Diabetes (DM) is one of the chronic diseases that develop due to severe inflammation and manifests in an increase in pro-inflammatory cytokines and chemotaxis mediated by B and T lymphocytes, such as IL-1β and TNF-α, leading to insulin resistance (36). In mice model, the immunomodulatory activity of propolis was found to improve the innate immune response. It induces the up-regulation of Toll-like receptors 2 (TLR-2) and TLR-4, which leads to the activation of lymphocytes, and CCL21- and CXCL12-mediated chemotaxis by B and T lymphocytes. Also, propolis helps to restore the levels of IL-1β, IL-6, Il-2, Il-7, and TNF-α (37, 38). In diabetic male rats model, propolis decreases serum immunoglobulin (IgG, IgA, and IgE), that controls B and T lymphocyte proliferation (39). The peptic bee pollen polysaccharide (RBPP-P) of Rosa rugosa shows a regulatory effect toward certain pro-inflammatory cytokines that raise insulin resistance, e.g. TNF-α and IL-6. Treatment with RBPP-P decreases TNF-α and IL-6 levels, resulting in less insulin resistance observed in the tissues of mice fed with a high-fat diet (40).

Furthermore, DM is characterized by hyperglycemia, glycosuria, and dyslipidemia. Dyslipidemia and hyperglycemia induce the propagation of reactive oxygen species (ROS), which lead to cellular dysfunction and oxidative injuries, especially to the heart, kidney, and liver tissues (41). Propolis, royal jelly, and bee pollen act against the oxidative stress that arises in different diseases, e.g., DM (42). Propolis has anti-hyperglycemia, dyslipidemia, and antioxidant properties, which could be attributed to its polyphenolic content, e.g., α-amylase, α-glucosidase, and caffeic acid phenethyl ester (CAPE) (43, 44). Propolis improves lipid profile metabolism and decreases the ROS levels in blood, liver, and lymph nodes (45). Intraperitoneal administration of water-soluble-derivative of propolis (WSDP) or (–)-epigallocatechin gallate (EGCG) (50 mg/kg/day) in alloxan-induced diabetic mice for 7 days lead to reduce in lipid peroxidation in liver, kidney, brain tissues, and reduce DNA damage in peripheral lymphocytes of diabetic mice (46). WSDP and ethanolic propolis extract increased the animal body weight and the life span of treated mice vs. the untreated mice mediated by the improvement of the fatty acid metabolism impairment (47). In addition to this, propolis significantly controls body weight and bone homeostasis (48). An ethanolic extract of propolis has reduced hyperglycemia and protected the pancreatic and renal tissue of STZ-induced diabetic rats that received 30 or 15% propolis extract at a dosage of 50 ml/kg for 4 weeks. Blood sugar levels decreased from 393 ± 192.7 to 154 ± 28.0 mg/dl and from 386 ± 141.1 to 331.5 ± 123.74 mg/dl, was observed in the diabetic groups treated with 30 and 15% propolis, respectively. An improvement at the pancreatic, hepatic, and renal tissue levels was seen in both groups treated with propolis compared with the control group. The IC₅₀ results for α-amylase (0.62 ± 0.00 μg/ml) and α-glucosidase (40.40 ± 0.09 μg/ml) whereas, CAPE and chrysin were the dominant phenolics (43). Bee pollen or date palm pollen suspension (100 mg/kg) administration for four weeks has shown to reduce body, testis, and pancreas weight and insulin resistance in STZ-induced diabetic Wistar male rats. The protective effect of bee pollen was found to be associated with a decrease in NO and LPx-biomarkers of oxidative stress and increase in glutathione (GSH), GSH-S-transferase, GSH peroxidase, and superoxide dismutase (SOD) antioxidant defense markers (49).

Propolis, royal jelly, and honey have been the subject of various clinical studies, as shown from the data presented in Table 1. Propolis administrated at different doses (300 and 400 mg) has shown to aid in the modulation of the glycemic mediators fasting serum glucose (FSG) and glycosylated hemoglobin A1C (HbA1C) in subjects with type 2 DM (T2DM) (51, 52). Meanwhile, the oral administration of encapsulated propolis has enhanced liver and kidney functions as well as lipid profiles by increasing high density lipoprotein (HDL) levels and glucose metabolism and decreasing the levels of HbA1C by 8%, 2-h postprandial (2 hpp), homeostasis model assessment of β-cell function (HOMA-β), and TNF-α as shown in Table 1 (55). The oral administration of encapsulated royal jelly (1,000 mg) three times per day for eight weeks has led to a decrease in glucose (−9.4 ± 13.5 mg/dL vs. 4 ± 8.2 mg/dL in the placebo group) and an increase of serum apolipoprotein A-I (ApoA-I) (34.4 ± 53.3 mg/dL vs. −1.08 ± 32.6 mg/dL in the placebo group) levels and thus diminish the risk of cardiovascular diseases (CVDs) in patients with T2DM (53). Figure 2 outlines the therapeutic potential of bee products in preclinical and clinical studies of diabetes, how different factors influence them, and how they are associated with the underlying pathogenesis.

In the 19^th century, the detection of leukocytes in tumor cells was the first indication of the link between cancer and inflammation since 20% of cancers could be attributed to inflammation. Inflammation is involved in the different steps of tumor development, e.g., initiation, promotion, malignancy, invasion, and metastasis (58). The term chemoprevention describes the inhibition of the processes of mutagenesis, carcinogenesis, proliferation, and the progression of tumor cells using natural or synthetic compounds (59, 60).

Honey and its polyphenolic compounds, e.g. pinobanksin, pinocembrin, luteolin, galangin, chrysin, and quercetin (3,3′,4′,5,7-pentahydroxyflavanone), shown to have anti-inflammatory, immunomodulatory, anti-proliferative, and anti-metastatic properties. They were found to induce apoptosis and showed antioxidative activity toward several cancer types (61). Tyrosine-phosphorylated signal transducer and transcription three activator (p-STAT3) is a major player in lung and breast cancer (62). Manuka honey (MH) has shown to have an inhibitory effect on p-STAT3 in the triple-negative breast cancer cell line MDA-MB-231 and non-small cell lung cancer cell line A549. MH targets the IL-6 receptor α chain (IL-6Rα), preventing its binding to IL-6 by ~60%, thus decreasing the level of glycoprotein (gp130) and tyrosine-phosphorylated JAK2, which are important components of IL-6Rα. Galangin, chrysin, quercetin, and luteolin are the major flavonoid compounds in MH that can inhibit the binding of IL-6Rα and IL-6 by 34.3, 31.8, 29.2, and 22.4%, respectively, at a concentration of 50 μM (63).

Propolis containing mainly polyphenolic compounds has exhibited chemoprevention and tumor growth inhibition abilities, as well as antioxidant, pro-oxidant, and immunoprotective properties (64–66). These compounds have been reported to induce apoptosis, inhibit matrix metalloproteinase, regulate cell proliferation by promoting cytotoxicity, modulate gene methylation (67), and exhibit anti-inflammatory and anti-angiogenic activities toward urothelial and bladder cancer (68). WSDP and its polyphenolic compounds caffeic acid (CA) and CAPE show immunomodulatory properties and control the growth and spread of tumors. The administration of WSDP, CA, and CAPE at dose 50 or 150 mg/kg via intravenous injection into mice with mammary carcinoma was shown to decrease the number of colonies. In contrast, subcutaneous administration inhibited tumor growth and increased the survival of the mice. In the proposed mechanism, the phenolic compounds initiate the anti-tumor activity of macrophages, which help to block the metastasis process and increase hydrogen peroxide production, which modulates lymphocyte function. This is in agreement with the inhibition response of spleen cells toward the administration of polyclonal mitogens (phytohemagglutinin (PHA), concanavalin A (ConA), pokeweed mitogen (PWM), and LPS in mice treated with CA (65). WSDP inhibits IL-1, which is associated with B and T cell proliferation (65).

Also, 10-HDA in royal jelly exhibits anti-inflammatory properties toward human colon adenocarcinoma cells. 10-HDA inhibits the production of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-8 in WiDR human adenocarcinoma cell (BCRC 60157). Receptor antagonist cytokine (LI-1ra) production induced by 10-HDA at doses of 0.1–3 mM helps to reduce tumor growth and stop the production of IL-8 and IL-1, which are causative factors in the development of some cancers, including pancreatic and colon carcinoma (69). CAPE causes distinctive changes to breast cancer stem cells (bCSCs) as it halts the generation of malignant cells by suppressing their self-generation and CD44 clonal expansion. Additionally, the results suggest that MDA-231-derived bCSCs treated with CAPE are less susceptible to malignant infections (70). TRAIL is an effective endogenous anticancer agent that promotes apoptosis, especially of tumor cells. An ethanolic extract of green propolis promote TRAIL-mediated apoptosis in LNCaP prostate cancer cells via the modulation of the intrinsic and extrinsic apoptotic pathways and alteration of the NF-κB activity. Brazilian green propolis able to enhance TRAIL-mediated apoptosis, which could be one of the mechanisms responsible for its cancer-preventive properties. The major components of Brazilian green propolis determined by high-performance liquid chromatography (HPLC) including; quercetin, artepillin C, kaempferol (KAE), and p-coumaric acid. Brazilian EEP at 50 μg/mL and its components exhibit better free radical scavenging than the other compounds in the propolis extract at 50 μg/mL. Quercetin was the most bioactive compound that induces cell death and apoptosis toward LNCaP (71). Collectively, galangin, chrysin, CA, CAPE, and 10-HDA are the common bioactive components of bee products that show anticancer activity (Figure 3).

Despite its potential anticancer activity, clinical studies/trials on propolis are limited due to its poor physicochemical properties and oral bioavailability. Thus, the encapsulation of propolis extract in nanoparticle systems has been suggested. Through a well-designed polymeric architecture, propolis encapsulation in nano-in-microparticles (NIMs) enhances bioavailability, therapeutic efficiency, and controlled drug release. Nano spray drying is a method for producing polymeric nanoparticles, microparticles, and NIMs that contain a variety of bioactive compounds and drugs. The prepared spray-dried NIMs of propolis extract have been supplemented orally for the treatment of colon and liver cancer and were found to promote the cytotoxicity of human liver (HepG2) and colon (HCT-116) carcinoma cell lines (67, 72).

The application of propolis and lycopene extract nanoemulsions is safe and has been shown to have a highly protective effect on skin cells against UV irradiation, which induces different skin cancers via erythema and pigmentation. Nanoemulsions have been widely applied in the delivery of poorly soluble drugs. Nanoemulsions have been shown to increase solubility, kinetic stability, and decrease collagenase activity (73). Also, the trapping of bee venom components in nanoparticles may help to reduce its unselective toxicity and improve its prospects for application as a therapeutic anticancer agent (74).

Anti-inflammatory and antioxidant properties of honey, propolis, royal jelly, and bee pollen can explain the impact of bee products against different types of cancer. As demonstrated in Table 2, honey and propolis are used to treat oral mucositis, lymphoblastic leukemia, and head and neck malignancies, whereas bee pollen is used to treat renal cell carcinoma (75, 77–81). Additionally, propolis and honey reduced the risk of oral mucositis induced by undergoing radiotherapy treatment, as shown in Table 2. The anti-oxidant and anti-inflammatory activities of encapsulated royal jelly (400 mg) were studied and proven protective against the fatigue and anorexia induced by tyrosine kinase inhibitors (TKIs) in patients with renal cell carcinoma (RCC) (76).

Inflammation is a common predisposing factor of atherosclerosis and hypertension, and consequently, CVDs. Hypertension is a global problem and one of the leading causes of CVDs e.g., cerebral stroke, acute myocardial infarction, and heart failure. The renin–angiotensin system (RAAS) is essential in regulating blood pressure and maintaining inflammatory processes in CVDs. The use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers, and direct renin inhibitors to inhibit RAAS pharmacological action is effective in the treatment of hypertension (82).

The antioxidant properties of bee pollen polyphenols have been shown to play an important role in inhibiting the angiotensin-converting enzyme. The supplementation of bee pollen extract (0.1 and 1 g/kg for 16 weeks) decrease the high levels of ACEIs and angiotensin II-induced by high-fat diets in C57BL6 mice, leading to an enhancement in endothelial function due to the modulatory effect it has on RAAS (Figure 4) (83). It has also been noted that protease N-treated royal jelly (Pro-RJ) with Ile–Tyr (IY), Val–Tyr (VY), and Ile–Val–Tyr (IVY) shows high inhibitory activity toward ACEIs. The oral administration of Pro-RJ peptide (IY, VY, or IVY) or a peptide mixture (IY, VY, and IVY) for 28 days was shown to yield anti-hypertensive activity. The long-lasting hypotensive activity of royal jelly protein (RJPH) has been attributed to its small molecular weight peptide content and its fast digestion time (84, 85). Major RJPH 1 (MRJP1) is another bioactive component of royal jelly that has shown anti-hypertensive activity. MRJP1 exhibits a high regulatory effect on blood pressure via its action on vascular smooth muscle cells (VSMCs). The MRJP1 shows a protective effect against the contraction, abnormal migration, and proliferation of VSMCs by reducing their movement and energy supply. VSMCs regulate blood pressure as they play the main role in blood vessel contraction and relaxation. Also, the proliferation of VSMCs and the increase in its numbers leads to a reduction in the blood vessel diameter, which in turn affects blood flow (86).

The pathophysiological condition of hypertension is manifested by the decrease in NO production, prostacyclin, and endothelium-derived hyperpolarizing factor, which are endothelium-derived relaxing factors of vascular endothelial cells. Royal jelly has a muscarinic receptor agonist effect that is similar to acetylcholine, which increases NO formation and vasorelaxation via the NO/cGMP pathway and calcium channels. An increase in NO formation promotes vasodilation and hypotension (84). A total of 200 mg/kg of propolis supplementation has reduced oxidative stress in hypertensive rats treated with NO-nitro-L-arginine methyl ester NO synthase inhibitor (Figure 4). ROS causes NO loss by its conversion into a peroxynitrite oxidant. The antioxidative effect of propolis helps in reducing ROS, increasing the levels of NO synthesis, and enhancing the endothelial function (87).

In clinical studies, it was reported that the utilization of mouthwash containing propolis causes a reduction in the harmful effect of oral bacteria, hence disrupting NO levels and leading to a decrease in blood pressure (88).

Periodontal disease is a phenomenon where the periodontal tissue accumulates bacterial plaque followed by a secondary immune and inflammatory response (89). The anti-inflammatory, antioxidant, antibacterial, anti-caries, and antiplaque properties of propolis support its use in preventing and treating a variety of oral disorders, including dental plaque, gingiva, caries, and oral cancer (90, 91). The formation of dental caries is a chronic process in which a chemical interaction occurs between acid-producing tooth-adherent bacteria and fermented carbohydrate, resulting in dental decay. The most popular pathogenic factor is the high consumption of sugars, as a high number of microorganisms, especially S. mutans, which is the most predominant carcinogenic factor in caries (92). The anti-caries and antiplaque activities of crude extracts or hexane fractions of Brazilian propolis have been tested in vitro and in vivo. The suggested mechanism for the anti-caries activity of propolis is related to the antibacterial action against S. sobrinus and S. mutans and the inhibition of glucosyltransferase (GTF) enzyme (90, 93). Propolis extracts' cariostatic effects are linked to GTF inhibition rather than antibacterial activity (90). For five weeks, the rats were given hexane fraction of propolis topically twice a day. In in vivo study, the fraction greatly reduced the incidence of smooth surface caries while maintaining the percentage of S. sobriuns biofilms in the animals' plaque. The high fatty acid content of Brazilian propolis comprising palmitic, oleic, and stearic acids, enables it to exhibit highly potent anti-caries activity when incorporated in a rat diet (93).

The other components in propolis, e.g., CAPE and quercetin exhibit anti-caries properties. CAPE has an antibacterial effect on the most prevalent oral bacteria (S. mutans, S. sobrinus, Actinomyces viscosus, and Lactobacillus acidophilus) and contributes toward a decrease in the formation of biofilms, as well as reducing their thickness. The antibacterial effect of CAPE is mostly observed toward S. mutans. It has been suggested that CAPE penetrates the thick extracellular matrix biofilm and damages the cells, increasing the number of dead bacteria. When administered at half of its minimum inhibitory concentration (MIC), CAPE has been shown to reduce the acidity of S. mutans at pH 5, resulting in cell death (94). Quercetin in the Ardabil EEP with a MIC value in the range of 3.12–100 μg/mL was shown to inhibit the growth of oral streptococci and reduce biofilm formation (95). Topical treatment of red propolis (800 μg/mL) in the form of neovestitol–vestitol has been shown to prevent the formation of biofilm and reduce the bacteria-derived exopolysaccharide (EPS)-rich matrix building of biofilm. The proposed mechanism of action for this is via the inhibition of the GTF-derived EPS enzyme activity, which contributes toward the development of EPS by producing soluble glucan or suppressing certain genes linked with the stress and survival of S. mutans (96). Topical application of an EEP varnish (15% propolis) or its bioactive fraction twice a day for 4–5 weeks on rat teeth has been shown to exhibit anti-caries activity comparable to that of the drug conventionally used to treat caries, GS/Duraphat^®. Also, no toxic effects on fibroblast or osteoblast cells were observed (90).

The protective and treatment effects of propolis as anti-caries, anti-dental plaques, and anti-gingivitis in periodontal diseases have been detected in various clinical studies (Table 3). Propolis or extract reduces dental biofilm formation, raises salivary pH, reduces plaque formation, and protects the oral cavity from bacterial infection (97, 98, 103).

Vomiting, nausea, postprandial abdominal pain, and weight loss are typical symptoms associated with peptic ulcer. The term “peptic ulcer” refers to the irritation of the digestive tract, mostly of the stomach or proximal duodenum wall because of the hyper secretion of peptic acid. The use of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin, and Helicobacter pylori infections could all lead to peptic ulcers (5). H. pylori are Gram-negative bacteria that infect the human mucosa. H. pylori as a causative factor in gastric inflammatory, ulcers, and cancers stimulate the expression of the outer membrane proteins related to epithelial gastric cells (142). Bacterial honey, Bacillus subtilis, is a source of different types of levans. Bacillus sp. levan (200 mg/kg) has been shown to act as a probiotic agent against gastric ulcers induced by ethanol in adult male Sprague–Dawley rats. The probiotic activity of levan enables it to cover the stomach epithelial cells and prevent the adhesion of H. pylori (143). The suggested mechanism of the gastro-protective effects of propolis and its isolated metabolites drupanin, artepillin C, kaempferide, and aromadendrin-4-O-methyl-ether are mostly associated with their anti-inflammatory, antioxidant, and inhibitory properties toward gastric secretion (144).

The administration of hydroalcoholic extracts of red propolis (HERP, 250 and 500 mg/kg) or its formononetin isoflavonoid (10 mg/kg) has provided protection against ulcer formation, decreased the volume of gastric secretions, and led to healing the damaged areas of the mucosa in a dose-dependent manner. HERP has been shown to inhibit H. pylori infection and decrease the diameter of the affected zone by 13.0 ± 2.0 mm at 100 mg/mL (145). The MAPK and NF-κB pathways promote the pathogenic action of H. pylori. An ethanolic extract of Korean propolis has reduced levels of pro-inflammatory interleukins, such as IL-12, IL-8, IL-1β, and COX-2 via the inhibition of the MAPK and NF-κB pathways (146). KAE (160 mg/kg) causes a decrease of TNF-α by 48% and IL-1β by 37% in the gastric ulcer. It also increases the level of NO vasodilator factor and increasing the blood flow to the gastric mucosa (147).

Bee venom has been shown to exhibit anti-inflammatory and anti-apoptotic properties and have a protective effect against NSAID-induced gastric ulcers. An intraperitoneal injection of 2 mg/kg of bee venom into Sprague–Dawley rats with ASA-induced peptic ulcers has been shown to reduce the levels of pro-inflammatory cytokines, such as TNF-α and maintain normal levels of antioxidant enzymes, such as SOD and GSH. In addition, it decreases the expression of caspase-3 and B-cell lymphoma associated X, and enhances the recovery of mucosal damage and inhibiting apoptosis in gastric cells (148). Propolis, honey, and bee venom mostly demonstrate protective and healing effects on peptic ulcers because of their anti-inflammatory, antioxidant, and antimicrobial properties (Figure 5).