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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Natural Product Chemistry
- Sprache: Englisch
Frontiers in Natural Product Chemistry is a book series devoted to publishing monographs that highlight important advances in natural product chemistry. The series covers all aspects of research in the chemistry and biochemistry of naturally occurring compounds, including research on natural substances derived from plants, microbes and animals. Reviews of structure elucidation, biological activity, organic and experimental synthesis of natural products as well as developments of new methods are also included in the series.
Volume nine of the series brings together 7 reviews on a variety of natural products and sources along with a chapter on the basics of investigating antioxidant activity.
Propolis and its key chemical constituents: a promising natural product in therapeutic applications
Investigation of the effects of using omega-3 fatty acids on egg quality in functional egg production
Quercetin, a flavonoid with remarkable anticancer activity
Swertiamarin for the treatment of metabolic syndrome
Overview of traditional uses, phytochemistry and pharmacology of Peganum harmala l.
Investigation of measurement methods of antioxidant activity and involved mechanisms
Recent progress on natural and synthetic flavanone and its derivatives
Role of virgin coconut oil as a multiple health promoting function oil
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Seitenzahl: 483
Veröffentlichungsjahr: 2022
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PREFACE
Frontiers in Natural Product Chemistry presents recent advances in the chemistry and biochemistry of naturally occurring compounds. It covers a range of topics, including important research on natural substances. The book is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information regarding bioactive natural products.
The chapters in this volume are written by eminent authorities in the field. Sathiyanarayanan et al. present a detailed review of the therapeutic potential of Propolis and its isolated key chemical constituents in chapter 1. Bölek and Tosya, in chapter 2, examine the effects of using omega-3 fatty acids on egg quality in functional egg production. Kumar et al. summarize the anticancer activities of Quercetin (QCT) on various cancer cells in chapter 3 of the book. Ahmad, in chapter 4, suggests that swertiamarin could be considered as a potential therapeutic agent for the treatment of metabolic syndrome. Bhardwaj et al., in the next chapter summarize the various traditional uses, pharmacological properties, and phytochemistry of Peganum harmala L. In chapter 6, Sahari and Ardestani discuss the methods of measurement of antioxidant activity and involved mechanisms. Pirani et al. explain the recent progress in natural and synthetic flavanones and their derivatives in the next chapter. Long et al., in the last chapter, discuss multiple beneficial effects of virgin coconut oil (VCO) and the mechanisms of therapeutic effects towards human health management.
I hope that the readers will find these reviews valuable and thought-provoking so that they may trigger further research in the quest for new and novel therapies against various diseases. I am grateful for the timely efforts made by the editorial personnel, especially Mr. Mahmood Alam (Editorial Director), Mr. Obaid Sadiq (In-charge Books Department), and Miss Asma Ahmed (Senior Manager Publications) at Bentham Science Publishers.
List of Contributors
Propolis and its Key Chemical Constituents: A Promising Natural Product in Therapeutic Applications
Harshad S. Kapare1,Sadhana S. Raut2,L. Sathiyanarayanan3,*Abstract
Propolis is a natural resinous and waxy product obtained from honey bee combs. Although propolis has been now explored globally for its wide range of chemical constituents and its therapeutic value, the detailed investigation of pharmacological activities of its key chemical constituents and its analogues is in its infancy. In this study, a detailed review of the therapeutic potential of propolis and its isolated key chemical constituents was carried out to provide basic literature data required for further detailed investigation and discover new therapeutic potential molecules from propolis. Till now, more than 300 isolated chemical compounds are reported from worldwide propolis samples that include the presence of various polyphenols, flavonoids, esters, beta-steroids, aromatic aldehydes, alcohols, etc. Some specific chemical constituents of propolis, such as pinocembrin, are reported for its potential neuroprotective action with reduced neurodegeneration in the cerebral cortex and enhanced cognitive function in Aβ25-35-treated mice. Galangin is also well proven for acetylcholinesterase enzyme inhibition and AβPP-Selective BACE inhibitor (ASBI), which may be developed as a new therapeutic agent for Alzheimer's disease. Caffeic acid phenethyl ester is reported as a moiety isolated from European propolis; it is present even in the form of a mixture of caffeic acid esters and phenethyl ester for antibacterial and antifungal properties. In vitro and in vivo evidence suggested that caffeic acid phenethyl ester has cytotoxic mechanisms, including the activation of p21protein, p38 MAPK, p53, and JNK kinase activity, inhibition of NF-B, and increased caspase-3 or 7 activity. Various pharmacological activities are reported for different propolis extracts, as well as for its constituents that include antioxidant, anti-ulcer, anti-cancer, antiviral, anti-microbial, anti-inflammatory, anti-fungal, etc. Propolis possesses tremendous therapeutic potential, and it is also reported worldwide in various traditional systems of medicine. In this study, the key chemical constituents, pharma-
cological activities, various critical issues in its application in drug delivery, and detailed investigation on approaches for formulation development to enhance biopharmaceutical aspects of propolis have been reviewed.
INTRODUCTION
Natural Products
Natural products have been used as medicinal agents and defensive compounds to slow the progression and effects of different diseases for thousands of years. The use of natural products is reported more than 85-90% of the population for their primary health services. About 73% of the pharmaceutical products are derived from natural products [1]. Natural product study in the pharmaceutical industry has decreased in the last 5-10 years due to the incompatibility of traditional natural product extract libraries with high-throughput screening [2].
There are some advantages of natural products as an entity in drug discovery, given as follows:
There is structural and chemical diversity in natural entities. As a result, researchers are focusing on synthesizing new chemical entities with advanced techniques, such as computational molecular modelling, etc. Due to drug-likeness and biological friendliness features, they exhibit advanced binding characteristics.
Natural product structures have biochemical specificity, making them good candidates for drug development lead structures. Enzymatic interactions are responsible for the synthesis of natural products. As a result, protein binding is involved in their biological function.
Secondary metabolites from natural products are very susceptible to have biological activity as compared to synthetic compounds [3].
Over the last few decades, developments in genomics and structural biology have revealed a complete picture of the variety of proteins targeted by natural products. Aside from these factors, emerging lead generation techniques have rekindled interest in natural products in drug development [4].
Propolis
Natural products are increasingly being used to treat a wide range of diseases. Natural products have always been used as an alternative to conventional allopathic formulations in the medical field. Propolis is one such natural substance that has gone unnoticed despite its potential applications in a wide range of diseases, such as acne, herpes simplex and genitalis, and neurodermatitis, and also in wound healing, burn treatment. The term propolis is derived from the Greek word “pro” before, and “polis” city or defender of the city [5]. The Egyptians were well aware of its anti-putrefactive properties and embalmed their cadavers with bee glue. Propolis was used as an antipyretic by the Incas. It was used by Greek and Roman physicians as a mouth disinfectant, antiseptic, and in wound healing treatments for topical therapy of cutaneous and mucosal wounds. In Folk Georgian medicine, propolis ointment was used for the treatment of diseases. There was a custom of placing a propolis cake on the belly button of a newborn baby, and they also rubbed propolis on children's toys. Propolis is widely used in folk medicine, particularly for the treatment of corns. People inhale propolis when they have respiratory tract or lung problems. It is also useful for burns and angina. Propolis has also been used successfully to treat wounds during the Anglo-Boer War and World War II; it was used as an anti-inflammatory with vaseline in the preparation of an ointment to heal war wounds. Because antibiotics were not yet available, this helped save the lives of many soldiers. It was also used in hospitals. 1969, Union of Soviet Socialist Republics (USSR) accepted the use of propolis 30% as anorthomedix medicine (30% alcoholic solution of propolis). As a result, this product has gained popularity as a traditional (folk) medicine for health improvement and disease prevention. It has also been used in mouthwash and toothpaste to prevent caries, treat gingivitis and stomatitis, as well as cough syrups, oral pills, lozenges, ointments, lotions, and vitamins. Propolis is frequently used by therapists to treat inflammations, viral diseases, fungal infections, ulcers, and superficial burns along with acupuncture, ayurveda and homeopathy [6], and the healing properties of propolis were recognized by Greek civilizations. Hippocrates, the father of modern medicine, also used propolis to treat sores and ulcers. Over the last ten years, significant research on propolis has been conducted in the United States, Australia, the United Kingdom, and Europe, particularly in Eastern Europe. Propolis is available in a variety of forms on the global market, including capsules, lozenges, tincture, cream, mouth rinses, and toothpaste [5].
In ancient times, propolis was been widely used by different cultures for various purposes, among which its use in medicine is included. Currently, research is being carried out on its activity, effects, and possible uses in biology and medicine. The most prominent are its application as a dietary supplement, its use in the pharmaceutical industry and clinical applications in animal science [5]. The physical appearance of raw propolis shows a waxy substance with yellowish-brown to dark brown colour, as shown in Fig. (1)
Fig. 1) Raw Propolis.Chemical Composition and Medicinal Properties of Propolis
Honey Bees (Apis mellifera L.) collect propolis from various plant species and mix it with wax and other substances [7]. Propolis is used as a sealant for unwanted open spaces in the hive. It has been reported that propolis is collected from resins of conifers, poplars, birch, alder, pine, willow, palm, Baccharis dracunculifolia, and Dalbergia ecastaphyllum [8-10] The chemical composition of propolis is susceptible to the geographical location, botanical origin [11-14], and bee species [14]. Propolis is made up of resin and balsams (50- 60%), pollen (5-10%), and other constituents, such as amino acids, minerals, Vitamins A and B complex, and the highly active biochemical substances known as bioflavonoids, phenols, and aromatic compounds [15]. Its gross composition is elaborated in Table 1. It mainly contains polyphenols and flavonoids, such as chrysin, apigenin, galangin, kaempferol, pinocembrin, naringenin,caffeic acid, caffeic acid phenethyl ester, cinnamic acid, p-coumaric acid, ferulic acid, and isoferulic acid, etc. The chemical structures of some important chemical constituents is shown in Fig.2 and an overview of chemical constituents with their pharmacological activities in (Fig. 3) [16].
Fig. (2)) Chemical structures of key chemical constituents of Propolis analyzed by HPLC technique.The following main chemical constituents of propolis have been reported for various pharmacological activities [25-41].
Pinocembrin
Pinocembrin (5, 7-dihydroxyflavanone) (PINO) is one of the most abundant flavonoids that is isolated from honey and propolis. PINO is probably a promising pharmacological candidate. It has a vast range of pharmacological activities, including antimicrobial, anti-inflammatory, antioxidant, anti-cancer and neuroprotective activities, as shown in Fig. (4).
PINO has 256.25 g/mol molecular weight and good lipid solubility, allowing it to cross the BBB via passive transport, implying that this candidate drug could be used to treat brain diseases [42]. On the basis of clinical and preclinical experiments, PINO can be absorbed quickly and distributed widely without leaving behind significant residues, suggesting that it has a favourable PK profile. As a result, PINO is a promising natural small-molecule drug with promising future development prospects.
The neuroprotective effect of Indian propolis with its impact on behavioural and biochemical aspects was studied. It was suggested that Indian Propolis gave neuroprotective activity due to the abundant presence of PINO in it. Ethanolic extract of Indian propolis was administered orally to Wistar rats at the doses of 100, 200 and 300 mg/kg. Behavioural models were studied with the use of Morris water maze and Radial Arm maze. Biochemical parameters were also evaluated, including the estimation of oxidative stress parameters, brain monoamines (Norepinephrine, Dopamine and 5-Hydroxytryptamine) and cholinergic marker (Acetylcholinesterase enzyme) [43].
Fig. (4)) Pharmacological activities of Pinocembrin.PINO is reported to have neuroprotective activity through in vitro study. In primary cortical neurons subjected to oxygen–glucose deprivation/reoxygenation (OGD/R), it has been shown to reduce lactate dehydrogenase release, increase neuronal viability, increase glutathione levels, inhibit NO and ROS development, and down-regulate the expression of neuronal NO synthase (nNOS) and iNOS [44].
Chinese propolis, with PINO, protects against neuronal toxicity induced by Endoplasmic Reticulum (ER) stress [45]. The decrease in caspase-3 activity has been exhibited in tunicamycin-induced SH-Sy5y cells. In the glutamate-induced SH-Sy5y cell line, it reduces the release of cytochrome C from mitochondria into the cytoplasm and the synthesis of pro-apoptotic Bax [45].
PINO has the ability to regulate mitochondrial function as well as apoptosis. It decreased caspase-3 expression and increased PARP degradation in primary neurons exposed to OGD/R [44].
It was proved that PINO protects the BBB in vitro. It increased mitochondrial membrane potential and protected cultured rat cerebral microvascular endothelial cells from OGD/R damage. The findings indicated that PINO has both neuroprotective and vascular protective properties, reinforcing its therapeutic potential in stroke [46].
It was discovered that PINO inhibits angiotensin II-induced increases in MYPT1/Thr696 phosphorylation and ROCK1 expression. Furthermore, it has been shown to inhibit angiotensin II-induced vasoconstriction in the rat aorta by suppressing [Ca2+] and ERK1/2 activation, as well as blocking the angiotensin II type I receptor (AT1R) [47].
The PI3K/AKT/eNOS pathway was also used to show that PINO enhanced the biological functions of bone marrow-derived endothelial progenitor cells (EPCs) [48]. there is a need to find more evidence to confirm the in vitro and in vivo effects of it on cardiovascular diseases.
In a murine macrophage and endotoxin-induced acute lung injury model, PINO inhibits proinflammatory cytokines, in part by reducing MAPK and NF-B activation levels in vitro. In a mouse model of lipopolysaccharide (LPS)-induced inflammation, pretreatment with PINO at a dose of 50 mg/kg administered intraperitoneally attenuated inflammation and reduced lung damage in vivo. Also, pretreatment with PINO (intraperitoneal, 20 mg/kg or 50 mg/kg) reduced mortality from LPS-induced endotoxin shock in mice [49].
In 1977, PINO was discovered to have antifungal properties [50]. Since then, studies have shown that pinocembrin can significantly reduce the activity of Candida albicans [51], Penicillium italicum [52], Staphylococcus aureus [53], Streptococcus mutans [54], E. coli [55], and Neisseria gonorrhoeae [56].
In LX-2 cells and rat HSCs, PINO inhibits the expression of fibrotic markers (HSC-T6). It can minimize ROS accumulation by increasing the expression and activity of silent mating type information regulation 2 homolog 3 (SIRT3) and then activating SOD2. The PI3K/Akt signaling pathway is also inhibited by PINO, resulting in decreased transforming growth factor-beta production and nuclear translocation inhibition of transcription factors Sma and Mad-related protein (Smad). Pinocembrin also stimulates glycogen synthase kinase 3 by acting on SIRT3, resulting in an increased Smad protein degradation [57]. Pinocembrin-7-O-[300-O-galloyl-400,600-hexahydroxydiphenoyl]--glucose is a PINO derivative that contributes significantly to the Smad protein degradation, hepatoprotective effects [58]. It has been suggested that it could be used as a drug candidate to treat liver diseases.
Furthermore, studies have shown that PINO can prevent kidney damage caused by diabetes, but when the kidney is damaged, it will aggravate the organ’s condition [59]. It has been suggested that PINO can be used to avoid kidney damage before it occurs. It can improve insulin resistance by increasing the activities of hexokinase and pyruvate kinase through the Akt/mTOR signaling pathway [60]. All mechanisms are collectively explained in Fig. (5).
Fig. (5)) Various Mechanisms of Pinocembrin.Polyphenols and Flavonoids from Propolis and Therapeutic Potential
Apis mellifera L. a species of honeybee from the plant barks and leaf buds collects resins and add some salivary enzymes into it. In this way, they carry out the process of mastication and use this material. So, this propolis material is a mixture of resin and beeswax. The exact source of resin remains unknown since the observation of bees on their foraging trips is difficult. In the production of propolis, bees are scraping the resins from flowers and leaf buds and further mixing salivary enzymes with the process of mastication [61]. This propolis product is generally utilized by bees in building their nests for smoothening internal wall linings, sealing any cracks, and making the entrance of the hive entrance small to prevent the entry of extruders. Propolis has antifungal and antimicrobial effects that are also beneficial for the protection of bee colonies against diseases or infection [18].
The literature reveals that generally, this process of propolis collection has been reported by a species of Apis mellifera honeybee. Only a few Asian species, mostly stingless bees, have been described for collecting and producing comparable resinous compounds and using them for similar purposes. An ethanolic extract of propolis has been reported for the inhibition of human hepatic and uterine carcinoma cells in vitro.
Propolis was also found to have a cytotoxic and cytostatic effect in vitro against hamster ovary cancer cells and sarcoma type tumors in mice. Artepillin C is a chemical constituent isolated from propolis that has been shown to possess a cytotoxic effect on human gastric carcinoma cells, human lung cancer cells and mouse colon carcinoma cells in vitro.
The use of propolis for the treatment in stomach ulcers has also been reported in Indian folk medicine. The positive effects were also reported for the prevention and treatment of various diseases using animal models. Ethanolic extract of propolis was reported for anti-secretory activity, which reduces gastric juice and pH. Clinical trials also demonstrated the antimicrobial potential of propolis.
Depending upon the plant source accessible to propolis, the composition of propolis is varied, which changes its morphology, colour and odour, ultimately affecting the pharmacological activities. The recent reports reveal around 150 compounds isolated from samples of propolis from a single source, but more than 180 compounds are still not isolated. As geographical origin changes, variations are observed in the chemical composition and pharmacological activities of propolis [62]. The colour of the propolis sample is generally observed from yellowish to dark brown in colour. It is observed to be soft and sticky in the temperature range of 250 C - 450 C [63] and at a temperature less than 150 C and toward a frozen state, it becomes hard and brittle. While in the range from 60 to 70° C, it melts and a liquid state was observed [62].
Aqueous and ethanolic extracts of propolis were analysed phytochemically and examined for their antiviral activity in vitro. Different polyphenols, flavonoids and phenylcarboxylic acids were identified as major constituents. Synergistic effects of flavones and flavonols against herpes simplex virus type 1 in cell culture have been reported. The in vitro activity against herpes simplex virus type 1 was investigated for flavonoids identified in propolis. Flavanols were observed to be more active than flavones. In this study, the efficacy against HSV- 1 of binary flavone flavonol has been investigated. The synergistic effects of propolis demonstrated that propolis is more active than its individual isolated constituents [62]. Antibacterial, antifungal and antiviral activities of propolis of different geographic origins have been studied, and the study reported that all samples were active against the fungal, Gram-positive bacteria and antiviral activity. The activities of all samples collected from different geographical sources were found to be similar, although they varies in their chemical composition [64]. The chemical composition and antimicrobial activity of European propolis have been studied. Propolis samples from Austria, Germany and France were analyzed by GC/MS for antimicrobial activity against Staphylococcus aureus, E. coli and Candida albicans. German propolis was found to be the highest antimicrobial potent against Staphylococcus aureus and E. coli, whereas Austrian propolis has the highest potential against Candida albicans. French propolis was effective against all pathogens it was found to be less than German and Austrian propolis [65].
In vitro antifungal activity of propolis extract on Candida albicans and Cryptococcus neoforman has been reported. The minimum inhibitory concentration of propolis for C. neoformans and C. albicans were 2 and 16 mg/ml, respectively, as observed in microbroth culture assay. Propolis showed fungicidal activity against C. neoformans, whereas propolis possessed fungistatic activity against C. albicans. The MFC (minimum fungicidal concentration) for C. neoformans was 8 mg/ml. Cell morphology of C. neoformans was affected by the treatment of propolis. In scanning electron microscopes, the appearance of cell rupture was reported [66]. The antimicrobial activity of propolis on oral microorganisms has been studied. Ethanolic extracts of propolis were studied for enzyme inhibition activity and growth inhibition of bacteria. All propolis samples of different regions of Brazil inhibited both glucosyltransferase activity and the growth of S. mutans [67]. Antibacterial and DPPH Free Radical-scavenging activities of the ethanol extract of propolis collected from various regions in Taiwan during different time periods were tested for their antibacterial and antioxidative activities [68].
Orsolic et al. supported the immunomodulatory effect as well as the anti carcinogenic potential of propolis and its polyphenolic chemical components. This study also reported antagonistic effects of multiple components on each other [69]. Concentration-dependent apoptosis effects were reported for propolis on lymphoma cells. This study also reported apoptosis through the activation of caspase-dependent pathways [70]. One scientific study demonstrated the toxic, genotoxic, mutagenic and antimutagenic effects of propolis extract from Argentina. The cytotoxicity assays and lethality test were studied. Results suggest a potential anticarcinogenic activity of propolis and chalcone isolated from it [71]. Cheng-Chun Choua et al. reported antibacterial activity of propolis against Staphylococcus aureus. This study investigated antimicrobial activity of the ethanolic extract of propolis collected at different periods from various regions in Taiwan against Staphylococcus aureus. The antibacterial activity against S. aureus was observed to depend upon concentration, collection area and time [72]. The evaluation of propolis effect on macrophage activation was studied with the determination of NO and H2O2 in male BALB/c mice. The results show that propolis induces a discreet elevation in H2O2 release and a mild inhibition of NO generation, depending on concentration. Data suggest that propolis acts on host non-specific immunity by macrophage activation [73]. Hsin-yi yang et al. demonstrated antibacterial activity of propolis Ethanol Extract against Streptococcus mutans as influenced by concentration, temperature, pH and cell age. Bacteriostatic and bactericidal effects of propolis extracts were observed against Str. Mutans [74]. In vitro and in vivo antileishmanial activities of a Brazilian green propolis extract for the first time were studied, where in vivo antileishmanial activity has been reported for hydroalcoholic extract Brazilian green propolis [75]. Motomura M et al. studied the apoptosis effect of methanolic extract of propolis on U937 cells with the activation of caspase-3 and down regulation of protein Bcl-2 [76]. E. M. Muli et al., reported antimicrobial properties of propolis and honey from the kenyan stingless bee Dactylurina schimidti. This study investigated the antimicrobial activity of ethanolic extract of propolis and honey samples of stingless bee, Dactylurina schimidti [77].
Szliszka E et al. reported apoptosis-inducing effect of ethanolic extract of propolis in HeLa cell lines. The study results demonstrated a remarkable reduction in TNF-related apoptosis [78]. Seda Vatansever H et al. studied anti-tumor potential of ethanolic extract of propolis, which also proved to be a better source of polyphenols and flavonoids through caspase activation in breast cancer cell lines. The study also reported concentration-dependent activity of propolis extract [79].
The above report also supported the result from a study where propolis is reported to induce apoptosis by releasing cytochrome C from mitochondria to the cytosol and also the activation of caspase-3 in human leukemia HL-60 cells [80].
Hendi NKK et al. performed in vitro antibacterial and antifungal activity of Iraqi propolis. Antimicrobial activities of crude ethanolic extract of Al-Museiab propolis was studied against some of the bacterial and fungal isolates. Ethanolic extract was found to be the most active of all the propolis extracts studied [81]. MAE Watanabe et al. reported cytotoxic constituents of propolis inducing anticancer effects. Seven different propolis extracts from Turkey were investigated on the human breast cell line MCF-7, and it was concluded that propolis may exert anti tumour effects by increasing apoptosis through the caspase pathway [82]. Jayakumar R et al. reported in vitro anticancer and antimicrobial activity of propolis nanoparticles with the mechanism of internalization of the nanoparticles by the cancer cells. The study revealed that Indian propolis nanoparticles could be a good substitute for the existing materials against cancer. The cytotoxicity of propolis nanoparticles against MCF-7, using MTT assay and the minimal concentration toxic to the cancer cells were found [83]. Sawicka D et al., 2012 reported anticancer activity of propolis from Poland. The antitumor activity of ethanol extract of propolis (EEP), which is one of the richest sources of phenolic acids and flavonoids on human breast cancer cell line MCF-7, shows that apoptosis induction is strongly dependent on the concentration and dilutions of EEP [84]. In vitro anticancer activity of Indian stingless bee propolis was reported, where an ethanolic extract of Indian propolis (EEP) was studied for cytotoxic and apoptotic effect on MCF-7 (human breast cancer cell line) [85]. Kapare et al. investigated a polymeric nanoparticle system composed of ethanolic extract of Indian propolis loaded in polycaprolactone nanoparticles. The study reported detailed formulation development, characterization in vitro cytotoxicity study of ethanolic extract of Indian propolis and its developed formulations. The study demonstrated good cytotoxic potential of propolis and enhanced activity for developed formulation due to improved solubility and nanoparticle characteristics on breast cancer and colon cancer cell lines. The developed nanocarrier system is suggested for applicability in drug delivery [86]. Other studies in continuation with this demonstrated better performance in terms of cytotoxic potential of Indian propolis. In this study, a polymeric nanoparticle system composed of ethanolic extract of Indian propolis loaded in PLGA polymer with folic acid attached as a ligand on the surface of PLGA. The study demonstrated 43.34% improved performance in terms of GI 50 value with nanocarrier formulation for ethanolic extract of Indian propolis. The in vitro performance further reflected in an in vivo study with Dalton's Ascites Lymphoma model in tumour cell reduction. This study also demonstrated higher amounts of polyphenol and flavonoids contents in the ethanolic extract of Indian propolis with more than 300 constituents that synergistically contribute in pharmacological activity. This drug delivery system was suggested for further investigation for biomedical applications [87]. Kujumgiev A et al. reported effects of geographical origin on the various activities of propolis. In this study, all samples were observed to be active in terms of pharmacological activities. As per changes in geographical parameters like temperature, climate, etc., the chemical composition varies that impacts the potency [84]. Propolis from Egypt has been reported to have antitumor and protective effects in mice with Ehrlich ascites carcinoma. The study was carried out with propolis at a dose of 160 mg/kg. A significant reduction was observed in tumor count with flow cytometric analysis at the S phase [88]. Various reports on immune-modulatory, anti inflammatory, anti-ulcer and anti-diabetic potential of propolis have been reported worldwide [89-93].
Drago L et al. developed novel formulations of propolis and were investigated them for anti microbial activity. The study demonstrated antibacterial and antiviral potential of the developed novel formulation of propolis extract through interference in bacterial adhesion in human oral cells. The formulation characteristics are also proven for improvement in the application of propolis in respiratory tract infections [94]. Shimizu T et al. reported antiviral activity of propolis on in vitro and in vivo influenza virus. The activity was confirmed at 10 mg/kg in a dose-dependent manner in mice. A significant reduction in virus yield in lung fluids was observed [95].
The effects of propolis on different pathways of apoptosis are shown in Fig. (6).
Fig. (6)) Effects of propolis on different apoptosis pathways.Nanaware S et al. studied the neuroprotective effect of Indian propolis and its impact on behavioural and biochemical aspects. The ethanolic extract of Indian propolis was administered orally to Wistar rats at doses of 100, 200 and 300 mg/kg. Behavioural and biochemical parameters were evaluated. The study demonstrated anti-alzheimer potential of Indian propolis through multiple mechanisms [43]. This study also extended to investigate marker-based standardization and nutraceutical applications of Indian propolis. Propolis extract was standardized by HPTLC analysis. The study results demonstrated the high nutraceutical value of propolis and free from pesticides and heavy metals [96]. Kwon M et al. studied antiviral potential with possible mechanisms in Brazilian propolis with its chemical constituents. This study concluded the blockage of virus entry inside the cell, which further causes destruction and replication that further interfere with expressions of intercellular adhesion molecule-1 and interleukin-6 [97]. Kapare HS et al. investigated in detail parameters in terms of extraction, standardization, cytotoxicity, and safety profile of Indian propolis. The study also highlighted the key role of CAPE for cytotoxicity potential. The standardization was reported by the newly developed RPHPLC method. The cytotoxicity potential was reported both in vitro as well in vivo. EEIP demonstrated better anti-cancer potential than individual CAPE in the breast as well lung cancer. Also, it was proven to be safe for internal use and can be further developed for biomedical applications [98]. Seif M et al. reported the affectivity and applicability of propolis in antiviral therapy. This study demonstrated the effective and safe use of natural product propolis against COVID 19 [99].
Caffeic Acid Phenethyl Ester (CAPE)
CAPE is one of the vital compounds, which have been reported for good anticancer potential. It was initially reported in 1979 in the form of a mixture of caffeic acid ester and phenethyl ester responsible for the antifungal and antibacterial activity for European propolis. Further, with the investigation of this molecule for good cytotoxic potential, its popularity among researchers was significantly increased, and till now, it was the most individually studied molecule from propolis in terms of various pharmacological activities at the molecular mechanism level. CAPE was reported for cytotoxic effects by the induction of apoptosis in human colon and pancreatic cells and inhibited the growth of C6 glioma cells in vivo. CAPE is also reported extensively for the inhibition of NF-κB activation. The dietary intake of CAPE was found to be beneficial in cancer patients with a high level of activated NF-κB in various cancers like lungs, thyroid, colon, breast etc [100, 101].
Rossi A et al., 2002 studied and demonstrated the inhibition effect of CAPE on cyclooxygenase activity on J774 macrophages. This study was carried out on methanolic propolis extract in the presence as well as the absence of CAPE and along with some other key chemical constituents. The inhibition effect of COX-1 and COX-2 in J774 macrophages was demonstrated. The findings from this study suggested that along with propolis extracts, the presence of its key constituents like CAPE, Galangin, etc., improve and contribute to its activity [102]. One more study was reported by Ansorge S et al., for the pharmacological effect of CAPE in the down-regulation of DNA synthesis as well the production of inflammatory cytokines induced production of TGF-b 1 in immune cells of humans. The study supported as evidence of anti-inflammatory and immune regulatory activity of CAPE [103]. Ilhan A et al. reported anti-inflammatory effect of CAPE. A study was performed on allergic encephalomyelitis-induced oxidative stress in rats. The anti-inflammatory mechanism was reported by the inhibition of production of ROS at the level of transcription with suppression of NF kappa-B activation as well as by direct inhibition of catalysis effect of inducible NO synthase [104]. Koksel O et al.. demonstrated immune-modulatory, anti-inflammatory, anti-microbial, antioxidant, anti carcinogenic potential of CAPE. The study was carried out in lipopolysaccharide-induced lung injury in rats. The favourable and significant effects in reduction of inflammation as well as in tissue damage were observed [106]. The majority of pharmacological effects of propolis in the presence of CAPE were experimentally demonstrated [102-105].
The effect of CAPE in breast cancer modulation through epigenetically mediated mechanisms was reported by Coral Omene et al. This study also reported various effects, including antibacterial, antiviral, antifungal and anticancer for CAPE. The CAPE was well proven for significant effects in tumour suppression by multiple pathways. The study also reported enhanced and improved potential of propolis in the of CAPE content [106]. The anti-metastatic action and immune modulator effects of CAPE on oral cancer cells were reported for oral submucous fibrosis, gingiva carcinoma as well as tongue squamous cells. A significant level of apoptosis with CAPE treatment was reported [106]. The detailed apoptosis mechanism of CAPE in HL-60 cells was investigated. The result showed that CAPE was able to enter rapidly inside the HL-60 cells and inhibited the cell growth with concentration as well as time-dependent pattern. The findings proved the potent apoptosis-inducing effect of CAPE through caspase-3 activation, up-regulation of Bax and downregulation of Bcl-2 [107]. CAPE showed antitumor promotion through induced apoptosis in mouse epidermal JB6 Cl 41 cells through p53- dependent and independent pathways [108]. The findings imply that the CAPE-induced p53-dependent apoptosis in C6 glioma cells was mediated by p38MAPK. [109]. CAPE is also well known for the inhibition of NFκB induced apoptosis through Fas signal activation in MCF-7 cells [110]. Hung MW et al. synthesized the derivatives of CAPE and investigated its apoptosis and antioxidant activities. The activities demonstrated mechanisms of caspase-8 activation and Mcl-1 downregulation [111]. Jin UH et al. investigated the apoptosis mechanism of CAPE in human myeloid leukemia through mitochondrial mediation [112]. Chen MJ et al. reported the inhibitory effects of CAPE on breast cancer stem cells. Various key aspects were reported in a mechanism that includes changes in bCSC and a significant decrease in CD44 content [113]. For a clear mechanistic understanding of the involvement of multiple pathways in pro-apoptotic effects, various studies have been reported. An enhanced activity of caspase-3 or caspase-7 was found as a mechanism in liver, cervical, ovarian, pancreatic and lung cancer cells [107-113]. Xu JW et al. reported various sources and effects of Caffeic acid, its regulation mechanism in the biological system through Rac1 GTPase activity, and NADPH oxidase, etc. The study reported the effects of a decrease in Rac1 level and the activation of NADPH oxidase [114]. Borrelli F et al. reported the tumour growth reduction ability of CAPE in in vivo rat model for colon cancer cells. 50 mg/kg intra peritonial CAPE injection showed a significant reduction in the development of tumors. A very important key finding was also reported that without the presence of CAPE, there is limited or no effect on anti cancer potential [115]. Kuo HC et al. reported an inhibitory effect in BALB/c-nu mice on C6 glioma cells. About 78% tumor volume reduction was observed at 10 mg/kg dose of CAPE. The data was supported by a histological study where reduction in mitosis positive cells reduction was observed [116].
CONCLUSION
Propolis and its isolated chemical constituents, specifically polyphenols and flavonoids, were well-proven and widely reported for a wide range of therapeutic potential. Despite of high therapeutic and nutritional value of this natural product, limited approaches have been reported on its formulation development and clinical applications. However, some of the studies reported have not explored the biopharmaceutical, formulation and clinical aspects in detail. So, it is worthwhile to study this natural product for novel extraction techniques, analysis and chemical profiling along with formulation development approaches to enhance its solubility and biopharmaceutical properties in order to make this product available on a commercial platform.
CONSENT FOR PUBLICATION
Not Applicable.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENTS
Declared none.
