnosis [46]. A review indicated that using honey for the treatment of venous ulcers yielded positive outcomes with good acceptance rates from the patients [47]. Honey is used in wound management and is effective among patients with locally infected wounds, DFU, Charcot foot ulcerations, and complex comorbid conditions that have failed hospital management [48]. In addition, there is excellent tolerability and minimal trauma to the wound bed in the presence of honey.

Natural honey is composed of enzymes that facilitate the absorption of molecules, such as sugars and starch. The sugar molecules in honey are in a form that can be easily absorbed by the body. Honey also provides some nutrients, such as minerals, phytochemicals, and flavonoids, that aid digestive processes in the body [49]. Pure honey has bactericidal properties against pathogenic bacteria and enteropathogens, including Salmonella spp., Escherichia coli, Shigella spp., and many other Gram-negative species [50].

The gastrointestinal tract (GIT) contains many important beneficial microbes. For example, Bifidobacteria is one of the microorganisms present primarily for the sustenance of a healthy GI system. It has been suggested that consuming foods rich in probiotics can increase the population of Bifidobacteria in the GIT. The biological activities and development of this bacteria are further enhanced in the presence of prebiotics. Studies have shown that natural honey contains high amount of prebiotics [51]. Some in vitro and in vivo experimental trials on honey have reported it as a prominent dietary supplement that hastens the growth of Lactobacillus and Bifidobacteria and catalyzes their probiotic potency in the GIT [52, 53]. Under in vitro conditions, prebiotic ingredients in honey such as inulin, oligofructose, and oligosaccharides promoted the increase in the numbers of Lactobacillus acidophilus and L. plantarum by 10100 folds, which was beneficial for the intestinal microbiota [54].

Honey is useful for the treatment of many oral diseases, including periodontal disease, stomatitis, and halitosis. In addition, it has also been applied for the prevention of dental plaque, gingivitis, mouth ulcers, and periodontitis. The antibacterial and anti-inflammatory properties of honey can stimulate the growth of granulation tissue, leading to the repair of damaged cells [55]. Porphyromonas gingivalis is a Gram-negative bacteria that causes periodontitis. Honey exerts antimicrobial activity against this anaerobic bacteria and prevents periodontal disease [56]. Inflammation of mucous membranes in the mouth (stomatitis) may induce redness and swelling of oral tissues and cause distinct and painful ulcers. Honey penetrates into the tissues very quickly and is effective against stomatitis [57, 58]. Halitosis is an oral health condition that causes malodorous breath. Most of the odor in the oral cavity is caused by the activity of degrading microbes [59]. A recent study has reported that honey consumption ameliorates halitosis due to its strong antibacterial activity resulting from its methylglyoxal component [60].

Pharyngitis, commonly known as sore throat, is an acute infection induced by Streptococcus spp. in the oropharynx and nasopharynx [61]. In addition to streptococci, viruses, nonstreptococcal bacteria, fungi, and irritants such as chemical pollutants may also cause sore throat. Manuka honey is effective for treating sore throat with its anti-inflammatory, antiviral, and antifungal properties. Honey coats the inner lining of the throat and destroys the harmful microbes while simultaneously soothing the throat [62, 63].

A survey has demonstrated that honey is superior to other treatments for cough induced by upper respiratory infections, including dextromethorphan and diphenhydramine [64]. The antioxidant and antimicrobial properties of honey aided in minimizing persistent cough and ameliorated sleep for both children and adults following honey intake (2.5ml). A comparative study on children with different natural products reported that honey was found to be the widely used remedy for pneumonia 82.4% [65].

Gastroesophageal reflux disease (GERD) is a mucosal infection caused by contents of abnormal gastric reflux into the esophagus and even the lungs. Symptoms of GERD include heartburn, inflammation, and acid regurgitation. Consumption of honey helps this condition by coating the esophagus and stomach lining, thus preventing the upward flow of food and gastric juice. Honey can further stimulate the tissues on the sphincter to assist in their regrowth and finally reduce the chances of acid reflux [66].

Dyspepsia is a chronic disease in which the GI organs, mainly the stomach and first part of the small intestine, function abnormally. It is a disease that causes epigastric pain, heartburn, bloating, and nausea as symptoms. Dyspepsia is the preliminary symptom of peptic ulcer which could eventually cause cancer. Gastritis refers to the irritation and inflammation of the lining of the stomach wall. Peptic ulcer denotes erosions or open painful ulcers on the lining of the stomach or duodenum. Honey have been identified as a potent inhibitor for gastritis and the peptic ulcer causing agent, Helicobacter pylori (H. pylori) [67]. Clinical surveys have shown that honey decreased the secretion of gastric acid and increased the healing effect. Thus, honey is taken as a dietary supplement for its antibacterial properties and protective effect [68]. The high sugar content and low pH in honey are the results of glucose oxidative conversion to gluconic acid by glucose oxidase. This mechanism releases hydrogen peroxide, which functions as an antibacterial agent. Glucose oxidase also acts on fibroblasts and epithelial cell activators required for the healing of ulcers caused by H. pylori [51].

Gastroenteritis, known as stomach or gastric flu, causes inflammation of the digestive tract. This condition may be due to foodborne, waterborne, and person-to-person spread of infectious agents. The symptoms of gastroenteritis include dehydration, watery diarrhea, bloating, abdominal cramps, and nausea. There are many infectious agents, such as Salmonella, Shigella, and Clostridium, that can cause this condition [69]. A clinical study by Abdulrahman, 2010, has reported the treatment of infantile gastroenteritis using honey. The study found that replacing the glucose in standard electrolyte oral rehydration solution (ORS) with honey reduced the recovery time of patients with gastroenteritis because the high sugar content in honey boosts electrolyte and water reabsorption in the gut [70].

Chronic constipation is a common and multifarious illness characterized by intolerable defecation (irregular stools and difficult stool passage). Difficult stool passage includes symptoms such as straining, hard to expel stool, a sense of incomplete evacuation, hard or lumpy stools, and prolonged time to pass stool [71]. Diarrhea is defined as a high frequency of bowel movements with watery stool. Honey has minimized the pathogenesis and duration of viral diarrhea compared to conventional antiviral therapy [72]. In another case, people diagnosed with inflammatory bowel syndrome (IBS) experiencing severe diarrhea or constipation, bloating, and stomach discomfort was successfully treated with raw Manuka honey on an empty stomach [73].

Honey helps to soothe pain, balance liver systems, and neutralize toxins. Complications in the liver system can be attributed to oxidative damage. Honey exhibits antioxidant activities that have a potential protective effect on the damaged liver. A study on paracetamol-induced liver damage rats showed that the antioxidant and hepatoprotective activity of honey minimized liver damage [74]. Honey, which has a 1:1 ratio of fructose to glucose, may help to promote better blood sugar level, which is useful for those suffering from fatty liver disease since it provides adequate glycogen storage in liver cells. Insufficient glycogen storage in the liver releases stress hormones that impair glucose metabolism over time. Impaired glucose metabolism leads to insulin resistance and is the main factor of fatty liver disease. Another study reported significant reduction in blood glucose levels after treatment with Tualang honey [75, 76].

Natural wild honey exerts cardioprotective and therapeutic impacts against epinephrine-induced cardiac disorders and vasomotor dysfunctions. A harmonized relationship between radical scavenging activity and the total phenolic content of honey has been observed [77]. Honey intake showed a significant reduction in risk factors of metabolic and cardiovascular diseases. Honey exhibits cardioprotective effects such as vasodilation, balancing vascular homeostasis, and improvements in lipid profile [78]. Flavonoids in honey improves coronary vasodilation, decreases the ability of platelets to form clots, prevents oxidation of low-density lipoproteins (LDL), increases high-density lipoproteins (HDL), and improves endothelial functions [79].

A study conducted to compare the metabolic response of honey has indicated its ameliorative effects against metabolic syndromes (MetS) [80]. MetS is denoted by hyperglycemia, hypertension, abdominal obesity, dyslipidemia, and intensified adaptability towards diabetes, kidney, and heart diseases. Polyphenols in honey reduce atherosclerotic lesions through the downregulation of inflammatory and angiogenic mechanisms [81]. A clinical study conducted on patients with hyperlipidemia showed that honey decreased total cholesterol (TC) and noticeably prevented the rise in plasma glucose levels. Nitric oxide (NO) is a metabolite present in honey that also has cardioprotective functions [82].

Imbalance in estrogen signaling pathways and propagating levels of estrogens have important roles in breast cancer growth and propagation [83]. Treatments for breast cancer are associated with targeting the estrogen receptor (ER) signaling pathway. Phytoestrogens are a subclass of phytochemicals with a common structure to the mammalian estrogen that enables them to bind to estrogen receptors. Several experimental studies have investigated the efficiency of honey in modulating the ER signaling pathway [84]. Another study has shown that honey has biphasic activity in MCF-7 cells. This biphasic activity of honey is represented by an antiestrogenic effect at lower concentrations and an estrogenic effect at higher concentrations, which is caused when phytoestrogens bind to estrogen receptors [85]. Moreover, quercetin has been reported to induce apoptotic effects through ER - and ER -dependent mechanisms. On the other hand, cytotoxic activities of Tualang honey in human breast cancer cells were demonstrated by elevated secretion of lactate dehydrogenase (LDH) and further illustrated the cytotoxic properties of honey. The study also showed that honey only exerts cytotoxic effects on breast cancer line and not on nonmalignant breast cells. Therefore, this indicates that Tualang honey shows highly specific and selective cytotoxic effects towards breast cancer cell lines and has a good potential as a chemotherapeutic agent [86].

The most common type of liver cancer is hepatocellular carcinoma (HCC). The antitumor effects of honey on liver cancer cells have been investigated in various experimental studies. Treatment of HepG2 cells with honey minimized the amount of nitric oxide (NO) levels in the cells and decreased the HepG2 cell number greatly. This increased the overall antioxidant profile of the cells. The survival of HepG2 cells is promoted by reactive oxygen species (ROS), and adequate levels of ROS trigger cell proliferation and differentiation. Decreasing the amount of NO resulting from honey treatment supported this study. Thus, reduced ROS and enhanced antioxidant efficacy inhibit cancerous cell proliferation and lowered the number of HepG2 cells [84]. Another study done by Abdel Aziz et al. investigated the effects of honey on HepG2 cell lines. The report showed that honey exerted cytotoxic, antimetastatic, and antiangiogenic effects on HepG2 cells based on different concentrations [87].

Most colorectal cancers begin as a polyp, which generally starts on the inner lining of the colon or rectum and grows towards the center. Some polyps are not dangerous but some will eventually grow into adenomas and can eventually result in cancer. A study [88] that investigated the chemopreventive effects of Gelam and Nenas monofloral honeys against colon cancer cell lines found that the honey inhibited proliferation of colon cancer cells. Hydrogen peroxide-induced inflammation in the colon cancer cells was used to examine the effect of honey. The results showed that honey curbed inflammation in the cancerous cells [88]. Another study was done to investigate the apoptotic effects of crude honey on colon cancer cell lines. The study confirmed the antiproliferative effect of honey in these cells. In addition, at high phenolic concentrations (such as those of quercetin and flavonoids), significant antiproliferative action against colon cancer cells was observed [89].

The molecular mechanisms resulting in the antiproliferative and anticancer effects of honey include cell cycle arrest, activation of mitochondrial pathway, induction of mitochondrial outer membrane permeabilization, induction of apoptosis, modulation of oxidative stress, reduction of inflammation, modulation of insulin signaling, and inhibition of angiogenesis in cancer cells (). In addition, honey shows potential effects on cancer cell by modulating proteins, genes, and cytokines that promote cancer.

Molecular mechanisms responsible for anticancer and antitumor activities of honey products. IRSinsulin receptor substrate, MAPKmitogen-activated protein kinase, NF-Bnuclear factor kappa B, IL-1interleukin-1 beta, IL-6interleukin-6, TNF-tumor necrosis factor alpha, iNOSinducible nitric oxide synthase, COXcyclooxygenase, ROSreactive oxygen species, Bcl-2B-cell lymphoma-2, and PARPpoly (ADP-ribose) polymerases.

Several components of honey such as chrysin, quercetin, and kaempferol have been shown to arrest cell cycle at various phases such as G0/G1, G1, and G2/M in human melanoma, renal, cervical, hepatoma, colon, and esophageal adenocarcinoma cell lines. The mitochondrial pathway entails a chain of interactions between stimuli such as nutrients, physical stress, oxidative stress, and damage during major cancer treatments including chemotherapy and radiotherapy. These stimuli cause several proteins located within the intermembrane space (IMS) of the mitochondria, such as cytochrome c, to be released, which eventually culminates in the death of the cell. Flavonoids in honey are effective in activating the mitochondrial pathway and discharging proteins with potential cytotoxicity. Induction of mitochondrial outer membrane permeabilization (MOMP) is the most prevalent anticancer mechanism, which causes the leakage of proteins from the IMS and inevitably results in cell death. Honey induces MOMP in cancer cell lines by decreasing the mitochondrial membrane potential. Honey has also been documented for amplifying the apoptotic effect of tamoxifen by intensified depolarization of the mitochondrial membrane. Flavonoid constituents of honey, such as quercetin, have been shown to trigger MOMP and lead to cancer cell death [84].

Apoptosis is a programmed cell death functioning to control cell growth and remove damaged cells from the system. This process also involves MOMP and results in the discharge of IMS proapoptotic proteins such as cytochrome c to activate caspase cascades which results in further disruption of mitochondria and finally results in cancer cell death. Influence of honey on enzymes, genes, and transcription factors corresponding to apoptosis has been investigated. Poly (ADP-ribose) polymerases (PARP) are crucial enzymes involved in apoptosis and DNA repair. Inhibition of PARP activity renders the cells unable to repair damaged DNA and pass through the G2 and M phases of the cell cycle. Thus, cell cycle is arrested. Because DNA repair is impaired due to nonfunctioning PARP, the cells are being classified as damaged, and consequently, apoptosis activity may be augmented.

Inhibition of PARP activity by flavonoids in honey is a potential strategy for targeting cancers with defective DNA-damage repair. Bcl-2 and Bax are antiapoptotic and proapoptotic proteins, respectively. Bcl-2 is generally overexpressed in cancer. Tumor suppressor p53 is a transcription factor commonly inactivated in various types of tumors. It modulates transcription of genes involved in apoptosis [84, 90]. Honey enhances the upregulation of Bax and downregulation of Bcl-2. In addition, it activates caspases 3 and 9 and induces p53, thereby inhibiting cancer.

Low levels of ROS intensify cell proliferation while high levels lead to oxidative damage that contributes to various types of cancer. Regulation of redox homeostasis is vital for normal cell growth and proliferation. In this regard, honey is an influential antioxidant and free radical scavenger. The inhibitory effect of honey on cancer growth and proliferation is due to its ability to modulate oxidative stress. Honey exhibits anticancer properties via antioxidant or pro-oxidant mechanisms that are selectively dependent on the state of oxidative stress in the cancer cells. If cancer growth is rapid under high levels of ROS, honey acts as an antioxidant to prevent cancer cell growth by minimizing oxidative stress and scavenging the ROS. On the other hand, under low levels of ROS, it may also act as a pro-oxidant and promotes cancer cell growth by further generation of ROS and maximizing oxidative stress. Thus, the effects of honey on cancer cell death are different under different conditions [84].

Inflammation is a contributing factor for the dysregulation of physiological processes, which leads to various malignancies and cancers. Mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-B) are the two main pathways responsible for inflammatory response in cells. Activation of MAPK and NF-B activates proinflammatory genes and generates inflammatory proteins or cytokines. These include cyclooxygenase-2 (COX-2), C-reactive protein (CRP), lipoxygenase-2 (LOX-2), interleukins (IL-1, IL-6), and TNF-. These components play crucial roles in both angiogenesis and inflammatory responses corresponding to cancer. IL-1, IL-6, and TNF- are cytokines that trigger cancer cell proliferation by maintaining the inflammatory phenotype in the tumor microenvironment. On the other hand, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) yield essential endogenous factors responsible for the tumor progression. The actions of iNOS can be either inductive or inhibitory depending on the tumor types.

Biological responses which facilitate inflammation can promote tumorigenesis as severe inflammation is the major factor for the development of cancer cells. Treating and soothing of inflammation aid to suppress the configuration of malignant and benign tumors. Honey helps to reduce the promotion and tumorigenesis and progression of cancer by reducing the expression of MAPK and NF-B in cancerous cells. MAPK cascades are the main signaling pathways in the regulation of cell proliferation, survival, and differentiation. NF-B is a transcription factor which is vital in the regulation of immune responses, inflammation, and oncogenesis. NF-B translocation to the nucleus and reduced IB degradation help to regulate the expression of genes involved in apoptosis and proliferation that are responsible for the development of cancer. Flavonoids found in honey have been shown to induce apoptosis and prevent the release of IL-1, IL-6, TNF-, iNOS, and COX-2 [84].

Tumors, malignancies, and cancers are usually enhanced by obesity and insulin-resistant type 2 diabetes mellitus. PI3K/Akt is an important pathway in insulin signaling. The PI3K/Akt pathway is also recognized in modulating substrates that are related to cellular growth, survival, and progression. Elevated levels of MAPK, NF-B, and insulin receptor substrate 1 (IRS-1) along with reduced levels of Akt expression have been actively linked to the development of insulin resistance. Honey components such as quercetin revive insulin resistance by increasing the expression of Akt while reducing the expression of IRS, MAPK, and NF-B. Modulation of insulin signaling by honey leads to anticancer activities [84].

Honey has debridement effects by boosting epithelialization and stimulates the development of granulation tissue through its angiogenic effect on the vasculature. Honey selectively stimulates angiogenesis in noncancer tissues through the production of hydrogen peroxide while inhibiting angiogenesis in cancer tissues. Honey has antiangiogenic effects that prevents the wound-healing response, reduces the viability of cancer cells, and lowers the incidence of metastasis by inhibiting the activities of gelatinase and protease. Honey prevents the development of cancer by blocking the three main stages of cancer formation known as initiation, proliferation, and progression [84].

Infection with parasites usually occurs upon contact with an infected surface. The symptoms of parasitic infection of the GI tract include abdominal pain, diarrhea, bloating, and nausea. Propolis has been reported to have several biological efficacies including anticancer, antioxidant, and anti-inflammatory activities (). There are a few studies that reported the clinical use of propolis in the treatment of viral infections. In one study, the in vitro effect of propolis ethanolic extract on the growth and adherence of Giardia duodenalis trophozoites was evaluated [91]. Propolis was shown to inhibit growth and adherence of the trophozoites. It also promoted the detachment of these parasitic organisms. Its efficacy against giardiasis has also been reported in a clinical study whereby children and adults with giardiasis-given propolis showed a cure rate between 52% and 60%, whereas those given the conventional drug showed a 40% cure rate. Another experimental study showed that propolis has antihistaminergic, anti-inflammatory, antiacid, and anti-H. pylori activities that can be used to treat gastric ulceration [92].

The biological activities of propolis.

Widespread causes of indicative vaginitis are bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC). The depletion of Lactobacillus spp. in the vagina is a distinguished feature of vaginal infections. The infection is accompanied by an overgrowth of vaginal pathogens such as yeast-like fungi and an elevated vaginal pH. Diabetes patients are more prone to having vaginal infections caused by Candida albicans. A study conducted on the application of 5% aqueous propolis solution resulted in an improvement in vaginal well-being [93]. In addition to providing antibiotic and antimycotic actions, propolis provides early symptomatic relief due to its anesthetic properties. Thus, propolis may be used for Recurrent Vulvovaginal Candidiasis (RVVC) and can be an alternative option for patients who are unable to take antibiotics due to a concurrent pharmacological treatment. The effectiveness of propolis against conventional antifungal nystatin has shown satisfactory results. Propolis extract solution (PES) also show low toxicity in human cells and can be an alternative treatment for chronic vaginitis. In addition, PES has antifungal properties and it can be used as antibiofilm material for RVVC to counteract biofilm growth of C. albicans and resistance in antifungal drug [94].

The oral cavity has an abundant bacterial microflora and excessive bacterial growth may lead to several conditions such as oral diseases. Studies have shown that propolis may restrict bacterial-plaque development and periodontitis-causing pathogens because of its antibacterial properties [95]. Propolis solutions exert a selectively lower cytotoxic action on human gum fibroblasts compared to chlorhexidine. In addition to that, mouthwash containing propolis have shown effectiveness in healing surgical wounds. This encourages the use of propolis in solutions used as mouthwash [96]. Propolis solution can also be used to disinfect toothbrushes [97]. A 3% ethanolic extract of propolis toothpaste gel showed greater potency against gingivitis caused by dental plague in a group of patients [98]. Propolis extracts have also helped cure halitosis, a condition where an individual experiences unpleasant breath predominantly due to poor oral hygiene. Propolis toothpaste or mouthwash is used for their ability to reduce growth of bacterial plaque and pathogenic microflora that causes gingivitis and periodontitis. Thus, propolis also plays a role as a therapeutic agent [95].

A study reported that propolis has potential towards human breast cancer treatment due to its antitumor activity by inducing apoptosis on human breast cancer cells. It also exhibits low or no toxicity towards normal cells due to its selectively toxic properties against tumor cells and is believed that propolis may become a prominent agent to treat breast cancer [99]. Another study investigating the effect of ethanolic extract of Algerian propolis on melanoma tumor growth has shown that galangin, a common flavonoid in propolis remarkably induced apoptosis and inhibited melanoma cells in vitro [100]. Turkish propolis has also been shown to exert a selective cytotoxic action on human lung cancer cells by inducing endoplasmic reticulum stress, apoptosis, and caspase activity and by reducing the mitochondrial membrane potential. This indicates that propolis is able to minimize the cancer cell proliferation [101].

Propolis is widely used in dermatological products such as creams and ointments. Its use in skin care products is based on its antiallergy, anti-inflammation, antimicrobial properties, and promotive action on collagen synthesis. A recent study comparing the effect of propolis and the conventional drug silver sulfadiazine showed that propolis notably decreased free radical activity in healing the wound beds which supported the repair process. A clinical study on acne patients using ethanolic extract propolis showed its high efficacy in the treatment of acne vulgaris [102]. Propolis also shows positive collagen metabolism in the wound during the healing process by increasing the collagen content of tissues [103]. A study demonstrated the use of propolis as an alternative therapy for wound healing to promote wound closure, especially under conditions such as human diabetic foot ulcer (DFU) [104].

The molecular mechanisms responsible for the wound-healing activity of propolis is shown in . Fibronectin (FN) is a multifunctional glycoprotein of high molecular weight, which influences the structural stability and functional properties of various organs and tissues (Stoffels, 2013). The fibronectin matrix and its accumulation are essential for cell migration, cell proliferation, cell differentiation, cell adhesion, apoptosis, cellular signaling, angiogenesis, collagen biosynthesis, re-epithelialization, clot formation, and platelet activity. Fibronectins are also important in the repair mechanisms for conditions such as glycoprotein intensified degradation, which leads to a defective cellular microenvironment and affliction in the structure of granulation tissues. This condition may prevent the wound from healing or inhibit the repair process. The accumulation of fibronectin in the extracellular space also modulates the secretion of other repairing components such as collagen type I and type III, tenascin, laminin, and fibrillin.

Molecular mechanism targeting wound-healing activity of propolis.

Propolis has demonstrated favorable effects in the wound-healing process such as antifungal and antibacterial activities due to its components such as flavonoids, phenolic compounds, terpenes, and enzymes. It also reduces the activity of free radicals (ROS) in the wound bed favoring the repair process. Propolis has also demonstrated great effects on collagen metabolism by increasing the amount of both type I and type III collagens in tissues. The reduction of ROS and accumulation of collagen aid in balancing the extracellular matrix and generating granulation tissues. Propolis is a potential apitherapeutic agent that is able to modify the metabolism of fibronectin by developing a fibrous network of extracellular matrix and inhibiting fibronectin disintegration. The active components in propolis such as quercetin and resveratrol inhibited fibronectin biosynthesis and TGF-dependent production of fibronectin, respectively, in C2C12 myoblasts. Both the components play important roles in regulating the expression of fibronectins. Studies have also shown that mobility and migration of epithelial cells are dependent on reduced fibronectin content in the extracellular matrix. Reduced amounts of this glycoprotein in propolis effectively treated wounds and produced granulation tissues. Therefore, the influence of propolis on fibronectin metabolism may alter the mechanism of wound healing [103]. Several health benefits of propolis related to gastrointestinal, gynecological care, oral health, skin care, and oncological treatments are tabulated in .

Selected propolis activities according to the health benefits.

Royal jelly is one of the honey bee products which have potential towards various human disease treatments. depicts the biological activities of royal jelly as an antioxidant, antitumor, antiaging, neurotropic, and anti-inflammatory agent.

Different types of biological activities of royal Jelly.

A randomized clinical study has reported that royal jelly is effective in reducing premenstrual syndrome [105]. A randomized clinical trial study reported the effectiveness of royal jelly in treatment of urinary problems and promotion of life quality in postmenopausal women [106]. Royal jelly has protective effects against Oxymetholone-induced reproductive toxin (OXM), which is an active steroid derived from testosterone as a defense mechanism. Recent studies have reported that royal jelly protects against the oxidative injuries in the mouse testes and that it contains spermatogenesis-stimulating compounds, which inhibit the production of proinflammatory cytokines [107]. Another study on male rabbits has indicated its positive effects on fertility, semen quality and output, and concentration of testosterone, total proteins, and glucose in the blood. The number of dead and abnormal sperm decreased with the reduction of biomarkers of oxidative stress [108]. Royal jelly has been traditionally used to treat menopause symptoms by rebalancing the hormonal concentration in the blood, decreasing follicle-stimulating hormones (FSH) and increasing the estrogen concentration in aged mice. A study showed that the changes in hormone levels resulting from royal jelly increased the amount of ovulated oocytes and their quality in aged rats [109].

The molecular mechanisms responsible for the antiaging activity of royal jelly are shown in . The quality of oocytes decreases with age and the depleted follicle pool hastens hormonal dysregulation. This hormonal dysfunction is responsible for the reduction in ovarian follicle size and oocyte quality. Oxidative stress is the main cause of aging. Increased oxidative stress and continuous ovulation causes loss of antioxidants such as SOD, catalase, and glutathione S-transferase (GST). It also minimizes the size of the follicle pool and oocyte quality. Oxidative stress is controlled by glutathione (GSH), glutathione S-transferase (GST), Glutathione S-Transferase Theta 1 (GSTT1), Bax, and Bcl-2. GSH, GST, and GSTT1 are direct ROS scavengers, which play a vital role in removing oxidative stress from the cell. Higher expression of Bax and lower expression of Bcl-2 also promote aging and reduces oocyte quality.

Molecular mechanism responsible for the antiaging activity of royal jelly.

FSH and luteinizing hormone (LH) are the hormones involved in the aging process. The amount of FSH and LH is controlled by estrogen (E2) and inhibin from the ovarian cells. Reduction of the follicle pool size results in an inadequate release of estrogen and inhibin, which results in a rise in FSH levels. This process then aids in the reduction of the follicle pool size and affects oocyte quality. This process promotes aging in the ovaries. In young ovarian cells, higher amount of estrogen (E2) and inhibins are needed to decrease the level of FSH and LH. This adaptation can be overcome by antiaging therapies such as supplemental consumption of royal jelly. The major active component present in royal jelly is 10-hydroxyl-2-decenoic acid. This compound enhances the synthesis of ovulation hormones, maintaining a lower expression of FSH and LH in young ovarian cells. It is also efficient in preventing the depletion of follicle pool and in enhancing hormonal regulation. Thus, royal jelly helps in preventing the aging process and is an influential antiaging product [109].

Poor mental state and performance such as in the case of Alzheimer's disease (AD) are mostly experienced by elderly individuals due to aging. Royal jelly stimulates physical and mental functions for the elderly and increases their appetite and weight. A study showed that royal jelly exerted neuroprotective effects in AD [110]. The behavioral and neurochemical effect of royal jelly was chemically examined in aged rats. The study confirmed a better cognitive performance and increased the life span in the older animals that had been given royal jelly. Another study reported that royal jelly contains longevity-promoting factors and extends the lifespan in the nematode Caenorhabditis elegans [111]. Another study have also reported the improved mental health in human upon ingestion of royal jelly for six months [112]. A few studies on the health benefits of royal jelly are given in .

Reports on health benefits of royal jelly.

Royal jelly enhances wound-healing activity. In both in vivo and in vitro wound-healing models, under the effect of royal jelly, human fibroblasts were able to migrate and increase levels of sphingolipids by decreasing the secretion and formation of collagen. Thus, royal jelly shortened the curing period of desquamated skin lesions [113]. Another study on the use of royal jelly have also exhibited protective action on human skin against ultraviolet B-induced photoaging by promoting collagen production [114]. Royal jelly dressing is also an effective way of treating diabetic foot ulcers besides standard treatments. This is due to its vasodilation effects around the affected wound, which can help to dilate the blood vessels to enhance blood flow. It also helps to prevents infections due to its antimicrobial activities [115].

The present review focused on the potential health benefits of bee products such as honey, propolis, and royal jelly. These products are highly rich in active components such as flavonoids, phenolic acid, phenolic compounds, terpenes, and enzymes, which have biological functions in preventing some diseases and promoting good health. Honey, propolis, and royal jelly have distinct efficacies with significant nutritional properties and functional values. Thus, these bee products can be developed into potent apitherapeutic agents. However, some precautions need to be taken in case of allergens associated with bee products and in finding the right intake dosage. Hence, it is necessary to conduct further studies to determine the critical mechanisms related to the pharmacological activities of these bee products and the appropriate amounts that can be taken in order to obtain promising health benefits.

The authors acknowledge the financial supports from the Research Acculturation Collaborative Effort (RACE) (R/RACE/A07.00/01147A/ 001/2015/000237) and a research university team grant (RUT) (1001/PPSP/853005).

The authors declare no conflicts of interest.

Originally posted here:
Honey, Propolis, and Royal Jelly: A Comprehensive Review ...