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Shards of electricity burned through Mr Ps flesh. Layers upon layers of subcutaneous fat unraveled, filling the operating room with a pungent, metallic odor, like singed hair at the neighborhood barbecue. Within a few minutes, the pearly white bone of the sternum stuck out before a vein split open, filling the operative field with blood.

Zap! Maroon juice turned into a crackly black mass.

Transplant surgery is all about timing, says Dr Brandon Guenthart, a cardiothoracic surgeon at Stanford University School of Medicine. Anesthesiologists put the patient to sleep after the retrieval team confirms the donor heart looks good. Two surgeons start operating an hour before the donor heart arrives in the hospital. They dont begin cutting the patients heart out until the donor heart has landed safely at the local airport.

And if the plane crashes? Knock on wood, says Guenthart. Theres unfortunately no wood in the operating room.

I was at Stanford hospital watching this heart transplant because of my interest in David Bennett, a 57-year-old man who had died back in March. On 7 January 2022, at the University of Maryland Medical Center, Bennett had received a landmark heart transplant from an unusual donor: a genetically modified pig.

In 2021, a record 41,354 human-to-human organ transplants were performed, but over 100,000 Americans are still stuck on the transplant list. Every day, 17 people die waiting because there simply arent enough organs to go around.

Xenotransplantation or transferring cells, tissues and organs between species promises to solve this shortage and to reshape how we think about human longevity.

Lost in this boundless potential, however, is the significance of the human-animal divide. People walking around with pig organs melded into their bodies human-animal cyborgs of sorts can seem dystopian. And with the zoonotic Sars-CoV-2 virus having killed more than 6 million people, violating the interface between humans and animals may just promise more catastrophe.

This tortuous relationship is nothing new, but its often sanitized and hidden from sight think grinning cows on milk cartons and secret bunkers for animal research. Left open is a whole host of questions, starting with the most complex of all: what does it mean to be human?

Humans are animals. But animals are not humans. And yet, our history is rife with a cultural imagination of hybridity. The ancient Egyptian god of the sky, Horus, was depicted with a falcon head and the goddess of war, Sekhmet, that of a lioness. Similarly, the Hindu god Ganesha was beheaded and then resurrected with an elephant head grafted on to his body. In ancient Greece, fantastical creatures roamed the myths, from the bull-headed Minotaur to the snake-haired Medusa.

Within this wealth of options, the International Xenotransplantation Association chose a more obscure mascot: the Lamassu, an Assyrian deity with the body of a bull, the wings of a bird, and the head of a man a grounding wisdom.

Xenotransplantation, as a research field, started only with cells and tissues. In 17th-century France and England, blood was transfused from animals to humans to cure a whole host of medical conditions. Spiritual meaning was imbued into the act: Since Christ is the lamb of God, one recipient wrote in a letter to the Royal Society, sheeps blood possess[es] a symbolic relationship with [his] blood. One patients violent fever was purportedly cured, as was another patients paralysis, but at least two others died soon after these xenotransfusions.

Other early xenotransplants would follow, including ones with the bone, cornea and skin. Perhaps most infamously, the French surgeon Serge Voronoff transplanted slices of chimpanzee and baboon testicles into men, and ape ovaries into women, to rejuvenate his patients zest for life. Thousands of these operations were performed around the world, but any reported benefit, such as reduced fatigue or increased sex drive, was probably only the placebo effect and quickly faded.

While cell and tissue xenotransplants have been performed for centuries, whole organ transplants were more difficult to figure out. Sewing all the blood vessels together is a tricky business. You have to put two floppy tubes together mouth-to-mouth, tying them tight enough that the patient doesnt bleed out, but delicately enough that the patient doesnt have major clotting either.

This was a Nobel prize-level problem that the French surgeon Alexis Carrel solved with a small embroidery needle and fine silk suture, and was recognized for in 1912. Hes sometimes known as the father of transplant surgery.

A half-century later in 1964, the University of Mississippi surgeon James Hardy attempted the worlds first cardiac transplant, transferring Bino the chimpanzees heart into the chest of the rapidly deteriorating 68-year-old Boyd Rush. Rush survived for only 90 minutes, with the chimp heart offering insufficient support and rejection quickly shutting down his body.

It was Baby Fae who truly set the stakes for xenotransplantation. She was a 12-day-old infant with hypoplastic left heart syndrome, a congenital abnormality where the left side of the heart is a sliver of its full form. The condition was a death sentence.

So, in 1984, surgeons at Loma Linda University, California, transplanted a walnut-sized baboon heart into Baby Faes chest. The conditions were almost perfect. The heart was well-sized, Baby Faes immune system was immature (and sympathetic), and the immunosuppressive drug cyclosporine could suppress attacks on the baboon heart.

After the operation, Baby Fae seemed to be doing well. Resting in her crib with a gauze-covered scar traversing her chest, she was just gulping down her formula and wailing with a lusty cry, according to the hospital spokeswoman. The hospital also released photos of Baby Fae talking with her mother, the phone receiver bigger than her entire torso.

She died 21 days after her operation, her immune system refusing to accept the new infant-baboon hybrid. Outrage from physicians and the public soon followed, with animal-rights activists protesting and bioethicists publishing articles like Baby Fae: The Anything Goes School of Human Experimentation.

Xenotransplantation died with Baby Fae, if only for a little while.

During surgery when the drapes are on, its not really a person, Guenthart said. Its a task.

Technically speaking, a heart transplant is pretty easy. It takes only five incisions to cut out the failing heart, and only five connections to put in the new one. Electrocautery in one hand, scissors in the other, you usually first cut out the superior vena cava the vessel bringing back blood to the heart from the head, neck, arms and chest because its the most accessible structure.

Next is the inferior vena cava, which brings back blood from down south but is a bit hard to reach. So, you cut off a portion of the hearts right chamber where this vessel drains into.

Then comes the aorta and pulmonary arteries in fairly simple, straightforward incisions. More difficult are the pulmonary veins, because these are four delicate vessels that are almost impossible to reconnect. The way around that is to lift the heart up and cut out a rim of left heart tissue from underneath. You create a swimming pool, or a little crater, Guenthart said. He paused. Thats just me giving a description. They dont actually call it a swimming pool.

Regardless of whether youre transplanting a human heart or pig heart into someone, the steps are essentially the same.

If you asked 99 doctors out of 100, they wouldnt be able to tell you if they were looking at a human chest or pig chest, Guenthart said.

Pigs are filthy animals, as conventional wisdom goes. Judaism and Islam prohibit consumption of pork and other unclean meat. The insult cops are pigs bears undeniable teeth. And in the Odyssey, the sorceress Circe transforms Odysseuss gluttonous men into swine.

Pigs are also highly intelligent animals, capable of showing emotions. Some 11,000 years ago, wild pigs may have domesticated themselves, recognizing a benefit to allyship with humans. They like playing fetch, are whizzes at navigating mazes, and can outsmart dogs and chimpanzees, according to their IQ tests.

Following the Baby Fae experiment, primates fell out of favor for xenotransplantation, and pigs became the new model organism for researchers to develop.

If you ask xenotransplantation experts today, theyll give a laundry list of reasons why pigs are better than baboons: they are more easily genetically manipulated, they can be raised in a sterile environment to reduce infections, and they can be grown to give organs of any size needed.

Its a nice packaged narrative, but Dr Brad Bolman, historian of science at the University of Chicago, argues that sheep, goats or some other animal could have been deemed suitable instead. At the outset, Bolman said, it wasnt obvious that pigs were the right replacement for non-human primates. But when pigs were chosen, the scientific ideals were constructed retroactively to make them seem like the clear choice all along.

Bolman says that pigs were chosen because it was socially and economically convenient. They produce large litters quickly, with piglets reaching adult human size in six months. Theres also an almost unlimited supply of them 700 million worldwide and as agricultural animals, they arent covered by the Animal Welfare Act.

We treat pigs in ways that we would never treat people, but we also recognize theyre so similar to us that theyre our models, said Dr Lisa Moses, a bioethicist and veterinarian at Harvard Medical School. You cant make sense of that because it doesnt make sense. Its one giant paradox. Pigs are close enough to give their lives for ours but not close enough that their plight gives us pause.

Maybe it should. If you subscribe to Kantian ethics, its wrong to use others as a means to an end, so it feels downright exploitative to genetically modify a pig and kill it for its heart. People for the Ethical Treatment of Animals (Peta) has thus decried pig-to-human transplants as unethical, dangerous, and a tremendous waste of resources, asserting that animals arent toolsheds to be raided but complex, intelligent beings. Kathy Guillermo, a senior vice-president at Peta, went even further to proclaim, pigs are people.

These ethical concerns arent new. In 1999, the Campaign for Responsible Transplantation protested in New York Citys famous Halloween Parade, with members dressed up as genetically engineered monsters. As millions of Americans watched the parade on TV, these snout-wearing attendants hoisted a 13ft-tall mad scientist puppet, sporting a dollar sign tie and clenching a pig-human hybrid.

But the xenotransplantation experts I spoke to often dismissed these ethical concerns by citing the structural fact of the global pork industry. The thinking goes that, if pigs are going to be eaten anyway, they might as well be used for science, a more valuable and noble pursuit.

If you think about eating in a slightly more capacious sense, Bolman said, eating is really about consumption and rendering animals destroyable. More than anything else, the edibility of pigs justifies their usage for xenotransplantation and research at large.

What science does is consume animals, even if they arent literally eaten, said Bolman. Science remains carnivorous.

Mr Ps new heart had arrived in the operating room a half-hour ago, and Guenthart was zigging and zagging a fine thread across the arc of two vessels to cinch them together.

Six oclock, seven oclock, eight oclock Guenthart stitched together one half of the artery before he grabbed another needle to run around counterclockwise. Once the two sutures had circled around and met at noon, he threw a right-handed knot, and then another. Then left-right-left-right-left-right, each opposing throw locking the last one into a square knot, Guentharts hands dancing with the fine thread.

During the entire operation, everyone in the operating room was chatting away, but now it was so silent you could hear the faint music that had been playing all along. This was the crucial moment where, with the donor heart actively dying, Guenthart was sewing as fast as he could to restore blood flow to the heart. Every second counted.

Clamp off, Guenthart finally announced. With the pressure released off the aorta, blood rushed into the coronary arteries and fed the heart.

Having graduated from medical school a decade ago, Guenhart joked that xenotransplant is the promise thats 10 years out and always will be. But he also sees Bennetts 60-day survival as an amazing milestone and xenotransplantation as the most promising solution for the organ shortage killing his patients.

After about 30 seconds, Mr Ps new heart started beating on its own, like a zombie rising from the dead. Guenthart hadnt connected any of the nerves and definitely nothing to his brain. The hearts internal pacemaker is the circus master of its own show.

Xenotransplantation requires selective humanization of a pig. If you transplant a pig heart into a human, just like that, it will get rejected. Specifically, itll turn an ugly black and be flooded with blood clots, according to Dr Richard Pierson, director of the Center for Transplantation Sciences at Massachusetts general hospital. (I spoke with Pierson as he was speeding down to the hospital for a human-to-human lung transplant, ambulance sirens hollering in the background.)

Because our immune police force is so good at its job, the Virginia-based biotech company Revivicor used the gene-editing technology Crispr to create a special line of pigs with 10 modifications. Four genes are knocked out, and six genes are added in.

So, what is the recipe for making a pig heart fit for humans?

1. Knock out three sugar genes that are only found in pigs. Most of us think if you have a pig with those three genes knocked out, thats probably better than just one. We dont know that for sure, Pierson said.

2. Knock out a growth hormone gene to prevent the pig heart from overgrowing its new home. Pierson said, Is growth at the graft going to be a problem? We dont know.

3. Add two complement inhibitor genes that prevent antibodies from destroying the pig heart and two anti-clotting genes that stop the patients blood from curdling inside the foreign organ.

4. Add two anti-inflammatory genes to prevent the pig heart from swelling up. One of these genes signals to the immune system that the pig heart is a friend (self), not food (nonself). That may or may not be necessary, said Pierson. It probably is helpful, but we havent proven that.

After all this cutting and pasting, the next challenge is to keep the pig clean. The last thing you want is to transplant a pig heart with viruses, bacteria and parasites that cause infections in humans.

Therefore, these pigs are raised in pathogen-free facilities. There are no windows. They dont go outside. The air is filtered and sterilized, said Dr Leo Buhler, editor-in-chief of the journal Xenotransplantation and professor of surgery at the University of Fribourg.

After the genetically engineered embryos are implanted, the surrogate sows have to undergo caesarian sections (a vaginal birth is more likely to cause an infection.) The piglets are then immediately taken to isolation boxes under infrared lights, allowed to suckle their mother only every two hours under scientist supervision.

After 24 hours, the sows are all removed from the facility, and the piglets are artificially fed with a motherless rearing system and formula. Any interaction with humans must happen with the highest level of personal protective equipment.

With this pig-in-a-bubble approach, you should get a line of pigs that has never had any contact with the outside world and whose exogenous, or external, viruses have all been eliminated. These pig hearts are safe to implant into humans then, right?

Not exactly. Bennetts heart still tested positive for pig endogenous retroviruses (PERV) viruses built into the porcine genome that can jump into human cells, at least in a Petri dish. Its an alarming example of zoonosis that could lead to a pandemic like Covid-19.

Whether or not those viruses can infect humans remains to be seen, but Pierson doesnt think it will be a major barrier to xenotransplantation. HIV drugs seem to be relatively effective against them, and Boston-based biotech company eGenesis has already made a 60-gene PERV-free pig.

So what does worry Pierson about xenotransplantation?

The unknown unknown, he said. You can run a battery of tests in search of viruses, but you might only find what youre looking for. And with a cocktail of immunosuppressants required to sedate our trigger-happy immune system, any infection that crosses the pig-human barrier could wreak devastating consequences.

Doesnt this all feel a bit premature, then? I ask Pierson.

Worry is not a reason not to do things. You need to take cautious steps forward. If the problem presents itself, you figure out a way to solve it. You dont just go home.

For months, Bennetts transplant had been shrouded in secrecy, but the details of the operation were finally unveiled in a mid-June report of the New England Journal of Medicine. One of the studys blockbuster findings was that Bennett was infected with a pig virus. The paper itself is neutral on the cause of death, but the cardiothoracic surgeon and study first-author Dr Bartley Griffith is slightly betting that a pig virus killed Bennett.

The pig virus hes referring to is not a PERV, however; its an external virus called porcine cytomegalovirus (pCMV).

pCMV is a member of the herpes family, and its human form is known for causing mononucleosis, the kissing disease. Dont let that fool you though. Cytomegalovirus causes inflammation and damage to the organ, Pierson told me. A lot of damage.

pCMV is also one of the viruses that Revivicor had supposedly eliminated from pigs through all their precautions; it has been a well-recognized threat to xenotransplantation for decades.

When it first showed up, we thought maybe it was just an error or something, Griffith said, discussing how a routine blood draw on the 20th day after surgery returned a tiny blip.

Possible pCMV infection was so unimaginable to Griffiths team that they werent even looking for this pig virus and discovered the infection only on accident. Griffith told me, The first thing we did is we went to the company and said, How can we possibly be seeing this?

One xenotransplantation expert who wished to remain anonymous for legal reasons thinks that Revivicor may have gotten a bit slack about their protocol. He says the evidence is clear that, with early weaning and all other precautions, pigs dont get pCMV.

Revivicor, of course, tested the donor pig several times with a nasal swab and PCR, getting negative results every single time. It looks like PCR is not sufficient to exclude silent pCMV that can reactivate in an immunosuppressed environment, Buhler wrote to me. He suggests that Revivicor made an honest mistake by not using a more specific test. (Revivicor did not respond to repeated queries sent by the Guardian.)

Regardless of why pCMV was missed, the results were gruesome on autopsy. After hitchhiking into Bennett, the virus seems to have exploded some capillaries and killed the heart.

But Griffith is continuing to march along, hoping to do another xenotransplant in the next few months, even if he isnt entirely sure yet why Bennett died. Whatever it was, hes confident that it can be overcome. A pCMV infection? Exclude it. Too much immunosuppression? Reduce it. The anti-pig antibodies they gave Bennett? Dont do that again.

Thats how you make progress, Griffith said. You admit where you made errors, and you try to limit them. But you move on.

In a world where we are humanizing pigs with Crispr and piggifying humans with xenotransplantation, what does it even mean for there to be a human-animal divide?

In some ways, the word divide is problematic. After all, theres no bright red line separating humans from other animals. Pigs and humans share 98% of genes, and that 2% is critically important. But its also just 2%.

Moses, the Harvard bioethicist, believes that the notion of a human-animal divide is an artificial construct. Theres been a concerted effort from the biomedical research community to enhance the perception of that divide, going back as far as Descartes and Francis Bacon, she said.

Built on a shaky foundation, the separation between animals and humans has been reified over millennia. Look no further than the impossibly low sticker prices of a pack of bacon that hides environmental externalities and inhumane conditions under a crisp cellophane wrap. Its easier to not think too hard about it.

But we cant not think hard about xenotransplantation. If its promise is to be realized, well have to, at the very least, create a whole new economy of factory farming, where pigs will be manufactured and slaughtered en masse to give us life.

Sure, 1.5 billion pigs are already killed each year. And sure, if the people you loved most had heart failure, lungs slowly drowning in fluid, their dilated heart twisting agonizingly, youd probably take the pig heart instead of gambling with the transplant list. I would, at least. But that shouldnt obviate the need to tread carefully here.

Dr Chris Walzer, executive director of the Wildlife Conservation Society, thinks xenotransplantation could benefit from the OneHealth framework the idea that human, animal and environmental health are all connected.

Take the Nipah virus as an example. Nipah is a zoonotic disease that has caused deadly outbreaks in Malaysia, Singapore, Bangladesh and India. For years, these outbreaks were a mystery to epidemiologists, who couldnt understand how the transmission chain worked between fruit bats the natural hosts of the virus and humans. And ultimately, it took a broadened perspective to solve this puzzle tracing how date palm trees bloomed in the winter, how fruit bats infused tree sap with saliva and urine, and how humans consumed that infected sap and got Nipah.

Its too simple to say pigs are people. And its too simple to say pigs are an unlimited supply of organs. Seventeen people die every day waiting on the transplant list, but xenotransplantation is about a whole lot more than just saving these lives.

Were all part of a shared ecology. And theres a danger to ignoring our interconnectedness.

Earlier that day, Guenthart had told Mr P that he was getting a new heart. Mr P started crying. Hes in his early 20s, and three months ago, his heart started failing without any apparent reason. His doctors still arent sure why.

It was hard for me to not also start crying, Guenthart said.

A heart transplant is a highly technical operation, but for the patient, its a chance at life. When David Bennett had his xenotransplant, he didnt just get a pig heart; he got two more months of life. He watched the Los Angeles Rams win the Super Bowl. He sang America the Beautiful with his therapist. He spent time with his five grandchildren, every day begging his surgeons to let him go home to his dog Lucky.

Now that the transplant was over, Guenthart was calling Mr Ps mom.

The surgery went really well. The new heart looks beautiful, and hes doing amazing. Hes asleep right now, and were sending him over to sleep in the ICU.

Yes, hes going to be two floors above where he was before.

Normal visiting hours are from 8am to 7pm, but you can call them at any time and get updates directly from his nurse.

Of course, youre so welcome, and I hope to see you tomorrow.

Original post:
Pig to human heart transplants are the future. Are we ready for it? - The Guardian

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 ...