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Propolis for Metabolic Health: Polyphenols Target Inflammation, Oxidative Stress, and Insulin Resistance

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Introduction

Propolis, a natural resinous substance produced by honey bees from plant exudates, has garnered increasing scientific attention for its multifaceted therapeutic properties. Traditionally celebrated for its antimicrobial and anti-inflammatory effects, propolis harbours a complex array of bioactive compounds- including flavonoid, phenolic acids, and terpenoids-that contribute to its diverse pharmacological potential. Recent research has begun to illuminate the promising role of propolis as therapeutic agent in management of metabolic syndrome-a cluster of conditions characterized by abdominal obesity, hypertension, dyslipidaemia, and insulin resistance that dramatically increase the risk of chronic diseases such as type 2 diabetes and cardiovascular disorders.

As the global prevalence of metabolic syndrome and its associated chronic diseases continues to rise, prompted by shifting lifestyles and dietary habits, there is an urgent need for innovative and accessible interventions. Propolis, with its antioxidant, anti-inflammatory, and hypolipidemic activities, presents a compelling natural candidate for adjunct therapy and disease prevention in metabolic syndrome. This emerging evidence position propolis at the intersection of traditional medicine and modern health tech innovation, inviting a closer examination of its mechanisms of action and clinical applications in combating the burden of metabolic and chronic diseases.

Propolis: Composition and Therapeutic Potential

Composition

Propolis is a complex, resinous substance collected by honey bees from plant buds and exudates, mixed with bee enzymes and beeswax. Its composition is notably diverse, typically comprising:

  • Resin (50-70%)
  • Waxes (30-50%)
  • Pollen (5-10%)
  • Other Components: amino acids, vitamins (B,C,E)minerals (calcium, magnesium, zinc), sugars, and a wide array of bioactive compounds such as flavonoids, phenolic acids, terpenoids, and aromatic compounds [1-5].

The chemical profile of propolis varies based on geographic region, botanical sources, and bee species. However, flavonoids (e.g., galangin, chrysin, apigenin, pinocembrin, quercetin), and phenolic acids (e.g., caffeic, ferulic, cinnamic acids) are consistently recognized as tis most significant bioactive groups [2,4,6]. Other notable constituents include terpenoids, steroids, hydrocarbons, amino acids, and sugars [2-4,7]. Over 300 different chemical constituents have been identified, each contributing to the biological properties of propolis [1,4].

Therapeutic Potential of Propolis

Propolis exhibits a broad spectrum of therapeutic activities, which have been extensively studied and supported by modern research:

  • Antioxidant Activity: The rich polyphenol content, especially flavonoids and phenolic acids, confers strong antioxidant capacity, helping to neutralize free radicals and reduce oxidative stress- a key factor in the pathogenesis of metabolic syndrome and associated chronic diseases [2,6,8].
  • Anti-inflammatory Effects: Propolis and its constituents modulate pro-inflammatory cytokines and inhibit inflammatory pathways, providing potent anti-inflammatory benefits. This is particularly relevant to chronic conditions where inflammation plays a fundamental role, such as a cardiovascular disease and diabetes [9-11].
  • Antimicrobial Properties: It demonstrates substantial antibacterial, antiviral, and antifungal activities, attributed primarily to its flavonoids, aromatic acids, and terpenoids, making it a natural defense agent against infections [4,8,9].
  • Metabolic Benefits: Emerging evidence supports propolis as a beneficial agent in metabolic syndrome by improving lipid profiles, reducing blood glucose levels, and enhancing insulin sensitivity, attributed to its anti-inflammatory and antioxidant effects [11].
  • Additional Activities: Propolis also has immunomodulatory, wound-healing, and anticancer actions, with some compounds (e.g., caffeic acid phenethyl ester) showing promise in inhibiting tumor growth and protecting cells against chemotherapy-induced damage [8,12].

Taken together, the unique composition of propolis, particularly its abundance of polyphenols and flavonoids, underpins its wide-ranging pharmacological effects. These properties make propolis a promising natural agent for adjunct management in metabolic syndrome and chronic diseases related to inflammation and oxidative stress [2,9,11].

Mechanism of Action

Propolis exerts its therapeutic effects on metabolic diseases through several well-established molecular and cellular mechanisms, especially impacting inflammation, oxidative stress, and glucose metabolism

  1. Modulation of Inflammatory Pathways
    • Inhibition of Pro-inflammatory Cytokines: Propolis reduces levels of key inflammatory markers such as C-reactive protein (CRP), tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), monocyte chemoattractant protein-1(MCP-1). These reductions mitigate the chronic low-grade inflammation characteristic of metabolic syndrome and related chronic diseases [9,13].
    • Suppression of NF-kB and Other Pathways: Caffeic acid phenethyl ester (CAPE), a major bioactive in propolis, inhibits the activation of nuclear factor-kappa B(NF-kB), a transcription factor responsible for inducing inflammatory responses. CAPE also interferes with other signalling cascades, such as Jun N-terminal kinase (JNK) and the NLRP3 inflammasome, reducing the production of inflammatory cytokines and enzymes like inducible nitric oxide synthase (iNOS) [9,13,14].
    • Downregulation of AGE/RAGE Interactions: Advanced glycation end products (AGEs) and their receptor (RAGE) contribute to metabolic dysfunction through the generation of reactive oxygen species (ROS) and inflammatory signalling, Flavonoids in propolis disrupt these interactions, further curbing inflammation and cellular damage [15].
  2. Antioxidant Activity
    • Scavenging Reactive Oxygen Species (ROS): Polyphenols and flavonoids from propolis directly neutralize ROS, reducing oxidative damage to cellular components such as DNA, lipids and proteins-an essential effect because oxidative stress is a root cause of insulin resistance and chronic disease progression [14,16,.
    • Upregulation of Endogenous Antioxidant Defenses: Propolis increases the expression and activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase, as well as the levels of glutathione (GSH). This effect is mediated, in part, by the activation of the Nrf2 signalling pathway, which governs antioxidant gene expression [9,13].
  3. Improvement of Insulin Sensitivity and Glucose Homeostasis:
    • Enhancement of Insulin Signalling: Propolis has been shown to increase membrane translocation of GLUT4 (glucose transporter)l, improve insulin receptor phosphorylation, and enhance insulin sensitivity in peripheral tissues, resulting in better glucose uptake and disposal [14,15].
    • Suppression of Hepatic Gluconeogenesis: Artepilin C, a compound in Brazilian green propolis, inhibits the CREB/CRTC2 transcriptional complex in the liver, reducing the expression of gluconeogenic genes. This lowering of hepatic glucose output leads to improved glycaemic control [15].
    • Improvement of Pancreatic b-cell Function: Propolis protects and may even regenerate pancreatic b-cells, stabilizing and enhancing insulin secretion. It also reduces insulin resistance as measured in both animal and human studies, with reported improvements in HOMA-IR and Matsuda indices [14].
  4. Modulation of Lipid Metabolism and Adipogenesis
    • Lipid-Lowering Effects: Propolis lowers serum triglycerides and LDL cholesterol and increases HDL cholesterol. It also reduces liver fat accumulation by downregulating genes such as SREBP-1c and upregulating PPAR-a, favourably influencing lipid metabolism and reducing non-alcoholic fatty liver disease (NAFLD) risk.
    • Adipose Tissue Effects: By inhibiting pro-inflammatory signalling in adipocytes and enhancing adiponectin secretion, propolis improves adipose tissue function and overall metabolic health [9,13].
  5. Additional Actions
    • Gut Microbiota Modulation: Evidence indicates propolis exerts beneficial effects on gut microbial composition which can further support metabolic health.
    • Glucose Absorption Modulation: Propolis inhibits intestinal a-glucosidase, thus slowing carbohydrate digestion and reducing postprandial blood glucose spikes.

In summary, propolis counteracts the pathogenesis of metabolic diseases via anti-inflammatory, antioxidant, and metabolic regulatory actions, with major bioactive compounds like CAPE, artepilin C, chrysin, and various flavonoids working in concert, This natural product represents a versatile adjunct for preventing and managing metabolic syndrome and its complications [9,13,15].

Figure 1. Mechanism of Action of Propolis in Metabolic syndrome

Propolis in Cardiovascular Diseases

Anti-atherosclerotic Action

Propolis modulates lipid metabolism by reducing low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL) cholesterol, thereby supressing atherosclerotic plaque formation. It inhibits macrophage apoptosis, vascular smooth muscle proliferation and metalloproteinase activity, all critical to plaque stability and the prevention of arterial narrowing. Polyphenols and flavonoids in propolis also attenuate inflammation in arterial walls by downregulating genes involved in cytokine and adhesion molecule production [19,20,21].

Antihypertensive Effects:

Propolis lowers blood pressure by several mechanisms:

  1. Increasing Nitric Oxide (NO) Bioavailability: Propolis enhances endothelial NO synthase (eNOS) expression, resulting in vasodilation and improved vascular relaxation Phenolics and amino acids present contribute this effect [21-23].
  2. Antioxidant Action: Flavonoids and other phenolic compounds effectively scavenge reactive oxygen species (ROS), protecting blood vessels from oxidative stress and restoring endothelial function. This relieves hypertension and reduces endothelial dysfunction [20,21,23].
  3. Anti-inflammatory Activity: Propolis reduces pro-inflammatory cytokines (for example IL-6, TNF-a) and inhibits NF-kB signalling, lowering systemic and vascular inflammation, which contributes to blood pressure normalization [21,22].
  4. Modulation of Lipid and Renal Pathways: Propolis improves lipid profiles and, in some cases, exerts mild diuretic effects, further reducing blood pressure [22,23].

Clinical and animal studies have shown significant reduction in systolic blood pressure with propolis supplementation, though effects on diastolic pressure can be more variable [24].

Antioxidant and Endothelial Protection:

By neutralizing ROS and increasing endogenous antioxidant enzymes (such as SOD and catalase), propolis defends endothelial cells, and cardiomyocytes against oxidative injury, a key mechanism in cardiovascular diseases [16,20,25]. Specific compounds like caffeic acid phenethyl ester (CAPE) also stimulate the Nrf2 pathway, leading to upregulation of antioxidant genes and suppression of vascular inflammation [22].

Anti-platelet and Anti-hemostatic Activity:

Propolis inhibit platelet aggregation, which helps prevent thrombus formation and acute atherothrombotic events like myocardial infarction. CAPE and other components reduce collagen-stimulated platelet activation, enhancing vascular safety [19,20].

Cardioprotective and Anti-remodelling Actions:

Propolis guards against myocardial injury, reduces left ventricular hypertrophy, and limits fibrosis. Its compounds were found to prevent left ventricular hypertrophy and improve heart tissue microstructure in animal models, often equalling standard antihypertensive therapy in efficacy [23,26].

MechanismKey Pathways/TargetsOutcomes for Cardiovascular Disease
Antioxidant­eNOS, Nrf2, SOD, CAT¯ Oxidative stress, improved endothelial function
Anti-inflammatory¯NF-kB, IL-6, TNF-a¯ Inflammation in vessels, lower CVD risk
Lipid Modulation­HDL, ¯ LDL, ­ ABCA1¯ Atherosclerosis, improved lipid profile
Vasodilatory­NO, ¯ endothelin-1¯ Blood pressure, improved perfusion
Anti-platelet¯ Platelet aggregation¯ Thrombosis, atherothrombotic events
Anti-remodeling¯ LVH, ¯ fibrosisCardio-protection, better cardiac function
Table 1. Mechanistic Summary Table

Clinical Evidence

Meta-analyses and clinical trials report that propolis intake significantly improves triglyceride, LDL, HDL, and systolic blood pressure values, with benefits extending to fasting glucose and insulin resistance parameters-an important overlap with metabolic syndrome and cardiovascular disease [24,27]. Effects are most pronounced with propolis rich in polyphenols and flavonoids, with Brazilian and Chinese Varieties often showing particular efficacy [19-21].

Figure 2. Propolis Mechanism of Action in Cardiovascular System

In summary, propolis supports cardiovascular health primarily through antioxidant protection, inflammation reduction, improvement of lipid profiles, enhancement of vasodilation, inhibition of platelet aggregation. These multidimensional effects make propolis a promising adjunct for cardiovascular risk management and disease prevention.

Antihypertensive Effects of Propolis

Propolis demonstrates significant antihypertensive effects, which have been validated in both preclinical and clinical research. Its blood pressure-lowering actions are mediated through several key mechanisms:

  1. Vasodilatation and Nitric Oxide (NO) Enhancement Propolis stimulates endothelial-dependent vasodilation mainly by increasing nitric oxide (NO) bioavailability. Flavonoids and amino acids present in propolis upregulate endothelial NO synthase (eNOS) expression and activity, leading to improved vascular relaxation and reduced vascular resistance. This vasodilatory effect is a primary driver of blood pressure reduction observed in animal models and human studies [19,28,29,30].
  2. Antioxidant and Anti-inflammatory Actions Propolis exerts strong antioxidant effects by scavenging reactive oxygen species (ROS) and upregulating endogenous antioxidant enzymes (such as catalase, SOD, and glutathione peroxidase). This action protects the vascular endothelium and reduces oxidative stress- a fundamental cause of hypertension [19,30]. Additionally, propolis suppresses pro-inflammatory cytokines (e.g.TNF-a, IL-6), and inhibits NF-kB signalling, reducing vascular inflammation and promoting healthier vessel function [19,30].
  3. Inhibition of Catecholamine Synthesis Research indicates that propolis may inhibit the synthesis of catecholamines by downregulating tyrosine hydroxylase activity. Lower catecholamine levels result in decreased vasoconstriction and reduced blood pressure [19,28].
  4. Lipid Modulating and mild Diuretic Effects Propolis favourably modulates lipid metabolism by reducing LDL and increasing HDL cholesterol, which indirectly benefits blood pressure control by improving overall vascular health. Some studies have reported mild diuretic effects that appear to help reduce blood volume and contribute to antihypertensive activity [7,30].
  5. Bioactive Compounds Responsible The antihypertensive effects of propolis are largely attributed to its flavonoid content-such as isosakuranetin, dihydrokaempferide, kaempferide, betuletol, and chrysin- alongside phenolic acids and CAPE (caffeic acid phenethyl ester). These constituents are involved in vasodilation, antioxidant protection, and inflammation reduction [19,29,30].

Preclinical and Clinical Evidence

  • Animal Studies: Numerous experiments demonstrate that propolis administration significantly lowers both systolic and diastolic blood pressure in hypertensive animal models, with efficacy comparable to captopril in some studies [7,30].
  • Human Trial: Randomized controlled trials and meta-analyses report that propolis supplementation causes a modest but significant reduction in systolic blood pressure, although effects on diastolic pressure are sometimes less pronounced or not statistically significant [24,27,31].
  • Meta-analyses: Systematic reviews confirm a reduction in systolic blood pressure (by approximately 2-5 mmHg) in adults supplemented with propolis[24,27,31].
MechanismEvidence
↑Nitric oxide, vasodilationAnimal and human studies
↓Oxidative stress, inflammationClinical/ preclinical research
↓Catecholamine synthesisMechanistic animal studies
↓LDL/ ↑HDL, improved lipid profileHuman and animal studies
↑Antioxidant enzyme activityMolecular/ biochemical research
Table 2. Summary Table

In summary, propolis acts through multiple synergistic pathways-most notably by promoting vasodilation, quelling inflammation and oxidative stress, and supporting vascular health- to produce clinically meaningful antihypertensive effects in both animals models and humans [19,24,27,28-31].

Propolis in Type 2 Diabetes Mellitus

Propolis has demonstrated multiple beneficial effects in the management of type 2 diabetes mellitus (T2DM), as supported by both clinical and preclinical studies.

  • Glycaemic Control
    • Reduction in Fasting Blood Glucose (FBG) and HbA1C: Several randomized controlled trials and meta-analyses have shown that propolis supplementation significantly decreases FBG and HbA1C in patients with T2DM. For example, clinical studies found that propolis lowered FBG and HbA1C levels compared to placebo, indicating improved long-term glycaemic control [32-35].
    • Improvement in Insulin Sensitivity: Some research has reported reduction in insulin resistance indices, such as HOMA-IR, and increases in Matsuda index, suggesting enhanced insulin sensitivity. However, results about serum insulin levels are mixed, with some studies reporting improvement and others showing no significant change [32,33,36,37].
  • Mechanism of Action Propolis exerts its anti-diabetic action through several overlapping mechanisms:
    • Reduction of Glucose Absorption and a-glucosidase Inhibition: Propolis inhibits intestinal and a-glucosidase and sucrase enzymes, reducing carbohydrate digestion and glucose absorption, thus lowering postprandial glucose spikes [32].
    • Stimulation of Insulin Secretion: It has demonstrated the ability to stimulate pancreatic b-cells, increasing insulin secretion and facilitating glucose utilization by body cells [32,37].
    • Enhancement of Insulin Sensitivity: Flavonoids and other components in propolis can improve insulin receptor signalling and enhance sensitivity in peripheral tissues [36,37,38].
    • Anti-inflammatory and Antioxidant Actions: Propolis reduces oxidative stress and inflammation, major contributors to diabetic complications. It lowers malondialdehyde (MDA) levels, a marker of oxidative stress, and suppresses pro-inflammatory cytokine production (e.g., TNF-a, IL-6). This helps preserve pancreatic function and protect against diabetic organ damage [37,39,40].
    • Improved Lipid Profile: Propolis has been shown in some trials to reduce triglycerides and LDL cholesterol and increase HDL cholesterol, further supporting metabolic health in diabetics [36,41].
    • Protection of Renal and Hepatic Functional: Some studies observed that propolis helps maintain renal function (e.g., stable eGFR and uric acid) and may prevent the progression of diabetic nephropathy [34,42].
  • Clinical Evidence Highlights
    • In a placebo-controlled trial using 300 mg propolis twice daily for 12 weeks, T2DM patients displayed significant reductions in FPG, 2-hour post-load glucose, and HbA1C. The effect was comparable to metformin in some parameters [33,43].
    • Supplementing with 1,000 mg/day of Iranian propolis for 90 days led to reduced postprandial blood glucose, serum insulin, and insulin resistance, together with improved inflammatory markers and HDL cholesterol [34].
    • Propolis intake in animal models significantly lowered fasting blood glucose, improved antioxidant status, and reduced oxidative stress markers [44].
EffectEvidence/Outcome
↓FBG, ↓HbA1CHuman RCTs and meta-analyses [32,33,34,35]
↓nsulin sensitivity insulin resistanceMatsuda, HOMA-IR improvement [32,36,37]
↓Postprandial glucosea-glucosidase inhibition[32,33,37]
Anti-inflammatory & antioxidant↓TNF-a, IL-6, MDA, improved renal markers [37, 39,42]
Improved lipid profile↓TG, ↓LDL, ↓HDL [34,36,41]
Table 3. Summary Table

In summary, propolis provides promising adjunctive benefits in T2DM by improving glycaemic control, enhancing insulin sensitivity, reducing oxidative stress, and supporting lipid and organ health. These effects are attributed to its diverse flavonoids, phenolic acids, and other bioactive compounds, offering a multifactorial approach to diabetes management [32-34,37].

Figure 3. Propolis Effects in Insulin Mechanism

Propolis in Chronic Kidney Disease

Propolis has shown promising therapeutic potential in management of chronic kidney disease (CKD), largely due to its antioxidant, anti-inflammatory, and immunomodulatory properties. Both preclinical and clinical studies provide evidence for its beneficial effects:

Mechanism and Effects of Propolis in CKD

  1. Anti-inflammatory and Antioxidant Actions
    • Propolis contains flavonoids and polyphenols that significantly reduce oxidative stress and inflammation in kidney tissues. In animal models of CKD, propolis treatment decreases oxidative damage, lowers malondialdehyde (MDA), and enhances the activity of endogenous antioxidants like glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) [45,46].
    • Chronic inflammation in CKD involves upregulation of nuclear factor kappa B (NF-kB) and increased production of pro-inflammatory cytokines (e,g.,TNF-a, IL-6, MCP-1). propolis has been shown to suppress NF-kB activation and reduce the levels of these cytokines, thus attenuating the inflammatory cascade and slowing kidney damage, progression [45,47].
  2. Reduction of Proteinuria and Renal Injury
    • Several studies describe a reduction in proteinuria and preservation of renal function following propolis supplementation, especially in models of diabetic nephropathy or hypertensive nephropathy, This is linked to decreased inflammatory cell infiltration, improved lipid profile, and stabilization of glomerular structure [45,47].
    • In a study with Brazilian green propolis on CKD patients, supplementation over 12 months led to a progressive decrease in urinary monocyte chemoattractant protein-1 (MCP-1), a marker correlated with inflammation and proteinuria, suggesting a kidney protective role [46].
  3. Cellular Protection and Improvement of Renal Structure
    • Propolis mitigates apoptosis of renal cells by modulating apoptotic pathways, protecting podocytes (crucial glomerular cells), and preserving the integrity of the basement membrane, which is crucial for kidney filtration [45].
    • Animal studies also show prevention of fibrosis and reduction of glomerular and intestinal inflammation after propolis administration [45].
  4. Clinical Evidence
    • Clinical trials in CKD patients (non-dialysis and dialysis) report that propolis supplementation is generally safe, well-tolerated, and can improve specific quality of life measures. Although robust improvements in kidney function markers (such as GFR or creatinine) are not always observed in short trials, meaningful reductions in inflammatory markers and improvements in health-related quality of life have been documented [46,48].
    • Propolis supplementation may reduce plasma TNF-a and improve Nfr2 expression in patients on peritoneal dialysis, indicating potential to lower systemic inflammation and oxidative burden in CKD [48].
MechanismEffects in CKD
↓NF-kB, cytokines (TNF-a, IL-6, MCP-1)Reduced inflammation, slower progression of renal damage
↑Antioxidant enzymes, ↓MDAProtection against oxidative injury, improved renal cell health
↓Proteinuria, preserved glomerular structureAttenuation of protein leakage and kidney tissue deterioration
Protection of podocytes, ↓ fibrosisMaintained filtration barriers, limited scarring/fibrosis
Improved HRQoL in clinical trialsBetter symptoms, general and overall health
Table 4. Summary Table

Propolis exerts renoprotective effects in chronic kidney disease primarily through modulation of oxidative stress, suppression of pro-inflammatory pathways, reduction of proteinuria and protection of renal cells and tissue architecture. Its favourable safety profile and additional benefits-such as improvement in quality of life and systemic inflammation- support its role as an adjunctive natural therapy in CKD management [45,46,47,48]

Propolis in Non-Alcoholic Fatty Liver Disease

Propolis shows significant promise as a supportive therapy in non-alcoholic fatty liver disease (NAFLD), with effects confirmed in both animal and human studies. These are the key effects of propolis in NAFLD:

  • Reduction in Hepatic Steatosis and Fibrosis: Multiple randomized controlled trials have demonstrated that propolis supplementation can improve liver fat content (steatosis) and reduce the degree of liver fibrosis in patients with NAFLD. For example, one clinical study found that taking 250 mg of propolis twice daily for four months led to a significantly greater improvement in hepatic steatosis (measured by elastography) compared to placebo, and notable reduction in liver stiffness (a marker of fibrosis) [49].
  • Anti-inflammatory Properties: Propolis effectively reduces serum levels of pro-inflammatory markers, such as high-sensitivity C-reactive protein (hs-CRP), TNF-a, and toll-like receptor-4 (TLR-4), which are associated with liver inflammation and disease progression in NAFLD. This anti-inflammatory effect is critical in preventing the transition from simple steatosis to steatohepatitis and fibrosis [49,50].
  • Antioxidant Activity: Propolis significantly enhances antioxidant capacity, demonstrated by increased activity of enzymes like glutathione peroxidase (GPX) and reductions in markers of lipid peroxidation (such as malondialdehyde, MDA). This helps mitigate oxidative stress, a key driver of hepatocyte injury and disease progression in NAFLD [50,51,52].
  • Improvement of Glucose and Lipid Metabolism: Studies have shown improvement in glucose homeostasis, hepatic fibrosis score, and liver enzyme levels (such as ALT and AST) among patients receiving propolis. HOMA-IR and NAFLD fibrosis scores also decreased, while markers of insulin sensitivity (QUICKI) increased, reflecting a potential benefit in metabolic regulation [50].
  • Inhibition of ER Stress and Fibrotic Pathways: Animal and cell studies highlight that propolis-particularly Brazilian propolis-suppresses the expression of genes involved in endoplasmic reticulum (ER stress), which is tightly linked to liver fat deposition inflammation, and fibrosis. Components like kaempferol, found in propolis, protect hepatocytes by inhibiting ER stress and activating protective signalling pathways (e.g., MAPK/ERK) [52].
MechanismOutcome/Benefit in NAFLD
Inflammation (hs-CRP, TNF-a)Less progression to NASH and fibrosis [49,50]
Antioxidant enzyme activity, MDAProtection of hepatocytes from oxidative injury [51]
Hepatic steatosis and liver stiffnessImproved liver fat and fibrosis scores [49,50]
ER stress pathways, protective genesReduced cell injury; less fibrosis and inflammation [52]
Improved glucose/lipid homeostasisLower HOMA-IR, improved insulin sensitivity, better liver enzymes [50]
Table 5. Mechanistic Summary Table

In conclusion propolis supplementation, especially as an adjunct to dietary intervention, has been to shown to improve liver fat, reduce fibrosis, decrease inflammation, and bolster antioxidant defense in NAFLD patients, but larger and longer-term clinical trials are needed to confirm efficacy and optimal dosing [49-52].

Propolis in Alzheimer’s Disease

Propolis, especially Brazilian green propolis, is increasingly recognized for its neuroprotective effects in Alzheimer’s disease (AD), with evidence coming from both animal studies and clinical trials.

These are the mechanism of action in Alzheimer’s Disease

  • Anti-inflammatory and Immunomodulatory Effects: Propolis significantly suppresses neuroinflammation-a key driver of AD-by reducing the activation of microglia and astrocytes in the brain. In a mouse model of ADM propolis administration prevented learning and memory impairment induced by amyloid-beta, the hallmark protein of AD. Propolis downregulated key inflammatory markers, such as TREM2 and LCN2, and reduced plasma IL-6 levels, indicating suppression of both central and systemic inflammation. This moderation of glial cell activation helps protect neurons from amyloid-induced injury and preserve cognitive function [53].
  • Reduction of Amyloid Accumulation and Toxicity: Experimental and computational studies have shown that propolis-through its polyphenols and flavonoids-reduces amyloid beta aggregation and its cytotoxicity, both in vitro and in vivo. This helps mitigate one of the main pathological features of AD [54].
  • Antioxidant Protection: The high flavonoid and phenolic content of propolis confers potent antioxidant activity, reducing oxidative stress-a major factor in neuronal loss and cognitive decline in AD. Propolis treatment has been shown to increase the expression of antioxidant enzymes, decrease lipid peroxidation, and protect mitochondria and neuronal members [55,56].
  • Enhancement of Neurotrophic Factors and synaptic Plasticity: Propolis boost the expression of key neurotrophic factor (BDNF), which supports neuronal growth, survivability and synaptic plasticity. It also activates signalling pathways, including CREB and PPARa, involved in memory and neuroprotection [53,55].
  • Cognitive Benefits in Animal and Human Studies: In animal studies, propolis supplementation reversed cognitive deficits, improved memory and learning, and protected against behavioural and histopathological features of Alzheimer’s, including amyloid plaque accumulation and neuronal loss [55,56,57]. In a placebo-controlled human trial, elderly participants taking propolis supplements for 24 weeks demonstrated significant improvements in verbal memory and other cognitive domains compared to placebo. These effects were observed without serious adverse events [58].
  • Synergistic Effects with Alzheimer’s Medicines: Studies in Drosophila models have indicated that the combination of propolis with standard Alzheimer’s drugs (such as donepezil) resulted in greater cognitive improvement than either treatment alone [59].

Clinical and Experimental Evidence

  • Reduction in Cognitive Decline: Propolis intake prevented cognitive decline in both mouse models of AD and elderly humans at risk for dementia, with long-term intake (up to 24 months) showing benefits for memory and processing speed in clinical populations [53,58].
  • Neuroprotection and Synaptic Integrity: Propolis extracts increased neural viability, promoted dendritic growth, and enhanced BDNF expression, all key aspects in preserving brain structure and function in AD [53].

In conclusion, propolis exerts neuroprotective effects in Alzheimer’s disease primarily by inhibiting neuroinflammation, suppressing amyloid toxicity, providing antioxidant defense, and enhancing synaptic integrity. These actions translate to improved cognition and reduced progression of AD symptoms in animal models and human trials, supporting its status as a promising natural adjunct in preventing or managing AD-type dementia [53,54,55,58].

Supplement Formulations and Administration Routes

Propolis supplements are available in various formulations and can be administered through several through several routes, each with specific indications, safety considerations, and precautions.

These are some of the formulations of propolis supplements:

  • Capsules and Tablets: Common formulations include soft capsules, hard capsules, and compressed microcapsule tablets. These forms typically contain propolis extract (ranging from 100-1,500mg/day), often blended with carriers such as vegetable oils, binders (e.g., Avicel PH 102 in tablets), and sometimes with royal jelly or vitamin E oil. Tablets can be made through direct compression for dry extract microcapsules, while soft capsules are produced by emulsifying propolis in oils and enclosing in gelatin [60-62].
  • Tinctures and Extracts: Propolis tinctures are ethanol-based liquid extracts, typically standardized at 10-20% concentrations. A daily intake of 3×20 drops of 20% tincture equals roughly 200mg of propolis. These are used both orally and topically, depending on the indication [62].
  • Oral Sprays and Syrups: Propolis is formulated in oral sprays and syrups for sore throats, oral mucositis, and upper respiratory conditions, either as stand-alone or in combination with other botanical ingredients [62,63].
  • Ointments, Creams, and Gels: For skin, mucosal, or would application, propolis is included in creams (often 0.5-3%) and hydrogels for its antimicrobial and healing properties [64,65,66].

Administration Routes:

  • Oral: The most common and researched route for systemic effects. Used in capsules, tablets, tinctures, syrups, and lozenges. Doses in human studies typically range from 200-1,500 mg/day of standardized extract for adults [62,67,68].
  • Topical: Creams, gels, hydrogel dressings, and ointments for wounds, inflammation, and mucosal conditions, typically containing 0.5-3% propolis applied 2-5 times daily [62,65,66].
  • Other routes: Intranasal sprays and rectal suppositories have been explored in research, but are less common in commercial practice [69].

Safety Profile

  • General Safety: Propolis is considered possibly safe when used orally or topically and appropriately, with studies supporting safe ty for up to 10 months at 300mg/day in adults and lactating women [62,67,68,70].
  • Adverse Effects: Most adverse effects are allergic reactions, especially in individuals sensitive to bee products or pollen. These can manifest as contact dermatitis, oral ulcers (especially with lozenges), or systemic allergy (rare but possible) [67,68]
  • Milder reactions: Mouth or skin irritation, redness, or itching [68].
  • Drug Interactions: Propolis may slow blood clotting; combining it with anticoagulants, antiplatelet medications, or other supplements that affect clotting increases bleeding risk [71].
  • Contamination Concerns: Some supplements may contain heavy metals, pesticides, or contaminants. Choose products from reputable sources tested for purity.

Precautions and Contraindications

  • Allergies: Anyone with allergies to bees, bee products, honey, conifers, poplar, or Peru balsam should avoid propolis [66,71].
  • Bleeding Disorders of Surgery: Avoid if you have a bleeding disorder or are planned for surgery- discontinue at least two weeks prior, as propolis may slow blood clotting [70,71].
  • Asthma: People with asthma may have an increased risk of reaction and should avoid use unless allergy testing indicates otherwise [66,71].
  • Pregnancy and Children: Due to insufficient data, propolis is generally not recommended during pregnancy or for children under 2 years old Use breastfeeding women has been studied at 200-300mg/day for up to 10 months with no reported adverse effects [62,66].
  • General Precaution: Long-term continuous use in healthy individuals is not recommended unless directed by a healthcare professional [70].
FormulationAdministration RouteTypical DoseSafety/Precautions
Capsules/TabletsOral200-1,500 mg/day [62]Avoid in allergies, caution with bleeding disorders [67,68,70,71]
TinctureOral/ Topical200-400mg/day [62]Discontinue before surgery [67,70,71]
Cream/Ointment/GelTopical0.5-3%, 2-5x daily [65]Test for allergy to bee products [67,68]
Syrup/SprayOralVariableMouth ulcers may occur with lozenges [67,68]
Table 6. Common Formulations and Precautions

Propolis is supplied in capsules, tablets, tinctures, sprays, syrups, and topical gels, with oral and topical routes being the most common. It is generally well-tolerated but carries risks of allergic reactions, especially in those allergic to bee/plant products, and may increase bleeding risk. Use is not recommended during pregnancy, in young children, or for people with asthma or bleeding disorders without medical advice. Always select high-quality product and consult a healthcare provider before use [62,66,67,68,70,71].

Clinical Considerations for Supplementation

When recommending or using propolis supplements, several clinical considerations should be taken into account to ensure efficacy, minimize adverse effects, and promote safe use.

  1. Dosage and Duration
    • Evidence-Based Doses: Clinical studies have used a wide range of dosages, typically from 160 mg to 1,500 mg/day of standardized propolis extract in adults. The exact dose should be tailored to the condition being treated, formulation used (capsule, drops, syrup, etc.), and patients factors [13,72,73,74].
    • Duration: Duration in trials ranged from 2 weeks up to 96 weeks. Most short-term uses (up to 3 months) are well-tolerated, but longer-term use, especially at higher doses, should be supervised by a healthcare provider [13,72].
  2. Patient Selection and Baseline Assessment
    • Indication Alignment:Propolis has shown most benefit as an adjunct therapy in conditions characterized by inflammation and oxidative stress- such as metabolic syndrome, diabetes, chronic kidney disease, NAFLD, and inflammatory diseases [13,72,75].
    • Baseline Evaluation: Screening for bee product allergies, existing comorbidities (bleeding disorders, asthma), medication review (notably for anticoagulant/ antiplatelet use), and pregnancy/lactation status is essential before supplementation [67,76].
  3. Monitoring During Supplementation
    • Efficacy:Monitor clinical and laboratory parameters according to the indication (e,g., liver enzymes for NAFLD, HbA1C for diabetes, inflammatory markers for chronic inflammatory disease) [13,72,75,77]
    • Safety: Watch for signs of allergic reactions (rash, swelling, respiratory symptoms), oral or skin irritation, gastrointestinal issues, or sign of bleeding, especially in at-risk populations [67,76].
    • Anthropometrics: Some studies report a modest increase in weight or BMI with higher-dose propolis, so periodic weight assessment may be warranted, especially in those at risk of metabolic complications [32].
  4. Product Quality and Standardization
    • Source and Purity:Because supplement regulation varies, select brands that offer third-party testing, clear propolis extract standardization and certificates of analysis to limit the risk of adulteration or contaminants [78].
    • Standardization: Polyphenol and flavonoid content, contaminants, and batch-to-batch variation should be checked when available [78].
  5. Patient Education and Counselling
    • Allergy Precaution: Educate on signs of an allergic reaction and the importance of immediately discontinuing use if these occur [67,76].
    • Supplement Not a Substitute: Reinforce that propolis is complementary- never a substitute for evidence- based therapies and lifestyle modification [13]
    • Report Adverse Effects: Patients should seek medical attention if they experience abnormal bleeding, significant oral or skin reactions, or unexpected symptoms [67,76].
    • Pregnancy & Pediatric Use: Due to limited data, it is generally not recommended in pregnancy, lactation, or young children unless under strict medical supervision [67,76].
ConsiderationAction or Monitoring Recommendation
Dose/ DurationTailor to condition and formulation; shortest effective duration [13,72]
AllergiesScreen for bee/pollen/honey allergy before use [67,76]
Drug InteractionsCaution with anticoagulants, antiplatelets
Pregnancy/ ChildrenAvoid unless medical supervision [67,76]
QualityChoose standardized, quality-tested brands [78]
Efficacy/ Safety MonitoringLab and symptom monitoring as per indication [13,32,72]
Adverse Reaction EducationCounsel on allergic reactions and bleeding risk [67,76]
Table 7. Clinical Consideration

Propolis supplementation should be individualized, evidence-based, and monitored for safety, particularly in at-risk populations. Source quality, allergy risk, medication interactions, and patient education are critical for safe and effective use [13,67,72,74-76,78]

Future Directions

Propolis continues to be an exciting candidate in the prevention and management of metabolic syndrome and its chronic complications, such as type 2 diabetes, cardiovascular disease, NAFLD, chronic kidney disease, and neurodegeneration. Looking forward, several research and innovation pathways highlight its expanding therapeutic potential:

  1. Advanced Clinical Trials and Translational Research
  2. Molecular Mechanism Elucidation
  3. Personalized and Precision Nutrition
  4. Formulation Innovations and Nano-Delivery
  5. Integrative and Adjunctive Therapy
  6. Disease-Specific Expansions
  7. Regulatory and Quality Control Advances

In summary, the future of propolis as a therapeutic agent in metabolic syndrome and chronic disease lies in multi-disciplinary research, advanced formulation science, integrative medicine models, and a strong regulatory framework. Its pleiotropic actions on inflammations, oxidative stress, and metabolic pathways- if harnessed with evidence-based approaches- offer substantial promise for safer, more effective adjunctive therapy in the global fight against non-communicable chronic diseases [14,79,80].

Conclusion

Propolis is a promising multi-targeted natural agent for metabolic syndrome and related diseases, offering antioxidant, anti-inflammatory, and metabolic regulatory benefits, with a strong safety profile when used appropriately, Its integration into clinical practice will require standardized supplements, careful patients selection, and further high-quality research.

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