1 Introduction

Propolis, a natural resinous amalgam, is synthesized by honeybees using substances acquired from various plant sources, including buds and exudates. Its name originates from the Greek words “pro,” meaning “at the entrance to,” and “polis,” referring to “community” or “city,” signifying its role in hive defense. Often referred to as bee glue, propolis is integral to the structural integrity of beehives, utilized by bees for sealing crevices, reinforcing walls, and fortifying defenses against external threats such as predators and inclement weather conditions. Bees procure propolis from diverse plant species across varying temperate climates, ensuring the resilience and protection of their colonies.

In recent decades, propolis has been the subject of numerous global research areas, with extensive exploration into its chemical composition and biological attributes (Fig. 1). Widely recognized for its immune-stimulant properties, propolis is commonly utilized as a preventative measure against colds owing to its antibacterial and antiviral effects. Additionally, it serves as a natural remedy for various skin ailments, offering soothing and healing properties [1]. Its application extends to oral care, where it aids in treating minor ulcers and canker sores, alleviating urinary tract irritation and restoring gastric mucosa balance. Reportedly the propolis has been used a traditional remedy since ancient times this could be attributed that Propolis exhibits anti-cancer, antimicrobial, immune-stimulating activities, and antioxidant, including anti-inflammatory properties (Table 1). These biological activities of Propolis could be due to the presence of flavonoids and polyphenolic compounds [2]. In recent studies reported that propolis is used in the formulation of therapies for various non-communicable diseases, such as cancer, diabetes, cardiovascular diseases, arthritis, Alzheimer’s disease, and Parkinson’s disease (Table 1), are leading global and local causes of death. These diseases occur due to the production of free radicals, immune-suppression, DNA mutations and also alter the chemo-physiology, which ultimately lead to the aging of cells.

Fig. 1
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Flow chart of the process of the study selection

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Table 1 Showing the role of propolis in the treatment and development of drugs for microbial and non-microbial pathogenesis
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Propolis is used due to the presence of multiple purposes viz nutritional dietary supplements, conventional medicine due to presence of as an antiviral, anti-inflammatory, antitumor, antiseptic, anesthetic, cytostatic, hepatoprotective, antibacterial, antimycotic, antiprotozoa, choleric, spasmolytic, astringent, antioxidative, immune-stimulant and also in different sports.

1.1 Ethanomedicinal uses of propolis

Throughout history, diverse cultures across the globe have exhibited a profound comprehension of environmental dynamics and ecology. This has facilitated the preservation and dissemination of a wide arraactices and methodologies, particularly concerning use of plant and bee products, aimed at addressing and mitigating community health challenges effectively. In contemporary times, there has been a notable surge in the use of natural remedies within folk medicine. This trend is driven not only by their historical availability and cultural tradition but also by a burgeoning interest in scientific exploration. Researchers are increasingly investigating the potential of natural like propolis as alternative treatments for various diseases, thus expanding the scope of therapeutic options [18].

The World Health Organization (WHO) provides a definition of folk medicine (also known as traditional medicine) as encompassing the collective knowledge, skills, and practices rooted in the theories, beliefs, and experiences specific to diverse cultures. These practices, whether scientifically explainable or not, are employed for the preservation of health, as well as for the prevention, diagnosis, amelioration, or treatment of both physical and mental ailments.

The side effects associated with various medications used in the treatment of different disease, alongside limited accessibility to standard therapies within certain populations, underscore the relevance of exploring natural products. These products are often regarded as rich reservoirs of potential new drugs. Extracts derived from natural sources represent significant avenues for drug discovery, with many demonstrating promising bioactive constituents, particularly those with antioxidant properties, for addressing different diseases throughout human history, natural products have been employed as medicinal agents, often discovered through trial-and-error experimentation. Despite a historical perception that natural products lack pharmaceutical value, it's noteworthy that 80% of medical drugs post the industrial revolution was originally sourced from plant compounds and natural products, such as morphine, isolated from opium in the nineteenth century. Moreover, natural products continue to play a predominant role, contributing to 60% of anti-carcinogenic compounds and 75% of drugs utilized in treating infectious diseases.

Folk medicine has long used propolis as a bactericidal, antiviral, and antifungal medication to treat inflammations in various body parts throughout the world [19]. It was found in almost all home first-aid kits since it is useful as a local anaesthetic, for wound healing, and for skin regeneration [20]. Because propolis has been demonstrated to accelerate wound healing and ease a variety of discomforts, it has also been recommended in folk medicine for the treatment of purulent illnesses. Alternative and complementary medicine treated colds, flu, bronchial asthma, and other human ailments like stomach disorders using various propolis-based treatments, including sprays, ointments, and powders (mostly made of tinctures and ethanolic extracts) [21]. Furthermore, propolis is still a component of several dietary supplements, makeup, and even therapeutic candies. It has no nutritional value, in contrast to honey and bee pollen, but it has a potent, multidirectional biotic effect [22]. As a means of promoting health and averting disease, propolis has lately gained popularity in foods and drinks [23]. In addition to sore throats, dental cavities, and stomach ulcers, it is still used to heal burns and wounds. Propolis ethanolic extract has long been used as an immunomodulatory agent and recognised to have anti-inflammatory qualities [12]. It has a variety of applications in endodontics and shows promise for the future of dentistry [24]. Hydrophobic substances like propolis may become dispersible in aqueous systems by the application of propolis nanoparticle-based delivery techniques, hence addressing the issues related to low solubility. Recent investigations have unveiled potential mechanisms of action, paving the way for novel clinical applications.

Propolis is not only utilized in the treatment of conditions like psoriasis, pruritis ani, gingivitis, stomatitis, and rheumatic disorders, but it has also shown promise in the management of sprains. Additionally, propolis is incorporated into the formulations of cosmetics and dietary supplements, as highlighted by studies conducted.

1.2 Timely need of this review

This review is crucial due to the recent surge in research interest surrounding natural products with potential therapeutic applications. Propolis, with its rich chemical composition and diverse biological properties, has emerged as a standout candidate in this field. As scientists uncover new insights into its mechanisms of action and clinical applications, the necessity for comprehensive reviews to synthesize and contextualize this wealth of information becomes increasingly apparent. Moreover, propolis exhibits various pharmacological properties, such as antimicrobial, anti-inflammatory, antioxidant, and immunomodulatory effects, making it promising for various medical and wellness applications. Understanding the depth and breadth of biological activities propolis are essential for maximizing its therapeutic potential and exploring novel avenues for drug development and nutraceutical formulation. Additionally, the rising consumer interest in natural remedies and supplements underscores the need for evidence-based information on the health benefits of propolis. A comprehensive review can thus serve as a valuable resource for healthcare professionals, researchers, and consumers alike, aiding decision-making regarding its use in clinical practice and personal wellness regimens. Furthermore, by compiling and analyzing the latest research findings and identifying knowledge gaps, this review can guide future research directions and priorities in propolis pharmacology and therapeutics, fostering collaboration and dialogue among stakeholders and contributing to advancing our understanding of propolis as a natural remedy. Therefore, this review is timely and important, addressing the growing interest in natural products for health and wellness, highlighting therapeutic potential of propolis, providing evidence-based information, and guiding future research efforts in this promising field.

1.3 Current status of propolis in pharmaceutical and nutraceutical development

The current status of propolis in pharmaceutical or nutraceutical development reflects a burgeoning interest in exploiting its therapeutic potential across diverse medical and wellness applications. This natural substance, produced by honeybees, has garnered attention due to its multifaceted chemical composition and biological properties. In pharmaceutical realms, researchers are delving into propolis as a wellspring of innovative therapeutic agents aimed at addressing a spectrum of health conditions. Studies have reported its antimicrobial, anti-inflammatory, antioxidant, and immunomodulatory attributes, positioning it as a promising candidate for novel drug development. Investigations into propolis extracts and formulations are underway, targeting their efficacy in combating infectious diseases, mitigating inflammatory disorders, and bolstering immune function. Simultaneously, in nutraceutical development, propolis is being leveraged as a functional ingredient in dietary supplements and health products, with marketed benefits spanning immune support, skin health, oral care, and gastrointestinal wellness. Manufacturers are diversifying formulations, incorporating propolis extracts into capsules, tablets, tinctures, and topical creams to deliver its bioactive compounds effectively. The advancement of propolis in both pharmaceutical and nutraceutical sectors is propelled by ongoing research endeavors, aiming to elucidate its mechanisms of action, optimize extraction methods, standardize quality control measures, and evaluate safety and efficacy profiles. Collaborative efforts between academia, industry, and regulatory bodies are fostering innovation in propolis-based products, facilitating their integration into mainstream healthcare and wellness practices. Overall, the current trajectory underscores propolis as a valuable natural resource for enhancing human health and well-being, with continued research and investment poised to yield novel therapeutic solutions and broaden the array of propolis-based products accessible to consumers.

Due to the continuous evolution and upsurge in disease as well as disease-borne microbial and non-microbial diseases, there is need of antimicrobial agents as well as synthesis of new drugs from natural sources that could have positive impact on pathogenic and non-pathogenic diseases. Moreover, raw materials used in the synthesis of these remedies must be cost effective and least toxic. The review on propolis aims to consolidate and analyze recent research findings to provide a comprehensive understanding of its medicinal potential, aiding both researchers and healthcare professionals in utilizing propolis effectively for therapeutic purposes.

This review has focused specifically on the dynamic pharmacological potency and multifaceted biological activities of propolis. It synthesizes recent research findings to provide an updated understanding the medicinal potential of propolis, differential chemical constituents of propolis of different countries, offering insights into its evolving pharmacological effects and diverse biological activities. Additionally, it may incorporate perspectives not covered in previous reviews, enhancing its contribution to the existing literature on propolis.

2 Methods

The standard guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses were adhered to in order to enhance the quality of the systematic review and meta-analysis.

2.1 Search strategy

A comprehensive literature review was conducted to identify recent articles highlighting the therapeutic efficacy of propolis in disease management. The search spanned from 2005 to 2023 and encompassed multiple online databases including Google Scholar (https://scholar.google.com/), Scopus (https://www.scopus.com/), Web of Science (https://mjl.clarivate.com/search-results), Science Direct (https://www.sciencedirect.com/), and PubMed ((http://www.ncbi.nlm.nih.gov/pubmed). Various keywords such as “propolis antioxidant,” “anti-inflammatory,” “antibacterial,” “anti-diabetic,” “apoptotic,” “respiratory,” “gastrointestinal,” “cardiovascular,” and “nervous system” were employed either individually or in combination as inclusion criteria. Additionally, searches were conducted on platforms like Science Direct, Elsevier, Springer, and Nature Portfolio to explore the therapeutic roles of propolis and its constituents. Latest articles focusing on propolis’ antioxidant, anti-inflammatory, anticancer, and anti-diabetic properties were sought after in SCOPUS and Web of Science databases. Furthermore, available treatments for various pathological conditions such as viral diseases (including COVID-19), metabolic disorders (e.g., diabetes, obesity, hyperlipidemia), reproductive disorders (e.g., PCOS, infertility, oligospermia), neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s), hepatotoxicity, and renal toxicity were also investigated. Initially, nearly 200 results were obtained, and their abstracts were reviewed to assess relevance. Following additional exclusion criteria such as non-English language and unavailability of full-text manuscripts, approximately 110 research and review papers were critically examined for the compilation of the present article.

2.2 Study selection

First, irrelevant articles were filtered out by reviewing their titles and/or abstracts. Next, the full-text versions of the remaining studies were obtained and meticulously evaluated for several criteria, including study design, model used (in vivo or in vitro), interventions administered, and reported outcomes. Subsequently, randomized controlled trials (RCTs) exploring the efficacy of propolis, either as a therapeutic remedy or supplement, for various diseases were included. Studies involving the use of propolis as a therapeutic remedy for the treatment of different diseases with treatment durations of less than one week were excluded from the systematic review and meta-analysis. To ensure precision, each step of the study selection process was conducted independently by at least two authors, with any discrepancies resolved through consensus (Fig. 1).

2.3 Data extraction

A. H. and M. P., two researchers, separately and in duplicate, extracted relevant data using a data abstraction form for each included article. Consultation was the method used to resolve disputes. Subject characteristics (dose range tested, minimal active concentration, model used (in vitro or in vivo study), duration, type of extract used, and other basic pharmacological data, intervention details (type and dosage of propolis, type of placebo or control groups, and treatment duration), and level of interest outcomes (pharmacological properties such as antidiabetic, anticancer, cardiovascular, antihypertensive, anti-inflammatory, immunomodulatory, and reproductive related studies) were all recorded.

3 Results

3.1 Chemical constituents

The chemical composition of propolis constitutes resin (50–70%), wax and oil (30–50%), pollen (5–10%), carbohydrates, flavonoids, amino acids, phenols, vitamins B, C, and E, aromatic compounds, minerals, enzymes, fatty acids, terpenes, phenols, esters, hydrocarbons, and aromatic compounds(Fig. 2; Tables 2 and 3).

Fig. 2
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Showing the bee products with special emphasis on the detailed composition of propolis

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Table 2 Chemical constituents, molecular formulas, IPUAC name and identifiers
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Table 3 Chemical characterization and identified chemical compounds in propolis
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3.2 Pharmacological and biological importance of propolis

The chemical composition of propolis underscores its potential as a source of natural compounds with diverse pharmacological effects and therapeutic applications. Propolis exhibits various therapeutic properties in pharmaceuticals and medicines for the treatment of diverse chronic diseases. Notably, propolis exhibits efficacy in treating autoimmune diseases, diabetes, burns, wounds, gynecological issues, as well as conditions pertaining to the laryngological, dermatological, neurodegenerative, gastrointestinal, and respiratory tracts [63]. Moreover, its applications extend to cardiovascular disorders, with documented antimicrobial (antibacterial, antifungal, anti-protozoal), anticancer, hepatoprotective, anti-inflammatory, antiviral, anticancer and antioxidant activities (Tables 4 and 5). We delve into the bioactive components of propolis and their respective impacts on a spectrum of medical conditions and diseases. Figures 3, 4 and 5 summarize the pharmacological and Biological protective effect of propolis respectively. Propolis is used due to the presence of multiple purposes viz nutritional dietary supplements, conventional medicine due to presence of as an antiviral, anti-inflammatory, antitumor, antiseptic, anesthetic, cytostatic, hepatoprotective, antibacterial, antimycotic, antiprotozoa, choleric, spasmolytic, astringent, antioxidative, immune-stimulant and also in different sports.

Table 4 Summary of animal studies on pharmacological effect of propolis on different diseases
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Table 5 Summary clinical trials on pharmacological effects of propolis on different diseases
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Fig. 3
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Represents the free radical scavenging and DNA damaging potential of propolis induced by oxidative stress. Propolis neutralizes the free radicals (ROS, OH, O., NOS) due to the presence electron rich polyphenols and flavonoids by modulating the activities of antioxidative enzymes

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Fig. 4
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Inflammation primary sign of different diseases, propolis decreases the severity of inflammation due to the presence of different compounds such as CAPE and Galangin. Propolis decreases the level of inflammatory cytokins such as IL-10, IL-1B, TNF-α etc. and prevents and controls the different diseases such as gastrointestinal diseases, liver injury, diabetes, ulcerative colitis and cancer)

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Fig. 5
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Immune regulation is the primary device to keep the organism healthy. Propolis modulates the functions of immune system by working as antioxidant, anti-inflammatory and immunomodulatory agent

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The biological activities of propolis are attributed to its complex composition, which includes various polyphenols, flavonoids, phenolic acids, essential oils and other bioactive compound. The specific composition can vary depending on the geographic location and the types of plants available to the bees. Some of the notable biological activities of propolis includes antimicrobial activity (antibacterial, antifungal and antiviral), anti-inflammatory, antioxidant, anticancer and cardioprotective, immunomodulatory and wound healing effects (Tables 3 and 4).

3.3 Meta‐analysis

The results of the meta‐analysis revealed a significant reduction in Glucose level [− 120.51 mg/dl; 95% Confidence interval (CI) (− 22.88, − 2.05); I4 = 74%], Endotoxemia (induced by HFD) [− 0.58%; 95% CI (− 0.92, − 0.11); I2 = 70%],TNF-α (WMD: − 7.61; 95% CI − 8.33, − 3.76) and interleukin-6 (IL-6) (WMD: − 16.78; 95% CI − 33.53, − 0.40). ALT (WMD: − 4.93; 95% CI − 9.97, − 0.61) and aspartate aminotransferase (AST) (WMD: − 3.02; 95% CI − 4.12, − 1.04) following the administration of propolis. Fasting plasma glucose [− 14.09 mg/dl; 95% CI (− 22.87, − 2.06)] and hemoglobin A1C [− 0.56%; 95% CI (− 0.91, − 0.11)] following the administration of propolis.

4 Discussion

4.1 Effect of propolis on gastrointestinal (GIT) disease

Many gastrointestinal disorders, such as mucositis, colitis, gastritis, and peptic ulcers, are treated with propolis. Propolis lowers lipopolysaccharide (LPS) levels and down-regulates the Toll-like receptor 4 (TLR4) pathways as well as the expression of inflammatory markers when used in the treatment of gastric ulcers. Furthermore, it reduces inflammatory cytokines, raises glucose and serum triacylglycerol levels, and lessens endotoxemia in mice fed a high-fat diet by preventing dysbiosis (Figs. 4 and 5). By preventing the growth of harmful bacteria and strengthening the mucosal barrier, propolis also has a protective effect on the gastrointestinal tract. This helps to prevent or speed up the healing of leaky gut. Table 4 provides an overview of the clinical trials and animal research on propolis's anti-inflammatory properties, respectively. In the case of oral mucositis (OM), external applications of propolis (EUP) through pharmaceutical, cosmetic and oral products such as ointments, gels and mouthwashes have been employed to reduce oral infections, dental plaque, and for the treatment of stomatitis due to its antimicrobial efficacy. Consumption of propolis suppresses the levels of TNF-α and IL-1B by reducing lipid peroxidation in gastric tissues with simultaneousincreases the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx). Kaempferol decrease the pro-inflammatory response in damaged gastric tissue by increasing the production of nitric oxide (NO) and preserves gastric mucus glycoprotein [64]. In addition to this Quercetin (another component of Propolis) inhibits the activity of proton pump-ATPase in parietal cells, suppressing gastric acid secretion and peptic activity. Quercetin also increases secretion of mucin and mucosal prostaglandin E2 and helps in the treatment of gastric ulcers [65].

4.2 Protective effect of propolis on acetaminophen (APAP) induced liver injury

Acetaminophen (N-acetyl-p-aminophenol; APAP) is a widely used analgesic and antipyretic agent that can lead to hepatotoxicity. The APAP metabolite, NAPQI, induces mitochondrial dysfunction and generates reactive oxygen species (ROS), causing damage to phospholipid membranes and proteins and ultimately leads to the hepatocellular necrosis. NAPQI depletes glutathione and increase the production of H2O2 levels, which oxidize thioredoxin and dissociate it from apoptosis signalling-regulating kinase 1 (ASK-1) (Fig. 4 and Table 5). This triggers self-activation of ASK-1, leading to the phosphorylation of mitogen-activated protein kinase 4/7 and the activation of c-Jun N-terminal kinase (JNK) [66].

Prenylated phenylpropanoids and flavonoids, which have antioxidative and anti-inflammatory properties, have been found to be present in the ethanolic extract of Brazilian green propolis (EEBGP), which has been shown to reduce the incidence of hepatocellular necrosis by a number of mechanisms, including the removal of ROS, the modification of the inflammatory response, and the control of the metabolism and excretion of APAP and NAPQI. The percentage of hepatocellular necrosis is also decreased by EEBGP because it lowers the expression of inflammatory cytokines, such as IL-10 and IL-1β, on the mRNA [67]. By preventing hepatic damage caused by α-naphthyl-isothiocyanate or water immersion restraint stress, oral administration of EEBGP increases the levels of antioxidant enzymes’ messenger RNA (mRNA) (Fig. 4 and Table 4).

Acetaminophen (APAP) induced liver injury Kupffer produces various cytokines (interleukin IL-1β, IL-6, and IL-10), chemokines (CC-motif chemokine ligand 2 (CCL2) and CXC-motif chemokine ligand 2 (CXCL2). It has been studied that oral administration of caffeic acid phenethyl ester (CAPE) decreases the level of CYP2E1 protein and its enzymatic activity [68]. Moreover, it has been also reported that CAPE also reduces the leakage of AST, ALT, LDH, and SALP into circulation. This indicates that Propolis or combination of its bioactive components can be used a remedy for the treatment of hepatotoxicty. Previous studies have already stated that propolis extract increase the GSH levels by upregulating the activities of catalase (CAT), superoxide dismutases (SOD) in the liver and kidney and hence helps to mitigate the oxidative stress. Moreover, it also decreases the levels of serum bilirubin, albumin, urea, creatinine, and triglycerides, thus mitigating hepatic and renal damage.

4.3 Effect of propolis on diabetes and complications

4.3.1 Diabetes mellitus (Type 2)

Propolis exhibits therapeutic potential against the treatment of Type 2 Diabetes Mellitus (T2DM) and its associated complications (Fig. 6). Type 2 diabetes mellitus (T2DM) is characterized by elevated blood glucose levels due to insufficient insulin production. The exploration of natural compounds for prevention and treatment has gained traction, with propolis emerging as a subject of interest in research [69]. Propolis, renowned for its anti-inflammatory, antioxidant, and free radical-scavenging qualities, contains flavonoids that show promise as a treatment for a variety of complex illnesses, including type 2 diabetes [70] (Tables 4 and 5).

Fig. 6
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Propolis reduces the severity and controls the diabetes and polycystic ovarian syndrome (PCOS) by modulating the insulin secretion, receptor sensitivity, regulates the secretion of hormones (estrogen and progesterone). Moreover, propolis accelerates the activities of antioxidative enzymes thereby reduces the production of ROS and RNS hence decreases the oxidative stress. Administration of propolis also reduces the production of inflammatory cytokines and decreases the inflammation

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Flavonoids found in propolis, including luteolin, genistein, apigenin, chrysin, galangin, kaempferol, and pinocembrin, have been shown to have anti-diabetic properties. Additionally, propolis contains the flavanone glycoside naringin, which has lipid-lowering and insulin-like qualities. It also has anti-inflammatory, antioxidant, anticancer, antiapoptotic, and anti-osteoporosis effects in addition to reducing hyperglycemia and insulin resistance. When apigenin and naringin are given together, muscle cells' ability to absorb glucose and inhibit glycogen phosphorylase is increased (Fig. 6). The combined effects of these flavonoids lower blood glucose levels, identify insulin in serum or islets, and inhibit the release of insulin. Furthermore, propolis supplementation dramatically reduces blood glucose, serum insulin, and serum glycosylated hemoglobin (HbA1c) levels in patients with type 2 diabetes [71]. The antihyperglycemic effects of propolis extend to inhibiting glucose production from dietary carbohydrates and regulating postprandial glucose, thereby improving insulin resistance. Notably, propolis demonstrates efficacy in enhancing glycemic and lipid profiles in T2DM patients, positioning it as a promising agent for diabetes prevention and control. In the context of T2DM complications, such as diabetic nephropathy and hepatotoxicity, anti-inflammatory effects of propolis play a crucial role by inhibiting the production of inflammatory cytokines, including IL-1, IL-6, and TNF-α [72, 73]. Prolonged hyperglycemia, a hallmark of T2DM, leads to the formation of advanced glycation end products (AGEs) and subsequent activation of the RAGE pathway, resulting in the amplification of reactive oxygen species (ROS) production [74]. Ability of propolis to scavenge free radicals and modulate blood lipid metabolism mitigates oxidative stress-induced damage to organs, including the heart, kidneys, nerves, and eyes [75].

Furthermore, propolis-containing diets have been shown to attenuate LPS-TLR4 signalling in muscle cells, reducing protein abundance levels of TLR4, CD14, MD2, MyD88, IRAK-1, and TRAF6 [76]. Propolis protects vascular function against high glucose levels and demonstrates significant reductions in blood glucose, serum glycosylated hemoglobin (HbA1c), and insulin levels in T2DM patients [71]. The specific components of propolis, including ferulic acid and chlorogenic acid, contribute to its antidiabetic properties by stimulating insulin secretion, expressing GLUT4 and MAP kinase, and activating IRS-1 and PI3K signalling pathways [77]. Moreover, propolis exhibits hepatoprotective action against oxidative stress-induced liver injury by activating the Nrf2 signalling pathway and stimulating the production of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), NQO1, HO-1, and GST [78]. In summary, propolis, through its multifaceted mechanisms, emerges as a promising natural agent for the prevention and management of T2DM and its associated complications (Fig. 6). Tables 4 and 5 summarize the animal studies and clinical trials regarding the anti-diabetic effects of propolis respectively.

4.4 Effect of propolis on polycystic ovary syndrome (PCOS) and associated complications

It has been reported that propolis extract modulates glucose levelsby mitigating the detrimental effects of PCOS on blood sugar levels [78]. Notably, insulin levels did not significantly differ among the groups, indicating that propolis may have a specific impact on glucose regulation in PCOS [79]. Moreover, propolis supplementation reduces fasting blood glucose and Hb1Ac levels, along with a delay in disease progression by reducing oxidative stress and inflammation related to type 2-diabetes [77]. Propolis restores the biochemical, physiology, histological and molecular alterations inpolycystic ovarian syndrome (PCOS) (Fig. 6). Potential positive effect of propolis includes antioxidant properties with compounds like flavonoids and polyphenols, potentially mitigates oxidative stress implicated in PCOS [80]. Anti-inflammatory effects of propolis may indirectly affect PCOS-associated symptoms linked to chronic inflammation [81]. Various studies suggest that propolis helps to modulate the hormonal levels, including insulin and reproductive hormones (LH, FSH, estrogen and progesterone etc.) hence modulates the hormonal imbalances in PCOS [82]. Studies have also reported that propolis has potential to improve insulin sensitivity, a critical factor for the management of PCOS-associated insulin resistance (Table 4).

Moreover, it has been studied that administration of propolis attwo different concentrations of propolis (50 and 150 mg/kg) modulates the expression of p53, ovarian folliculogenesis, serum progesterone, and luteinizing hormone (LH) levels in PCOS rats [83]. The number of cystic follicles in PCOS rats was significantly lower in the propolis-treated group after 10 days of treatment than in the untreated group. Additionally, the propolis-treated group had significantly higher levels of LH. On the other hand, circulating progesterone levels did not differ significantly. Moreover, no group exhibited any detectable p53 immunoreactivity. However, these concentrations were able to control the ovarian follicular cells' structural integrity. It is significant to note that there are currently no human trial data available about propolis’s use in managing or treating PCOS [83, 84].

Other studies reported that rats with polycystic ovary syndrome (PCOS) exhibited increased glucose levels compared to the control group. Interestingly, the group treated with water-propolis extract also showed elevated glucose levels, albeit to a lesser extent than the untreated PCOS group, indicating a potential therapeutic role of propolis in mitigating the detrimental effects of PCOS, particularly in reducing high blood sugar levels. Insulin hormone levels did not show significant differences among the three groups, with a slight decrease observed in the untreated PCOS group compared to the control group. PCOS is associated with hyperandrogenism, chronic anovulation, and insulin resistance. Propolis supplementation has been shown to reduce fasting blood glucose and Hb1Ac levels, potentially delaying disease progression by reducing oxidative stress and inflammation associated with type 2 diabetes (Fig. 6).

Total cholesterol, triglycerides, and LDL-cholesterol levels increased significantly in both the PCOS group and the propolis-treated group compared to the control group. However, the levels in the treated group were lower than the untreated group, indicating a positive impact of propolis in reducing lipid levels. HDL-cholesterol, which decreased in the PCOS group, showed an increase with propolis administration [83].

Liver enzymes, crucial for detoxification, significantly increased in the PCOS group, but a non-significant decrease was observed in the propolis-treated group. Propolis, with its natural antioxidants, showed promise in revitalizing the liver and reducing damage associated with PCOS [83].The study revealed a significant decrease in the level of superoxide dismutase (SOD) in the PCOS group, indicating oxidative stress, while propolis treatment led to a significant increase in SOD levels and a significant decrease in malondialdehyde (MDA) levels compared to the untreated PCOS group. Oxidative stress is linked to PCOS-related issues such as obesity, insulin resistance, and chronic inflammation.

All measured hormones in the study exhibited significant differences between the three groups. Estrogen and progesterone levels decreased in the PCOS group, while propolis treatment led to an increase in these hormone levels. Prolactin levels, increased in the PCOS group, were normalized with propolis treatment. Propolis showed potential in restoring normal hormone levels and improving ovarian function.

Histological sections of ovaries revealed differences among the groups. The PCOS group displayed ovarian follicles with cystic formations, indicative of impaired hormonal actions. Propolis treatment resulted in a reduction in cystic follicles and an increase in normal antral follicles and corpus luteum, highlighting the antioxidant properties of propolis in preventing histopathological alterations in the ovaries. In summary, the study suggests that propolis may have therapeutic potential in mitigating the effects of PCOS, particularly in reducing blood glucose and lipid levels, improving liver function, alleviating oxidative stress, and restoring normal hormone levels and ovarian morphology [83]. Tables 4 and 5 summarize the animal studies and clinical trials regarding the effects of propolis on polycystic ovarian syndrome (PCOS) respectively.

4.5 Propolis and its effect on ulcerative colitis (UC)

Ulcerative colitis (UC) is a type of inflammatory bowel disease characterized by continuous inflammation in the colonic mucosa. In UC patients, the overstimulation of NF-κB results in elevated levels of pro-inflammatory cytokines, such as IL-1β, IL-6, TNF-α, and interferons (Table 5 and Fig. 4). Flavonoids have been identified as compounds that can suppress the activation of NF-κB and inhibit the expression of inflammatory genes [85].

Propolis, a natural resinous substance produced by bees, has been observed to decrease both gross and histological scores of tissue damage in UC, along with reducing the expression of the inducible isoform of nitric oxide synthase (iNOS) [86]. The presence of quercetin in propolis contributes to attenuating colitic damage by inhibiting the NF-κB pathway [87]. These findings suggest that propolis, with its anti-inflammatory properties; can be beneficial in mitigating the inflammatory response characteristic of UC.

Furthermore, gastritis and peptic ulcers are often associated with the overgrowth of H. pylori bacteria. Studies suggest that consuming propolis, with or without honey; can significantly reduce the symptoms of gastritis and peptic ulcers, while also promoting healing [88]. This highlights the broader therapeutic potential of propolis, extending its benefits beyond UC to conditions associated with bacterial overgrowth and gastrointestinal distress.

Caffeic acid phenethyl ester (CAPE), known as an inhibitor of NF-κB, exhibits protective effects on the epithelial barrier, preventing disruption, and induces apoptosis in macrophages. This compound also reduces myeloperoxidase (MPO) activity and the levels of pro-inflammatory cytokines [89]. These anti-inflammatory effects are crucial in addressing the continuous inflammation associated with UC.Therefore, it may concluded that anti-inflammatory properties of flavonoids, CAPE, and propolis, particularly in the context of UC. The ability of propolis to address tissue damage and its potential in managing conditions like gastritis and peptic ulcers further emphasize its multifaceted pharmacological benefits in gastrointestinal health (Table 4 and Fig. 4).

4.6 Antimicrobial activity

4.6.1 Antiviral activities

Propolis, derived from bees, has shown significant antiviral properties against various viruses. Bioactive compounds like flavonoids, including chrysin, kaempferol, acacetin, galangin, and quercetin, have been found to be effective against herpesvirus, adenovirus, rotavirus, and coronavirus strains, and against SARS-CoV-2 and influenza viruses [90]. Propolis has antiviral effects on HIV, with moronic acid inhibiting HIV activity in H9 lymphocytes. Propolis extracts from various sources inhibit HIV-1 infected cells without antagonizing antiretroviral drugs. Propolis's antiviral properties, particularly against herpes viruses, have been extensively researched, with synergistic relationships among propolis-derived phenolics contributing to its higher activity. Poplar propolis, containing phenolics, has antiviral activity against herpes simplex virus types 1 and 2, as well as stingless bee propolis. Animal models have also shown anti-herpetic activity, with ethanolic extracts reducing viral load and hydroalcoholic extracts reducing lesions and damage. Previous studied reported that propolis is having broad-spectrum antiviral potential, extending beyond herpes viruses to include rhinovirus, dengue, polio, rubella, picornavirus, and measles virus, highlighting its bioactive components’ potential [91].

4.6.2 Mechanisms of action of antiviral properties of propolis

Molecular docking and in silico studies reveal antiviral properties of propolis against SARS-CoV-2 [92]. Rutin and caffeic acid phenethyl ester effectively inhibit key targets, suggesting a multifaceted approach to viral inactivation. Propolis-derived compounds, such as Sulabiroins A, glyasperin A, and broussoflavonol F, have been found to bind to specific residues in Mpro’s catalytic sites, suggesting a targeted approach to disrupt viral proteins [93]. Kaempferol and p-coumaric acid have also shown antiviral properties. Propolis enhances myxovirus resistance 1 gene expression and facilitates zinc cation transport, inhibiting viral RNA-dependent RNA polymerase, a crucial factor in combating RNA viruses [94]. Propolis has been shown to have immunomodulatory effects on host immune functions during viral infections. It increases the expression of TRAIL, reduces oxidative stress, and induces the production of IFN-γ, a key stimulator of lymphocyte migration, in HSV infection models. Propolis's molecular studies reveal its antiviral properties, which can target various viral infection stages, modulate host immune responses, and mitigate viral replication’s harmful effects [95].

4.6.3 Antibacterial properties of propolis

Propolis, with its antibacterial properties, has been extensively studied in scientific literature, with a comprehensive review involving 600 bacterial strains providing insights into their susceptibility and minimal inhibitory concentration values [96]. Propolis's antibacterial efficacy is more pronounced against Gram-positive bacteria than Gram-negative ones, possibly due to the presence of bacterial hydrolytic enzymes in Gram-negative bacteria’s outer membrane. Propolis’s antimicrobial properties are often linked to its phenolic and flavonoid content, but their concentration doesn’t always correlate with in vitro activity, requiring further tests to establish standards for propolis’s biological activity. Propolis’s geographical origin significantly influences its antibacterial properties, with Middle East propolis showing the highest activity against both Gram-positive and Gram-negative strains. It also enhances the efficacy of conventional antibiotics and natural products like honey [96, 97]

4.6.4 Mechanisms of action of antibacterial properties of propolis

Propolis has a multifaceted antibacterial action, interfering with pathogenic factors like ATP production, reducing bacterial mobility, disrupting membrane potential, and impairing RNA and DNA production [96, 97]. Recent research reveals that propolis, when deposited on a surface, generates an exclusion zone (EZ) that excludes colloidal particles, a phenomenon largely independent of its composition and origin [98]. This physical barrier prevents pathogens from accessing surfaces like respiratory epithelium, thereby enhancing its biological activity [98]. Recent studies suggest the use of propolis-functionalized textiles in medical applications, such as wound dressing. Propolis-bonded cotton fibers showed antibacterial properties, and a bacteria-free zone (EZ) was found, suggesting potential defense against microorganisms in healthcare facilities. The acidic pH of Propolis isdue to its fixed negative charges, which align with mobile protons. This may explain its higher bactericidal activity against Gram-positive bacteria, which are less negative and more susceptible to mobile protons, requiring further research [98].

4.6.5 Antifungal activities

In a thorough analysis of propolis’ pharmacological characteristics, Wagh highlighted the fungicidal action against a range of fungi, including C. pelliculosa, C. parapsilosis, C. famata, C. glabrata, and Pichia ohmeri [46, 91] attributed to the presence of phenolic compounds [99]. Banskota et al. [49] identified specific constituents of propolis, such as 3-acetylpinobanksin, pinobanksin-3-acetate, pinocembrin, p-coumaric acid, and caffeic acid, out of over 26 compounds, exhibiting anti-fungal activity. Agüero et al. [100] proposed that 20,40-dihydroxy-3-methoxychalcone and 20,40-dihydroxychalcone were the main bioactive compounds responsible for antifungal activity in propolis extract, particularly against clinical isolates of T. rubrum and T. mentagrophytes. Galangin, pinocembrin, and 7-hydroxy-8-methoxyflavanone isolated from propolis samples displayed moderate antifungal activity [100]. Boisard et al. [101] suggested that the high content of flavonoids in French propolis contributed to its antifungal activity against C. albicans and C. glabrata species.

The induction of apoptosis via metacaspase and Ras signaling by propolis is the suggested mechanism of antifungal activity. [102]. Furthermore, the expression of several genes involved in pathogenesis, cell adhesion, biofilm formation, filamentous growth, and phenotypic switching is disrupted by propolis. [102]. Propolis’s phenolic component pinocembrin interferes with vital cellular functions like energy homeostasis and mycelia growth in a dose-dependent way. It also prevents the transition from yeast-like to hyphal growth. It has been specifically demonstrated that pinocembrin lowers the levels of phosphorylated adenosine nucleotides and damages the hyphae and cell membrane structure, leading to ionic leakage and the loss of soluble proteins in Penicillium italicum [91].

4.7 Antioxidant activity

Propolis and its components have a well-documented antioxidant activity [98], which regularly shows a decrease in oxidative stress markers. Endogenous antioxidant systems have developed defense mechanisms, such as enzymes like superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT), as well as antioxidant nutrients like ascorbic acid, glutathione, and flavonoids, to lessen tissue damage brought on by oxidative stress [103]. Concentrations of malondialdehyde are widely used as possible biomarkers for oxidative stress and as markers of oxidative lipid damage (Fig. 3). Propolis has the ability to efficiently neutralize free radicals due to the chemical makeup of its constituent polyphenols [104]. Propolis contains flavonoids, which are powerful antioxidants that can scavenge free radicals and protect cell membranes from lipid peroxidation [105].

Because of its high oxygen consumption, higher than average concentration of polyunsaturated fatty acids, and lower than average levels of antioxidant molecules, the brain—the most important organ of the central nervous system—is especially vulnerable to damage caused by free radicals [106]. Oxidative stress is linked to both acute and chronic brain injury, and it is a key factor in the pathophysiology of neuronal damage. Propolis and its derivatives seem to reduce lipid peroxidation, increase the activities of antioxidant enzymes, and inhibit the generation of free radicals in radiation-damaged brain tissue, thereby mitigating oxidative stress [106]. These results highlight the important function of propolis and its components as free radical scavengers and antioxidants in reducing oxidative stress in radiation-damaged brain tissue.

Furthermore, preclinical research suggests that pinocembrin, a propolis component, shields the rat brain from oxidative stress and ischemia–reperfusion-induced apoptosis in both in vitro and in vivo settings [107]. Administering pinocembrin preserved adequate glutathione content and SOD activity in transgenic mice at risk for Alzheimer's disease. By restoring antioxidant SOD and GPx activity, maintaining enzyme ratios, lowering lipid peroxidation, and preserving neuronal damage from permanent cerebral artery occlusion in mice, administration of Iranian brown propolis improved [108].

Due to its ability to activate transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF κB), activator protein 1, tumor protein, hypoxia inducible factor 1 alpha, peroxisome proliferator-activated receptor-gamma, and nuclear factor erythroid 2-related factor 2 (Nrf2), oxidative stress is a well-known cause of persistent chronic inflammation [109]. The DNA transcription-controlling protein complex known as NF-κB is involved in the way that cells react to a variety of stimuli, such as stress, cytokines, free radicals, UV radiation, oxidized low-density lipoproteins (LDL), and antigens from bacteria or viruses. The Nrf2 transcription factor, a key regulator of antioxidant proteins, is activated by propolis [110].

When Nrf2 binds to the antioxidant response element, it triggers the transcription of multiple antioxidant enzymes, such as heme oxygenase-1, GPx, glutathione reductase, CAT, SOD, and glutathione-S-transferase, as well as the regulatory and catalytic subunits of gamma-glutamate-cysteine ligase. Determining the clinical implications of the antioxidant activity of propolis is a challenging task (Table 4). But then we talk about propolis’s anti-inflammatory and neuroprotective qualities, which are derived from its antioxidant qualities [111].

4.8 Anti-inflammatory role of propolis

When activated macrophages are exposed to an inflammatory stimulus, they release pro-inflammatory cytokines like TNF-α, IL-1, and IL-6, which in turn stimulate the translocation of nuclear factor-kappa B (NF-κB) into the cytosol. Strong anti-inflammatory activity is demonstrated by propolis and its constituents against a range of inflammatory conditions, including asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, cardiovascular diseases (high blood pressure, heart disease), gastrointestinal disorders (inflammatory bowel disease), and lung diseases (chronic obstructive pulmonary disease, or COPD) (Table 5 and Fig. 4). One of the main ingredients, caffeic acid phenethyl ester (CAPE), has anti-inflammatory and neuroprotective/hepatoprotective qualities that make it useful in the treatment of some chronic illnesses. [71].

Previous studies suggests that connection between caffeic acid phenethyl ester (CAPE) and its inhibitory effects on key enzymes in the arachidonic acid (AA) metabolic pathways, namely lipoxygenase (LOX) and cyclooxygenase (COX). By inhibiting these enzymes, CAPE may disrupt the production of inflammatory mediators derived from AA. Moreover, in Jurkat cells (T-lymphocytes), CAPE has been demonstrated to inhibit NF-κB activation. This inhibition occurs by restricting the formation of nuclear factor of activated T cells (NFAT)-DNA and NF-κB DNA complexes, resulting in the attenuation of NF-κB-dependent transcription, as reported by Pahlavani et al. [71]. NF-κB is known to stimulate the production of nitric oxide synthase (NOS) enzyme. As NF-κB activation is inhibited by CAPE, it implies a potential downstream impact on the NF-κB-dependent induction of nitric oxide synthase. The connection between these findings suggests that CAPE's inhibition of NF-κB activation may lead to a reduction in the production of nitric oxide (NO), a known inflammatory mediator. Inflammatory cells and endothelial cells typically generate NO in response to NF-κB stimulation (Fig. 4). Consequently, CAPE's interference with NF-κB activation could contribute to the attenuation of NO production. Since NO is implicated in inflammation and tissue damage (Table 4), the inhibition of its synthesis by CAPE may contribute to the alleviation of pain and inflammation, as noted by Bhargava et al. [112].

It has been reported that there is direct connection between propolis and its anti-inflammatory properties through the modulation of various molecular pathways and mediators. Propolis acts as an anti-inflammatory biomolecules by targeting several key components involved in the inflammatory response [91]. Firstly, propolis inhibits and down-regulates the expression of Toll-like receptor 4 (TLR4), Myeloid differentiation primary response 88 (MyD88), interleukin-1 receptor-associated kinase 4 (IRAK4), Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-β (TRIF), Nucleotide-binding oligomerization domain-like receptor protein (NLRP) inflammasomes, and NF-κB [90]. These molecules are crucial players in the signalling cascades that lead to the activation of pro-inflammatory pathways. Additionally, propolis affects pro-inflammatory cytokines such as IL-1β, IL-6, interferon-gamma (IFN-γ), and TNF-α, which are downstream targets of NF-κB and contribute to the inflammatory response. By down-regulating the expression of these cytokines, propolis further dampens the inflammatory milieu. Furthermore, propolis demonstrates the ability to reduce the migration of immune cells, specifically macrophages and neutrophils [113]. This effect may be attributed to the down-regulation of chemokines CXCL9 and CXCL10 [91]. Chemokines play a crucial role in recruiting immune cells to inflammatory sites, and by reducing the expression of CXCL9 and CXCL-10, propolis may limit the migration of immune cells, thereby attenuating the inflammatory response [91]. Therefore, propolis appears to exert its anti-inflammatory effects through a multi-faceted approach, targeting key signalling molecules, inflammasomes, transcription factors (such as NF-κB), and pro-inflammatory cytokines, as well as modulating the migration of immune cells. This comprehensive action contributes to the overall anti-inflammatory properties of propolis, as highlighted by Zulhendri [91] (Fig. 4). Tables 4 and 5 summarize the animal studies and clinical trials regarding the anti-inflammatory effects of propolis respectively.

4.9 Propolis and its effect on cancer

Propolis exhibits robust anticancer effects by orchestrating a multifaceted approach that includes the inhibition of cell proliferation and the induction of apoptosis in cancer cells (Fig. 7). This is achieved through the regulation of pivotal signalling pathways, including p53-mediated, β-catenin, ERK1/2, MAPK, and NF-κB [114]. The interference with the cell cycle is another facet of propolis's impact, attributed to its ability to induce autophagy, enact epigenetic modulations, and hinder the invasion and metastasis of cancer cells by suppressing the expression of metastatic proteins such as matrix metalloproteinases (MMPs) and curtailing neo-angiogenesis [114].

Fig. 7
figure 7

Propolis decreases the incidence of cardiovascular diseases (trachycardia, myocardium necrosis, edema, atherosclerosis) by regulating the level and activities of different enzymes (cardiac markers) by regulating the lipid metabolism (propolis decreases the level of cholesterol, triglycerides, LDL, and VLDL but increasing the level of HDL), propolis also maintains the status of gut microbiota and also decreases the oxidative stress by increasing the activities of enzymes

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Propolis's influence extends to the molecular level, where it modulates the expression of p53 proteins and ANXA7 while inhibiting the NF-κB pathway [71]. The cytotoxicity induced by propolis is evident across various cancer types, including breast cancer (MCF-7) and cervical cancer (HeLa cells), where it inhibits cancer cell secretion and growth [115]. Compounds within propolis, notably Betulin and its derivatives, contribute to retarding tumor cell growth and migration by regulating cyclin-dependent kinases (CDK) enzymes and inducing apoptosis [14].

In the realm of cancer-related inflammation, propolis emerges as a potent regulator, inhibiting inflammatory mediators such as TNF-α, iNOS, COX-1/2, LOX, PGs, and IL1-β. This multifaceted inhibition encompasses various mechanisms associated with cancer-related inflammation, as highlighted by studies. Furthermore, propolis extract demonstrates significant apoptotic effects by upregulating pro-apoptotic proteins (BAX, caspase-3, and cytochrome-c) and downregulating antiapoptotic protein B-cell lymphoma-2 (BCL2) (Fig. 7) in tested cancer cell lines [116].

Propolis's anticancer potential is attributed to specific compounds like Artepillin C (ARC) and Caffeic acid phenethyl ester (CAPE). ARC from Brazilian propolis disrupts mortalin-p53 complexes, inducing cell death. CAPE, on the other hand, exhibits antitumor activity against fibroblasts in oral submucous fibrosis and oral squamous cell carcinoma, inhibiting cell transformation and inducing cell death [114]. Additionally, CAPE induces autophagy in breast cancer cells (MDA-MB-231) and disrupts various signaling networks in prostate cancer cells [117].

Through mechanisms involving neuro-feedback (NFB), B-cell lymphoma-extra-large [bcl-X (L)], and COX-2, the bioactive flavonoid galangin found in propolis exhibits anti-cancer effects [118]. It also causes melanoma cells to undergo apoptosis by way of the mitochondrial pathway and has a suppressive effect on angiogenesis in ovarian cancer cells. Another propolis component called kaempferol inhibits the growth of human prostate cancer by squelching the expression of proliferating-cell nuclear antigen (PCNA) and vascular cell adhesion molecule-1 (VCAM-1) [119] (Fig. 7).

Propolis has an effect on human breast cancer cells as well. It inhibits the expression of VEGF, EGFR, and multidrug resistance (MDR) genes. It is remarkable that CAPE plays a role in lowering the malignancy potential of breast cancer stem cells, preventing progenitor formation, clonal growth, and self-renewal, as well as dramatically lowering CD44 expression. Additionally, it has been shown that essential oils extracted from Xinjiang propolis can cause cell cycle arrest and apoptosis in the human colorectal cancer cell line HTC-116 [120]. The animal research and clinical trials on propolis’s anticancer effects are summarized in Tables 4 and 5, respectively.

4.10 Propolis as a cardio protective remedy

Cardiovascular diseases are the leading cause of death worldwide, resulting in a huge financial burden and a major reduction in the quality of life for those who suffer from them. Propolis regulates the metabolism of glucose and lipoprotein, modulatesexpression of genes, reduces scavenger receptor activity (Fig. 8), suppression of inflammatory cytokines, and mitigation of oxidative stress [121]. Additionally, propolis has been found to enhance endothelial function and inhibit platelet aggregation [121]. In the intricate process of atherosclerosis, involving the accumulation and modification of plasma lipoproteins, propolis emerges as a potential preventive strategy for cardiovascular disorders (Table 4). Numerous studies indicate that dietary polyphenols, such as those found in propolis, may mitigate the risk of cardiovascular diseases and impede the development of atheromatous plaques. Notably, propolis has been shown to modulate lipid metabolism, reducing liver cholesterol and triglyceride content, as well as improving the serum lipid profile in animal models [122]. Recent studies have explored propolis’s preventive role in atherosclerosis, particularly in LDL receptor knockout mice (LDLr − / −). Different types of propolis extracts, rich in polyphenols, exhibited inhibitory effects on the area of atherosclerotic lesions when administered preventively. The most significant impact was observed with Brazilian red propolis, leading to both a reduction and regression of atherosclerotic lesions. The polyphenols in propolis contributed to these effects by improving the lipid profile and down-regulating pro-inflammatory cytokines, chemokines, and angiogenic factors. Propolis influences the lipid profile by diminishing total cholesterol and elevating HDL-cholesterol levels (Fig. 8). The proposed mechanism involves the upregulation of the ABCA1 receptor, associated with increased HDL levels [123]. Ethanol extracts of Brazilian red propolis (EERP) demonstrated enhanced ABCA1 promoter activity and increased cholesterol efflux [123]. Platelet aggregation, a key player in the atherosclerotic process, is influenced by propolis components, with CAPE notably inhibiting collagen-stimulated platelet aggregation [124]. Additionally, propolis regulates the levels of nitric oxide (NO), a crucial vasoactive mediator, protecting blood vessels when released in controlled concentrations. Propolis achieves this by decreasing NOS activity, thereby reducing oxidative and/or nitrosative stress. Moreover, propolis exhibits anti-inflammatory activities by inhibiting NO production and modulating NO levels in cardiovascular inflammatory processes. It also impacts the proliferation of vascular smooth muscle cells (VSMCs), a process implicated in atherosclerosis, with propolis components inhibiting VSMC proliferation in a dose-dependent manner [125]. Thus, propolis demonstrates multifaceted actions in preventing atherosclerosis, affecting lipid metabolism, platelet aggregation, nitric oxide levels, and the proliferation of vascular smooth muscle cells. These findings underscore the potential utility of polyphenols from propolis in the prevention of cardiovascular diseases (Fig. 8). Tables 4 and 5 summarize the animal studies and clinical trials regarding the cardioprotective effects of propolis respectively.

Fig. 8
figure 8

Propolis controls the different phases of cell cycle, prevents abnormal proliferation of cells, and induces apoptosis of cancer cells by activating the β-catenin, ERK1/2, MAPK, PI3K/AKT and NF-κB apoptotic pathway. Moreover, propolis also prevents the damage of cellular membrane and nuclear DNA induced by the free radicals. Propolis also induces the formation of apoptosome to accelerate the programmed cell death of abnormally proliferating cells

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4.11 Immunomodulatory effect of propolis

Propolis, with its constituents like CAPE, cinnamic acids, and artepillin C, significantly impacts nonspecific immunity by influencing the activity of neutrophils and monocytes/macrophages [113].Neutrophil leukocytes are crucial in nonspecific immunity, while monocytes/macrophages provide defense against microbial infections (Table 4). Phagocytosis is a key mechanism. Studies show propolis enhances phagocytic activity and motility of neutrophils and monocytes, activating peritoneal macrophages and increasing their responsiveness to IFN-γ, thereby enhancing their bactericidal activity against pathogens [95].

Propolis, a plant-based plant, has been found to improve phagocytosis in macrophages infected with Staphylococcus aureus, increase bactericidal activity against Salmonella typhimurium, and exhibit immunostimulatory effects on parasitic infections, fungal infections, and fungal diseases [113]. Its effects extend beyond phagocytosis to include anti-inflammatory and antioxidant properties. Propolis, a plant rich in phenolic acids and flavonoids, acts as a free radical scavenger and inhibits inflammatory mediator production by monocytes and neutrophils. Propolis is a potent immunomodulator that regulates cytokine secretion, reducing pro-inflammatory cytokines and inhibiting chemokines, making it a promising candidate for further research in immunotherapy (Fig. 3), as it enhances phagocytosis and reduces inflammation [126].

T and B cells are essential in peripheral blood mononuclear cells (PBMC), playing a crucial role in adaptive immune defense against infections. They interact with various antigens, forming distinct populations with unique immune functions, ensuring overall health. Bacteria are engulfed by macrophages, recognized by MHC II, which binds to CD4 + T lymphocytes, initiating immune activation. These cells express cytokines, regulating cellular growth and differentiation, and optimizing the immune response. Cytokines, primarily produced by CD4 + cells, play a crucial role in the development of humoral and cellular immunity, activating CD8 cytotoxic T cells and B cell activation. Propolis significantly impacts monocytes and T and B lymphocytes in immunomodulation. It stimulates lymphocyte proliferation but can also act as immunosuppressants, with concentration-dependent effects. Researchers study propolis's mechanisms on T lymphocytes. CAPE, a phenolic compound in propolis, effectively inhibits T cell activation by targeting NFAT and NF-κB transcription factors, affecting IL-2 gene transcription and CD25 expression [91, 113]. Propolis induces IL-2 production in PBMC, stimulating T cell activation and cellular and humoral immunity. It alters CD69 expression, with concentration-dependent effects. In vivo experiments show propolis stimulates T lymphocyte proliferation and enhances IL-2, IL-4, and IFN-γ secretion, bolstering immunity and improving inactivated vaccine efficacy. Propolis, including artepillin C, has potential for immunosuppressive therapy, particularly in graft-versus-host disease, by balancing immune responses during bone marrow transplants and suppressing cancer cells. Propolis's complex relationship with the immune system, including its inhibitory effects on leukemic cell growth and positive influence on granzyme expression in T cells, makes it a versatile therapeutic agent for both infectious and neoplastic diseases [113].

NK cells, a crucial lymphocyte subpopulation, exhibit higher resistance to Bulgarian propolis compared to Th and Tc cells. CAPE treatment reduces NK cell vitality, indicating a concentration-dependent impact on these cells, making them a cornerstone of host defense mechanisms [91]. It has been studied that propolis effect on NK cells is context-dependent, with some studies showing increased activity in rats, while others show no significant effect in aged mice. Propolis has potential antitumor effects due to its immune-modulating properties, including activation of macrophages, modulation of B and T lymphocytes, enhancement of NK cells, antibody proliferation, and cytokine production [127]. It also exhibits regulatory effects, including down-regulation of TLR-2 and HLA-DR expression. Propolis extracts have been found to have cytotoxic effects on Ehrlich carcinoma in mice and colon carcinogenesis in rats [126]. Propolis-activated macrophages increase cytokine production, enhancing NK cell cytotoxicity against tumor cells. Artepillin C, a propolis component, exhibits direct antitumor activity, modulating CD4 to CD8 T cell ratio [113].

Basophils and mast cells are crucial in allergic diseases like asthma. They produce IgE antibodies, triggering B lymphocytes to switch antigen-specific antibody classes and secrete IL-4. IgE antibodies bind to mast cells and basophils, releasing inflammatory mediators. Clinical studies show promising anti-allergic activity of propolis, with asthma patients showing reduced nocturnal attacks and improved ventilatory functions, and Brazilian green propolis inhibiting IgE production and inflammation. Propolis, a plant extract, has anti-allergic properties, inhibiting histamine release in mast cells and basophilic leukaemia cells. Chinese propolis extracts, containing chrysin and kaempferol, also impact immune response production [128]. Propolis has immunomodulatory and anti-inflammatory properties, affecting immune cells through signalling pathways and transcription factors. It activates immune cells but also has immunosuppressive effects. Propolis composition varies geographically, with CAPE in temperate zone and artepillin C in tropical regions. Tables 4 and 5 summarize the animal studies and clinical trials regarding the immunomodulatory effects of propolis respectively.

4.12 Wound healing effects

Wound healing is a vital physiological response to tissue injury, involving the replacement of damaged tissue with living one, despite advancements in understanding. It has been reported that propolis alcoholic extract is used as an ointment to wound healing, comparing it to a standard drug ointment. Key parameters like wound contraction, collagen, and protein were analyzed. The wound healing process involves inflammatory, proliferative, and remodeling phases. It has been reported that propolis extract significantly accelerated wound closure and contraction, with nearly 90% contraction observed in 14 days [129].This was due to increased collagen synthesis, faster wound healing, and improved tissue strength. The decrease in matrix molecules correlated with increased collagen content. Propolis, with its antioxidant properties, may help reduce oxidative stress during wound healing by enhancing protein synthesis and reducing DNA, RNA, and protein levels in treated wounds (Fig. 9). Propolis is rich in flavonoids, has been identified as a potential natural product for wound healing (Fig. 9 and Table 4). Its synergistic actions, including lipid peroxidation reduction and improved vascularity, make it a promising candidate for overcoming chronic wound defects [130]. Tables 4 and 5 summarize theanimal studies and clinical trials regarding the wound healing effectsof propolis, respectively.

Fig. 9
figure 9

Propolis is used in the formulation of different ointments and wound healing remedies due to its antimicrobial, antifungal, antibacterial and antioxidant activities. Propolis increases the process of angiogenesis and increases the secretion of anti-inflammatory cytokines; moreover, propolis along with honey increases the process of collagen formation that helps in the contraction and healing of wound

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5 Conclusion

The wealth of bioactive compounds within propolis, including flavonoids, phenolic acids, and terpenes, underscores its diverse therapeutic potential. Since ancient times, humans have used propolis as a remedy, primarily applying it as an antibacterial agent for treating wounds. Over the years, research spanning from earliest observations to recent experiments utilizing advanced molecular biology techniques has shed light on the diverse potential of propolis in wound management. Various forms of propolis have demonstrated efficacy in expediting the wound healing process and enhancing healing physiology, largely attributable to its immunomodulatory, antioxidant, anti-inflammatory, and antimicrobial properties. Additionally, its versatility extends its potential applications to various medical fields, including oncology, dermatology, and dentistry.

5.1 Future scope

There is a extreme need for increased clinical trials examining both propolis in isolation and its key active components. Moreover, therapeutic potency of propolis against common human pathogens and its potential role in inhibiting cancer development warrants investigation at in vitro and in vivo experimentation on animal models. Additionally, there is an intriguing avenue for research into advancing and standardizing novel methods of propolis delivery, such as utilizing nanotechnological approaches to develop specialized dressings. Further studies are warranted to validate the synergistic potential between conventional medications and propolis, which could pave the way for innovative adjunctive therapies. Overall, given the substantial volume of scientific literature on propolis in recent years, it is reasonable to anticipate that more in-depth research may unveil additional properties of propolis and expand its potential clinical applications. Crucially, the validation of traditional applications of propolis from folk medicine through modern research methodologies and clinical trials underscores its therapeutic promise.

6 Limitations

Nevertheless, before propolis can be widely integrated into medical practice, several challenges stemming from its inherent characteristics must be addressed. The primary obstacle lies in the variability in the chemical composition of propolis across different geographical regions, significantly impeding the standardization of propolis preparations. Standardization is paramount not only for healthcare practitioners but also for ensuring the reliability of research findings on propolis properties. One approach to standardization involves focusing on the concentration of key active constituents of propolis, believed to exert a synergistic effect [160, 161]. Additionally, determining the most optimal extraction methods, formulations, and modes of administration for propolis tailored to specific diseases presents another challenge to be tackled.

6.1 Summary of propolis biological and pharmaceutical importance

This review comprehensively explored the dynamic pharmacological potency and multifaceted biological activities exhibited by propolis, a natural resinous substance synthesized by bees. Propolis is rich in bioactive compounds, including flavonoids, phenolic acids, and terpenes, contributing to its diverse pharmacological effects. The documented antimicrobial properties highlight its potential in combating infectious agents, while its anti-inflammatory attributes suggest therapeutic applications in inflammatory conditions. Propolis emerges as a potent antioxidant, with the ability to neutralize free radicals and mitigate oxidative stress, a key factor in various pathological processes. Additionally, the immunomodulatory properties of propolis underscore its potential to modulate immune responses, offering implications for autoimmune disorders and immune-related conditions. This scientific exploration delves into the intricate mechanisms underlying propolis' interactions with biological pathways, providing valuable insights into its mode of action. The adaptability of propolis to different environmental conditions further underscores its appeal as a pharmacologically rich natural product. In conclusion, this review consolidates current knowledge on propolis, highlighting its promising pharmacological potential. The multifaceted biological activities exhibited by propolis position it as a compelling subject for further research, with implications for drug development and therapeutic interventions in various health contexts.

7 Future directions for research

7.1 Elucidation of mechanisms

Investigate and unravel the precise molecular and cellular mechanisms underlying the diverse pharmacological effects of propolis. A comprehensive understanding of these mechanisms will provide insights into specific targets and pathways, facilitating the development of more targeted therapeutic interventions.

7.2 Standardization of propolis extracts

Establish standardized methodologies for the extraction and characterization of bioactive compounds from propolis. This will ensure consistency in research outcomes and enable comparisons across studies. Standardization is crucial for advancing propolis from a traditional remedy to a scientifically validated therapeutic agent.

7.3 Clinical trials

Conduct well-designed clinical trials to evaluate the safety and efficacy of propolis in human subjects. Rigorous clinical studies will provide valuable data on dosage, administration routes, and potential side effects. This step is essential for translating preclinical findings into evidence-based medical practices.

7.4 Synergistic effects with pharmaceuticals

Explore potential synergistic effects between propolis and conventional pharmaceuticals. Investigate whether propolis can enhance the efficacy of existing drugs or reduce their side effects, opening avenues for combination therapies that maximize therapeutic outcomes.

7.5 Exploration of novel applications

Investigate novel applications of propolis beyond its traditional uses. Explore its potential in emerging areas such as neurodegenerative diseases, metabolic disorders, and cancer. Systematically explore different formulations and delivery methods to enhance bioavailability and therapeutic efficacy.

7.6 Identification of biomarkers

Identify biomarkers associated with propolis responsiveness and efficacy. This will enable personalized medicine approaches, allowing for targeted propolis interventions based on individual patient characteristics.

7.7 Ecological and geographical variability

Investigate how ecological and geographical factors influence the composition and pharmacological properties of propolis. Understanding these variations can lead to the identification of specific chemotypes with enhanced therapeutic potential.

7.8 Safety profiles

Systematically evaluate the safety profiles of propolis, especially with prolonged use. This includes assessing potential interactions with medications and understanding any contraindications, ensuring its safe integration into diverse healthcare practices.

By addressing these research directions, the scientific community can unlock the full therapeutic potential of propolis and pave the way for its integration into mainstream medicine. This approach holds promise for developing innovative treatments and expanding the scope of propolis in healthcare practices.