Propolis is a resinous material collected by bees from plant buds and exudates, mixed with bee enzymes, pollen and wax. The term propolis derives from two Greek words, pro (which means for or in defense of) and polis (which means the city), reflecting its application by bees to help protect the hive. The chemical composition of propolis is directly determined by the geographical location, but polyphenols, phenolic acids, caffeic acid phenethyl ester (CAPE), flavonoids, diterpenes, amino acids, vitamins and minerals are predominant constituents.

“Poplar-type” propolis has the widest spread in the world, in the temperate zones from Europe, Asia, or North America. Different species of Pine (Pinus spp.), Prunus spp., Acacia spp. and also birch (Betula pendula), horsechestnut (Aesculus hippocastanum), and willow (Salix spp) are also important sources of resins for poplar-type propolis⁽¹⁾. New Zealand propolis is usually of the poplar-type, obtained by honey bees largely from exudates of poplar.

Propolis is reported to possess a huge array of biological properties, with more than 270 review papers alone published in the scientific literature. Key actions include antimicrobial, anti-inflammatory, antioxidant, anti-cancer, anti-diabetic as well as cardioprotective and neuroprotective activities. Other potentially useful properties continue to be reported by researchers, on a regular basis.

Antiviral:

Immune modulatory effects have been assigned to propolis for many centuries, with effects on both the cellular and humoral immune responses, including increased antibody production^{(2, 3)}.

In the early 1990s, propolis flavonoids were shown to reduce of the infectivity and replication of some herpes virus, adenovirus, rotavirus, and coronavirus strains⁽⁴⁾. Potent activity against the herpes simplex type 1 virus has been reported particularly for an ethanolic propolis extract⁽⁵⁾. Antiviral activity and a dose-dependent reduction in influenza virus yields in the bronchoalveolar lavage fluids of lungs, and prolonged survival times of influenza infected mice, has been reported following administration of 2 and 10mg/kg doses of propolis three times daily⁽⁶⁾. Improved platelet counts and a shortened duration of hospitalization in patients with the Dengue Fever virus, was seen following seven days propolis administration⁽⁷⁾.  Enhanced immune responses including lymphocyte proliferation and antibody production after administration of a recombinant HIV-1 vaccine to mice, were recently reported when propolis was used as an adjuvant⁽⁸⁾. These and its anti-inflammatory properties, suggest the possibility of using it as an adjuvant to other vaccines⁽³⁾.

When I reviewed potential phytomedicinal treatment options for COVID-19 early last year, propolis was one of the most compelling agents I evaluated, based upon the published literature at the time. Since then and with research into plant-derived treatments having received increased funding, this view is now further supported by in vitro and clinical studies^(9-16).

Brazilian researchers have just published the results of a controlled clinical trial in which propolis was given as an adjunct treatment in hospitalized COVID-19 patients⁽¹³⁾. Three groups of 40 patients were assigned to receive standard hospital care plus an oral dose of 400 mg or 800 mg/day of Brazilian green propolis for seven days, or standard care alone. The primary end point was the time to clinical improvement, defined as the length of hospital stay or oxygen therapy dependency duration. Secondary outcomes included acute kidney injury and need for intensive care or vasoactive drugs.

The length of hospital stay post-intervention was statistically shorter in both propolis groups than in the control group (lower dose, median 7 days versus 12 days; (95% confidence interval [CI] −6.23 to −0.07; p = 0.049) and higher dose, median 6 days versus 12 days (95% CI −7.00 to −1.09; p = 0.009). A lower rate of acute kidney injury than in the controls (4.8 vs 23.8%) was also reported in the high dose propolis group. No patient discontinued propolis treatment due to adverse events.

While further studies are called for, this study suggests the addition of propolis to standard hospital care procedures could have significant clinical benefits in some COVID-19 patients⁽¹³⁾.

Other encouraging reports of late include in vitro inhibition of COVID-19 viral replication by Eqyptian propolis (an activity enhanced by liposomal encapsulation)⁽⁹⁾, and inhibition of COVID-19 protease as well as angiotensin-converting enzyme-2 (a receptor for SARS-CoV-2 in the human body), by compounds derived from Indonesian propolis^{(14, 15)}. Molecular simulations also suggest that propolis flavonoids may inhibit viral spike fusion in host cells, and viral-host interactions that trigger the cytokine storm⁽¹⁶⁾.

Anti-inflammatory

Hundreds of papers report immunomodulatory and anti-inflammatory activities for different types of propolis, including inhibition of COX-2 and nitric oxide synthesis, reduced levels of inflammatory cytokines, and antioxidant activities⁽¹⁷⁾. A review of six clinical studies involving 406 participants, found a significant reduction in levels of inflammatory markers including serum CRP and TNF-alpha, following propolis intake⁽¹⁸⁾.

In pre-clinical studies, propolis promoted immunoregulation of pro-inflammatory cytokines and exhibited several potential mechanisms to help to reduce the risk of a cytokine storm⁽¹⁰⁾.

As effective anti-inflammatory concentrations of propolis seem significantly lower than antibacterial and antiviral ones, these studies suggest anti-inflammatory properties may be its most important feature^{(3, 19)}.

Use as an adjuvant treatment in autoimmune conditions such as asthma has received some clinical trial support ^{(20, 21)}.

Antibacterial:

The first data published regarding the antibacterial activity of propolis extract dates back to 1980, in which sensitivity of Streptococcus species to propolis extract was reported⁽²²⁾. Since then propolis has been tested on more than 600 strains of bacteria, with encouraging findings⁽²³⁾. Greater activity has been measured against Gram-positive than Gram-negative bacteria, with antimicrobial activity varying depending on the region of the world from which the propolis was sourced.

Many novel antimicrobial compounds have been identified in propolis, several of which can help overcome antimicrobial resistance of multidrug resistant bacteria. Synergistic effect against bacterial strains such as Escherichia coli and Staphylococcus aureus have been reported for combinations with honey or other antibiotics⁽²⁴⁾.

A clinical trial involving the simultaneous admin of propolis and melatonin in patients with primary sepsis, is currently underway⁽²⁵⁾.

Dental applications–

The anti-inflammatory, antibacterial and antifungal properties of propolis also have many potential applications in dentistry, as alternatives to current antimicrobial and conventional agents^(26-29).  Indications that have been supported by studies including clinical trials, include to heal dental surgical wounds, as an intracanal irrigant, a mouthwash or toothpaste, and for the treatment of periodontitis and gum inflammation, and denture stomatitis⁽²⁹⁾.

Wound healing:

One of the oldest traditional applications of propolis is its application to disinfect skin and to improve wound healing. Its widespread antimicrobial activities in addition to inhibitory effects on biofilm formation, and anti-inflammatory actions, are undoubtedly largely contributory.  Enhancement in the wound repair abilities of keratinocytes, has also been reported recently⁽³⁰⁾.

Most in vivo studies undertaken on different wound models suggest beneficial roles of propolis on experimental wound healing^(31,32), although products and doses used have been variable.

A review of 5 clinical trials involving the use of propolis mouthwash in cancer therapy-induced oral mucositis, found it to be both effective and safe⁽³³⁾. Post-tonsillectomy pain and wound healing was also significantly improved following use of propolis orally and by gargle, in a Korean clinical trial involving 130 tonsillectomy and adenotonsillectomy patients⁽³⁴⁾.

A shorter healing time and improved symptom picture was reported for a 0.5% propolis cream compared to acyclovir 5% cream, in a Slovakian trial involving 198 patients with herpes labialis⁽³⁵⁾.

Mixing different propolis samples collected from different locations in Iraq resulted in superior antimicrobial and wound healing properties than measured in individual propolis⁽³⁶⁾.

Cancer-protective?

Most diterpenes isolated from propolis possess cytotoxic activities (37 Aminimoghadamfarouj, Nematolahi 2017), and a plethora of in vitro studies have documented cytotoxic effects of many different propolis extracts against various types of cancer. These include head and neck, lung, liver, brain (glioma), pancreas, kidney, prostate, skin (melanoma), breast, oral, esophagus, gastric, colorectal, and bladder cancers^(37-42).

Propolis is likely to exhibit chemoprotective or anti-cancer effects due to the presence of phytochemicals with pro-apoptotic, cytotoxic, anti-proliferative, anti-metastatic, anti-invasive, anti-angiogenic and anti-genotoxic or anti-mutagenic properties along with antioxidant, immunomodulatory, and anti-inflammatory functions.

A recent review into evidence-based complementary medicines to support chemotherapy treatment of pancreatic cancer patients, concluded that integrated management offers the best patient outcome, and that propolis was one of 9 most promising natural treatment agents identified⁽⁴³⁾. Clinical studies are justified, into the use of propolis as an adjuvant alongside standard chemotherapy treatment for the treatment of various cancers⁽⁴²⁾.

Cardiac health:

A recent review documents numerous potentially useful pharmacological properties of propolis in terms of cardiac health⁽⁴⁴⁾. These include anti platelet aggregation, antioxidant and anti-inflammatory activities, which may protect against vascular endothelial and cardiomyocyte dysfunction, and potentially thrombus formation.  Further in vivo studies are however needed to confirm these beneficial effects in the prevention of cardiovascular diseases, and pre-clinical research to assess cardiovascular effects of the different types of propolis, would be useful^{(17, 45)}.

Diabetes:

Various animal studies have found improvement in insulin resistance and increased sensitivity to insulin following propolis administration⁽⁴⁶⁾. Improvement in glycaemic status and antioxidant enzymes, and reduction in insulin resistance, have been reported following propolis treatment at 1500mg a day for 8 weeks, in type 2 diabetic patients⁽⁴⁷⁾.

A recent trial involving 12 months treatment of chronic kidney disease patients with Brazilian green propolis extract at a dose of 500mg/day, reported a significant reduction in proteinuria⁽⁴⁸⁾. Another found topical propolis improved healing when used as an adjuvant treatment in the care of diabetic foot wounds⁽⁴⁹⁾.

Anti-inflammatory properties of propolis, are likely to contribute to its favourable effects in some diabetic patients, as inflammatory cytokine production in diabetic patients is increased

Other properties

While propolis can be used in these and other conditions, caution should be taken due to some allergic reactions in some patients.

Evidence is also becoming apparent of potentially protective effects against drug-induced nephrotoxicity and various neurological and psychiatric conditions, for both propolis and caffeic acid phenethyl ester^{(50, 51).}

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