A Journey Along the Boulevard of Bioactive Compounds from Natural Sources, with Cosmetic and Pharmaceutical Potential: Bee Venom, Cobra Venom, Ficus carica

Abstract

Animal venom and plant extracts have been used since ancient times in traditional medicine worldwide. Natural components, valued for their safety and effectiveness, have been consistently used in cosmetic and pharmaceutical applications. We propose a journey along the boulevard of active compounds from natural sources, where bee venom (BV), cobra venom (CV), and Ficus carica reveal their individual therapeutic and cosmetic properties. The originality of this review lies in exploring the synergy of these bioactive sources, an approach that has not been presented in the literature. Although BV, CV, and Ficus carica have different origins and compositions, they have multiple common pharmacological and cosmetic actions, which make them ideal for inclusion in various products that can be used for skin care and health in general. Their anti-inflammatory, antioxidant, immunomodulatory, antimicrobial, neuroprotective, and regenerative properties give them an essential role in the creation of potential innovative and effective products in the pharmaceutical and cosmetics industry. Although many plant extracts have antioxidant and anti-inflammatory properties, Ficus carica was chosen due to its complex biochemical composition, which provides valuable benefits in skin regeneration and protection against oxidative stress. According to the International Nomenclature of Cosmetic Ingredients (INCI), Ficus carica is used in the form of an extract of fruits, leaves, juice, bark or stem, each having specific applicability in topical formulations; due to the diversity of bioactive compounds, it can amplify the effectiveness of BV and CV, helping to enhance their beneficial effects and reducing the risk of adverse effects, due to its well-tolerated nature. Thus, this combination of natural ingredients opens up new perspectives in the development of innovative products, optimizing efficiency and maintaining a favorable safety profile. In this context, due to the reported experimental results, the three natural sources caught our attention, and we conceived the present work, which is a review made following the analysis of the current progress in the study of the bioactive compounds present in BV, CV, and Ficus carica. We focused on the novelties regarding pharmacological and cosmetic actions presented in the literature, and we highlighted the safety profile, as well as the modern approaches regarding the delivery and transport systems of the active substances from the three natural sources, and we evaluated their prospects in therapeutic and cosmetic use. This paper not only expands our knowledge of bioactive compounds, but it can also generate new ideas and motivations for the research and development of innovative treatments and skincare methods.

1. Introduction

The interest in the use of natural resources in the formulation of various products to be used for the treatment of diseases has increased significantly in recent years. This trend is fueled by a desire to find safer and more effective alternatives to conventional treatments, which often come with unwanted side effects. Plants, insects, snakes, and other natural resources are recognized for their potential to provide biologically active agents, which can contribute to the development of new therapies for various conditions [1].

Animal venom is used by many species for defense, or to capture and digest prey. It is composed of complex mixtures of enzymatic and non-enzymatic components, each having distinct pathophysiological roles [2]. This venom does not contain a single toxin but is a sophisticated chemical cocktail, rich in pharmacologically active substances, such as proteins, peptides, and enzymes, with specific biological functions. In addition, venom also includes non-protein compounds such as carbohydrates, lipids, metal ions, and other substances, some of which have not yet been fully identified [3]. Venom research began with the goal of understanding the structure and functions of these substances, as well as their potential medical applications. Along the way, scientific interest in venom has increased due to the extraordinary complexity, specificity, and effectiveness of its components. Most of the substances in the composition of venoms are peptides that bind with high selectivity and affinity to various biological targets, including membrane receptors, ion channels, enzymes, and hemostatic pathways [4].

The bioactive substances present in natural products are a major resource in the cosmetic and pharmaceutical fields. The interest in products based on plant extracts has increased significantly due to their effectiveness and safety. They are used both in skin care and for the treatment of various dermatological and systemic conditions, having antioxidant, antibacterial, and regenerative properties. Extracts obtained from different parts of plants are rich in active compounds, such as terpenes, saponins, tannins, and vitamins, with positive effects on skin health [5,6,7,8,9].

In the cosmetics industry, there is a clear trend to replace synthetic ingredients with natural alternatives. This trend underlines the importance of identifying bioactive ingredients from the natural environment, especially from plants. The diversity of biological activities that some venoms and plants offer highlights their considerable potential in the development of new cosmetic and dermatological formulations [10].

BV, CV, and Ficus carica caught our attention due to the reported common pharmacological actions, which demonstrate a special potential to be included in the formulation of products for use in the cosmetic and pharmaceutical industries, and the novelty of this review lies in the presentation of the hypothesis of a possible synergy between these bioactive sources, based on the complementarity of the bioactive effects of each ingredient, an approach that has not been presented in the literature.

2. Bee Venom

Bees are flying insects that belong to the order Hymenoptera, suborder Apocrita, and are classified into seven families: Colletidae, Stenotritidae, Andrenidae, Halictidae, Melittidae, Megachilidae, and Apidae. The Apidae family also includes the Apis species, whose venoms are the most characterized, but the most studied from a pharmacological and cosmetic point of view is the Apis mellifera venom, to which we refer in this manuscript [11].

Bee products, especially venom and honey, have been used since ancient times, and their medicinal properties have been mentioned in the Bible and the Qur’an [11]. The therapeutic benefits of BV have a long history, being used as early as 3000 BC in traditional Oriental medicine to treat inflammatory diseases, in ancient Egypt from 4000 BC, and later, in the Greek and Roman historical periods, it was used by Aristotle, Galen, and Hippocrates [12,13]. BV is secreted by the venom gland located in the abdominal cavity of female bees and is used by them to defend themselves against enemies [14]. It is a clear liquid with a bitter taste and a distinct honey-like odor, a slightly acidic pH (4.5–5.5), and a specific gravity of 1.13 [15]. The freshly secreted venom is colorless, and when it dries, it forms a light-yellow powder. In freeze-dried form, after the elimination of the liquid phase, it becomes a light-gray to yellow-gray volatile powder, making it prone to volatilization and crystallization in air [16].

A correct collection method is essential to obtain the highest-quality BV. It is important that the venom is collected without contaminants to preserve its purity and efficacy, and the properties of the final product vary depending on the extraction process used [17]. The venom obtained by the electric-shock method is considered effective and is widely used in clinical applications [18]. After collection, BV undergoes processing to extract the active ingredients intended for medical use. Chromatographic separation and molecular genetic engineering methods are used, which allow the obtaining of specific compounds with distinct therapeutic properties [19].

2.1. Composition

The composition of BV can be influenced by several factors, such as bee species, season, and geographical location, and gives it different actions with potential applications in the cosmetic and pharmaceutical industry. BV consists mainly of water (88%), a variety of peptides, enzymes, and other compounds (lipids, carbohydrates, free amino acids, and minerals). The most important peptides are melittin (a small peptide of 26 amino acids that form pores in membranes), apamin (a neurotoxic peptide that degranulates mast cells), adolapin (a peptide with anti-inflammatory properties), seaplane, and protamine. The enzymes present in BV are phospholipase A2 (it degrades phospholipids in cell membranes), hyaluronidase, phosphatase, and α-glucosidase, and the biogenic amines are histamine and epinephrine [20,21,22]. The main components of BV and their pharmaceutical effects are presented in

Table 1. The main components of BV and their pharmacological actions.

Components	Pharmacological Actions	References
Melittin	Anti-inflammatory, anti-bacterial, antiviral, analgesic, anti-cancer, neuroprotective.	[23,24,25,26,27,28]
Apamin	Anti-fungal, antiviral, anti-inflammatory, analgesic.	[25,29]
Phospholipase A2	Anti-inflammatory, anti-protozoal, anti-cancer, immunomodulatory.	[30,31,32,33]
Hyaluronidase	Hydrolysis of hyaluronic acid.	[34]
Adolapin	Anti-inflammatory, analgesic, antipyretic.	[13,22,29,35]
The peptide of mast cell degranulation (MCD)	Anti-inflammatory.	[36,37]
Histamine	Permeability of blood vessels.	[38]

.

2.2. Pharmacological Actions

2.2.1. Analgesics

Numerous animal studies have shown that acupuncture with BV has significant anti-inflammatory and analgesic effects. The antinociceptive property is explained by counterirritation, which is the application of harmful stimuli in certain areas of the body leading to an increase in the pain threshold and a reduction in its perceived intensity. However, due to methodological limitations and the small number of clinical trials available, it is too early to draw definitive conclusions. However, the efficacy of BV acupuncture in the treatment of arthritis appears to be promising for future research [29,39].

2.2.2. Anti-Inflammatories

Melittin and apamin from BV have strong anti-inflammatory effects, inhibiting pro-inflammatory cytokines [40] and reducing the inflammatory response [41].

The anti-inflammatory effect has been demonstrated by Apis mellifera venom through studies that have concluded that it may be a potential treatment for rheumatoid arthritis. Administration in various concentrations in murine models has led to a reduction in edema in the paws, as well as a decrease in the arthritis index and inflammatory pain [42]. Moreover, BV has also demonstrated anti-inflammatory effects in the treatment of atopic dermatitis, demonstrating that it can become useful in treating this condition [43].

2.2.3. Antimicrobial

The antimicrobial action of BV has been demonstrated in various in vitro and in vivo experiments against bacteria, viruses, and fungi, with melittin having the ability to destroy the cell membranes of bacteria and viruses [44,45]. Thus, BV and melittin showed broad-spectrum antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, as well as against Escherichia coli, Staphylococcus aureus, and Borrelia burgdorferi [46,47,48,49,50].

BV and its constituents have been reported to exhibit prominent antiviral activities against various viruses, such as Herpes simplex, Enterovirus-71, Coxsackie, and Respiratory syncytial virus [51]. Moreover, it inhibited the entry stages of the hepatitis C virus infection cycle and demonstrated that it may have potential in HIV treatment [52,53].

Research has also proven the antifungal effect of BV against Malassezia furfur, Trichophyton mentagrophytes, Trichophyton rubrum, and Candida albicans [43,54,55]. Scientists’ analyses have also shown that BV also has important antiparasitic effects [56,57].

In addition, the results of studies have shown that melittin and apamin in the composition of BV have shown that they can inhibit the growth of Alternaria alternate and Aspergillus pillows, which are pathogens that grow in the nasal cavity and can cause inflammatory diseases of the upper respiratory tract, proving that the mechanism of action consists of inhibiting the production of chemical mediators, such as interleukin (IL)-6 and IL-8 [29,58].

2.2.4. Neuroprotective

BV has been shown to increase the effectiveness of multiple treatments against neurodegenerative diseases [59]. Apamin from BV has neuroprotective effects and can stimulate cognitive function by acting on potassium channels, and melittin exerts antioxidant and neuroprotective actions against neuronal oxidative stress and can be a potential therapeutic agent for neurodegenerative disorders [28,60]. It is also worth noting that improvements in motor symptoms of Parkinson’s have been reported following the administration of BV through acupuncture [61].

2.2.5. Antioxidant

The components of BV, especially melittin, have demonstrated antioxidant effects by reducing oxidative stress at the cellular level [62,63]. Also, Amwaprin, a newly identified protein in BV-inhibited cell growth, oxidative-stress-induced cytotoxicity, and inflammatory response in mammalian NIH-3T3 cells, reduced caspase-3 activity during oxidative stress, and provided protective activity against oxidative-stress-induced cell apoptosis in insect NIH-3T3 and Sf9 cells. The exertion of this protective effect against oxidative stress is due to its direct interaction with the cell membrane. At the same time, Amwaprin demonstrated free radical neutralization activity and protected DNA against oxidative damage. These findings suggest that its antioxidant properties are the result of synergy between its ability to scavenge free radicals and cell protection, highlighting an important role as an antioxidant agent [64].

2.2.6. Immunomodulators

BV has been shown to boost the immune system, particularly by activating T cells and macrophages and modulating the immune response, which may be beneficial in the treatment of autoimmune and inflammatory diseases [65,66].

2.2.7. Anti COVID-19

Through the proven pharmacological actions of strong antiviral, anti-inflammatory, and immunomodulatory, it can be suggested that BV treatment could be a potential complementary therapy for the prevention of severe acute respiratory syndrome—coronavirus 2 (SARS-CoV-2) [67,68,69].

3. Cobra Venom

Snakes are reptiles of the order Squamata and are part of the suborder Serpentes. They are found on all continents except Antarctica, and to date number about 3900 species. Their venoms are among the most complex of animal venoms, and the families most intensively studied in this regard are Viperidae, Crotalidae, and Elapidae [70,71]. The snakes of the family Elapidae are cobra, coral snakes, kraits, and mamba, and are known for their neurotoxic effects, which in most cases cause paralysis [72]. Cobra is a name that represents a group of venomous snakes that are part of the Elapidae family, and of this group, of pharmacological interest are the venom of the genus Naja (Naja kaouthia, Naja sumatrana, Naja pallid, Naja naja atra) and the genus Ophiophagus Hannah (king cobra) [70,71,72]

Snake venoms have been used to treat various ailments for thousands of years, especially in traditional Chinese medicine to treat opium addiction, and Indians have used it to treat pain by combining it with opium [73]. Starting with the second half of the twentieth century, due to advances in analytical techniques, snake venom began to be of increasing interest to researchers due to the identification of a rich content of molecules with pharmaceutical and cosmetic potential [74].

The pharmaceutical industry has produced several venom-derived drugs: Captopril (the first product to appear, approved by the Food and Drug Administration in 1981), Aggrastat, and Eptifibatide, all designed based on the components of snake venom [75,76]. Ximelagatran, a drug made by CV specialists, was a thrombin-inhibiting anticoagulant that was used as a blood thinner and direct thrombin inhibitor, but due to the appearance of hepatotoxicity reactions, the research stopped, and it was withdrawn from countries where it was already authorized [77].

CV is a pale-yellow viscous liquid that contains a complex mixture of bioactive substances, each of which has a specific role in capturing prey, acting together to immobilize prey and induce rapid and destructive toxic effects. Its composition can be influenced by factors such as habitat, diet, sex, and ontogenetic development [78]. To be used in various research, the venom is collected by milking, then to remove any impurities it is filtered through 0.45 μm filters, and subsequently, it is freeze-dried and stored at -20 °C until use [79].

3.1. Composition

The main components of CV are neurotoxins(low molecular weight peptides belonging to the three-finger protein family, including some alpha-neurotoxins, which can have a high selectivity for nicotinic acetylcholine receptors), cardiotoxins(polypeptides that affect heart muscle cells), phospholipase A2 (PLA 2), cobra venom factor (CVF), nerve growth factor (NGF), L-amino acid oxidase (LAAO), acetylcholinesterase, and many other substances [80,81]. The main components of BV and their pharmaceutical effects are presented in

Table 2. The main components of CV and their pharmacological actions.

Components	Pharmacological Actions	References
Cobratoxin	Analgesic, anti-inflammatory, anticonvulsant, antivirals	[82,83,84,85,86]
Cardiotoxins	Cardioprotective, anti-cancer	[87,88]
Phospholipase A2 (PLA2)	Anticoagulant, neuroprotective, antibacterial	[89,90,91,92]
Cobra venom factor (CVF)	Immunosuppressive	[93,94]
Nerve growth factor (NGF)	Neuroprotective, immunomodulators	[95]
L-amino Acid Oxidaze (LAAO)	Anti-cancer	[96,97]

.

3.2. Pharmacological Actions

Despite its toxicity, CV has demonstrated through various studies, a high degree of therapeutic potential through various actions:

3.2.1. Analgesics

Many studies have shown that CV has played an important role in relieving pain (cancer pain, neuralgia, arthralgia), having the ability to block essential components of the pain signaling system, especially ion channels [82,83,98]. Cobrotoxin or cobratide (a short-chain postsynaptic α-neurotoxin isolated from the venom of the snake, Naja atra) was approved in 1998 in combination with synthetic drugs as an analgesic for the treatment of moderate to severe pain [2,98]. It has also been shown to become a substitute for morphine, suppressing withdrawal symptoms caused by its use [99,100].

3.2.2. Anti-Inflammatories

CV has neurotoxic and enzymatic components that have anti-inflammatory effects, modulating the immune response and reducing inflammation in various experimental models. Cobrotoxin, cardiotoxin, and neurotoxin extracted from Naja naja atra venom have shown anti-inflammatory properties, acting by decreasing TNF-α and IL-1β levels, as well as reducing the enzymatic activities of myeloperoxidase (MPO) and iNOS [84,101]. These research-proven anti-inflammatory effects recommend CV as a potential candidate for the treatment of chronic inflammatory diseases [102,103].

3.2.3. Antioxidant

Although CV is best known for its toxic effects, some peptides and enzymes may help reduce oxidative stress through indirect mechanisms, such as modulating the immune response. CVF, isolated from Naja naja, has an activating effect on the complement system and has been used for studying the complement cascade, and the oxygen extracted from Naja oxiana venom has been shown to inhibit the formation of C3 convertase by blocking the classical complement pathway. These results highlight the potential of cobra venom in the development of inhibitory drugs, which are essential in combating various conditions, including autoimmune diseases [104].

3.2.4. Antimicrobial

CV contains enzymes and peptides with antimicrobial potential, which can inhibit the growth of bacteria and other pathogens, helping to reduce the risk of infections. Researchers reported that α-neurotoxins inhibited the replication and toxicity of several viruses both in vitro and in vivo [86,105]. The antibacterial effects of CV have been reported against numerous strains, including Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli [106].

3.2.5. Neuroprotectants

The researchers found that a secretory phospholipase A2 from the venom of the snake Naja sumatrana helps cells survive under oxidative stress. The A2-EPTX-NSm1a protein has been shown to protect neurons from oxidative stress damage by stopping apoptosis and altering protein expression related to neuronal inflammation and apoptosis. Thus, the possibility of using A2-EPTX-NSm1a or other proteins from the venom of the snake Naja sumatrana in drug discovery or for research into neurodegenerative diseases caused by oxidative stress is suggested [90].

3.2.6. Immunomodulators

CV has demonstrated immune system modulation activity by inhibiting excessive immune responses, making it useful in treating inflammatory or autoimmune conditions [107].

3.2.7. Anti COVID-19

Naja atra venom and cobrotoxin have been shown to inhibit lung inflammation, improve pulmonary gas exchange function, and attenuate the development of fibrotic lesions in the lungs, thus becoming potential therapeutic agents to treat COVID-19 patients [108,109,110].

3.2.8. Anticancer

The anticancer activities of CV represent one of the most promising therapeutic characteristics and have been intensively researched and reviewed in recent years, with the results proving that the CV causes irreversible changes in the cell, destroying it completely. In in vivo studies, Naja nigricollis venom has been shown to inhibit the growth of melanoma by such a mechanism. The cytotoxins CT1 and CT2 from Naja oxiana, CT3 from Naja kaouthia, and CT1 from Naja haje have also been shown to have this ability against human lung adenocarcinoma A549 and promyelocytic leukemia cells HL60 [111].

Cytotoxins isolated from the venom of the snake, Naja oxiana, demonstrated superior anticancer activity compared to cisplatin (a drug used in the treatment of cancer). Studies have shown that these toxins have minimal impact on normal cells and induce apoptosis in various cancer cell lines (HepG2, MCF-7, HL-60, and DU-145) via the lysosomal pathway and by releasing cathepsins into the cytosol [112].

Furthermore, one study showed that the venom of the Moroccan cobra Naja haje, in particular the F7 fraction obtained by gel filtration chromatography, demonstrated the strongest effect against hepatocellular carcinoma, an action associated with reduced toxicity compared to normal hepatocytes [113].

3.2.9. Other Pharmaceutical Effects of CV

Studies have reported that CV has also demonstrated protective effects on adriamycin-triggered nephrotic syndrome in rats, effects to improve lung gas exchange function and attenuate fibrotic lesions in the lungs, as well as beneficial effects in systemic lupus erythematosus [114,115,116,117].

4. Ficus carica

Figs are among the first plants cultivated by humans over 11,000 years ago [118,119]. The history of figs has its roots in the time of the Roman Empire, and their cultural and religious importance is also mentioned in sacred writings such as the Bible and the Qur’an [120]. The fig tree has been recognized since ancient times for its therapeutic benefits in treating various dermatological problems. In the fourteenth century, historical writings highlighted the knowledge of its healing properties, influenced by the studies of Dioscorides and Galenus of Pergamon [121,122,123].

The genus Ficus, part of the Moraceae family, includes about 850 species spread globally, making it one of the most extensive genera of angiosperms. Ficus carica is a small, deciduous tree, recognized as one of the largest genera of angiosperm plants, and it is a heterozygous species, popularly known as a “fig”. This tree has small, green, pedunculate flowers, which are hidden inside a fleshy receptacle, not visible from the outside; only the fruit are observable, and all the flowers are female and self-pollinating, a phenomenon characteristic of figs [122,124].

4.1. Composition

Ficus carica is a rich source of minerals, carbohydrates, vitamins, sugars, dietary fiber, organic acids, and phenolic compounds. Fig fruits, leaves, and latex have various components with anti-inflammatory action. Phytochemical analyses revealed the presence of alkaloids, tannins, glycosides, flavonoids, saponins, coumarins, phenols, sterols, terpenes, carbohydrates, and proteins in the fruit [125]. The fruits and leaves contain coumarins and flavonoids, compounds that are known for their antioxidants, anticancer, and anti-inflammatory effects [126,127]. There are 34 known flavonoids in Ficus carica leaves, and they have various properties, routine being very important from a pharmacological point of view, and having antidiabetic and antioxidant effects [128,129]. Ficus carica leaves contain six types of coumarins, which are associated with antioxidant, antibacterial, and antidiabetic activities, with umbelliferone being the most present coumarin [130,131]. Studies have found that the bark and fruits of Ficus carica contain 15 anthocyanin pigments, most of which contain cyanidin and pelargonidin derivatives [132].

Fig fruits were evaluated in a study that included six different varieties and varied colors (black, red, yellow, and green), for the content of total polyphenols, total flavonoids, and antioxidant properties. They exhibited the highest levels of antioxidant compounds, having the highest antioxidant capacity [133,134].

Total and individual phenolic compounds such as phenolic acid, chlorogenic acid, and flavonoids have been identified from fresh and dried fig peels. The amounts of phenolic substances were higher in dried figs due to the increased concentration in the dried peel [135]. Specialists have identified, following the specific analyses carried out, four free sugars (glucose, fructose, trehalose, and sucrose) and five organic acids (oxalic, quinic, malic, citric, and succinic) in the peel and pulp of a variety of figs from Portugal [136]. Polyphenols and carotenoids are two essential groups of phytochemicals present in figs, reflecting a diverse and valuable chemical composition. Among the major polyphenols are phenolic acids, flavones, flavanones, flavonols, anthocyanins, and proanthocyanidins, which contribute significantly to the antioxidant activity of figs. The high levels of phenolic compounds even exceed the concentrations found in red wine and tea, two of the most well-known sources of polyphenols [137]. In addition, anthocyanin-rich varieties of figs have a concentration comparable to that of blackberries and blueberries, thus highlighting their nutritional and antioxidant potential [135]. An evaluation of the different parts of figs (leaves, peel, and pulp) underlined the superiority of the leaves in terms of total polyphenol content and antioxidant capacity. Fig leaves stand out for these exceptional properties, considerably surpassing both the peel and the pulp in these aspects. This particular leaf quality gives them significant potential for nutritional and therapeutic uses [138,139].

Another important component of Ficus carica is psoralen, which is used in the treatment of skin diseases and is approved by the FDA as part of PUVA (Psoralene and ultraviolet A) therapy, making it effective for conditions such as eczema, psoriasis, and vitiligo, when combined with UV-A radiation [140]. Along with other natural remedies, such as piperine [141], psoralen is a photosensitizing substance used in the PUVA-therapy P from the application, or the internal administration of psoralene, followed by exposure to ultraviolet light in the treatment of vitiligo [142].

Figs also stand out as a valuable source of numerous micronutrients and macronutrients, including carbohydrates, essential vitamins, organic acids, dietary fiber, and minerals. This rich nutritional composition underlines their beneficial potential for health and their importance to a balanced diet [143].

4.2. Pharmacological Actions

The fig tree is recognized for its therapeutic potential in treating a variety of conditions, including diabetes, liver disease, asthma, ulcers, skin infections, gonorrhea, infections and disorders of the digestive, endocrine, reproductive, respiratory, gastrointestinal, and urinary systems [124,144]. The leaves are used as protection from the sun and as a chemoprotective agent. The fruits and leaves have anti-cancer and anti-acne properties: latex helps reduce viral titers, and the roots are useful in treating ringworm. Virtually all components of the Ficus carica plant have been documented with medical benefits, including anticancer activity against various cancers [124,145,146]. In the same context, fig extract seems to have applicability in the treatment of cardiovascular diseases due to its content of flavone, rutin, and quercetin [147].

4.2.1. Anticancer

The antitumor mechanisms of Ficus carica include the induction of apoptosis in tumor cells by decreasing Bcl-2 expression, the activation of caspases 3 and 9, the increase in pro-apoptotic markers Bax and PARP, facilitating programmed cell death [124,146].

Research has highlighted the viability of fig-leaf extracts in the prevention and treatment of cervical melanoma, due to compounds such as bergapten and psoralene, which demonstrate anticancer properties [148,149].

4.2.2. Antioxidant

The antioxidant activity of Ficus carica fruit extract was rated at 87%. Ficus carica is rich in two main categories of phenolic compounds: phenolic acids (such as gallic acid, chlorogenic acid, and syringic acid) and flavonoids (including catechin, epicatechin, and anthocyanins). These phenolic compounds are considered among the most effective natural antioxidants [150]. The antioxidant mechanism of Ficus carica is evidenced by the reduction of oxidative stress, which helps to combat organ toxicity by decreasing oxidation markers (MDA) and increasing the levels of antioxidants such as GSH, SOD and catalase, with this action restoring the functions of various organs, facilitating histological reconstruction and protecting cells from oxidative damage [124,144,150].

4.2.3. Hepatoprotective

An extract of petroleum ether from fig leaves was investigated for hepatoprotective activity in rats orally treated with 50 mg/kg rifampicin, and the significant reversal of the biochemical, histological, and functional changes caused by rifampicin suggested possible hepatoprotective activity [151].

4.2.4. Antibacterial and Antifungal

Ficus carica methanolic extract has demonstrated strong antibacterial activity against oral bacteria. The combined effects of methanolic extract with ampicillin or gentamicin had a synergistic effect against these bacteria, suggesting that figs could function as a natural antibacterial agent [152].

The extracts of hexane, chloroform, ethyl acetate, and methanol from Ficus carica latex were evaluated in vitro for their antimicrobial activity against five species of bacteria and seven strains of fungi, using the disk diffusion method. The methanolic fraction demonstrated complete inhibition against Candida albicans (100%) at a concentration of 500 μg/mL and had a bactericidal effect against Cryptococcus neoformanstag. Also, the methanolic extract (75%) showed significant inhibition of Microsporum canis, and the ethyl acetate extract showed strong activity at a concentration of 750 μg/mL [153].

4.2.5. Hypoglycemic

The leaf extract was found to produce a significant hypoglycemic effect when administered orally or intraperitoneally to diabetic rats treated with streptozotocin. Weight loss was prevented in treated diabetic rats, and plasma insulin levels greatly influenced the survival rate. The results obtained suggest that the aqueous fig extract has a notable hypoglycemic activity [154].

5. The Potential Uses of BV, CV, and Ficus carica in Skin Care and Treatment Products

As the most exposed organ of the body, the skin is vulnerable to numerous environmental factors, including variations in temperature, solar radiation, cigarette smoke, and ozone and chemical pollutants. These are all included in the concept of the “exposure”. This represents the set of influences to which a person is subjected from birth to the end of life and is a relatively new term [155,156]. Psychological stress manifests itself when external demands exceed a person’s adaptive resources, triggering changes at the emotional, behavioral, and physiological levels [157].

Oxidative stress in the skin is directly related to the appearance of age spots. The oxidation of lipids and proteins leads to the accumulation of lipofuscin, which, along with melanin, contributes to dark spots that are difficult to degrade by hydrolytic enzymes [158]. Oxidative and inflammatory processes stimulate the production of neutrophil elastase and metalloproteinase-8 (MMP-8), which contribute to the degradation of collagen and elastic fibers, thus favoring the appearance of wrinkles [159]. Preventing signs of aging, such as dry skin, loss of firmness and elasticity, or wrinkles, is a major challenge. Aging brings visible changes in the epidermis, dermis, and subcutaneous tissue. At the level of the epidermis, there are the thinning of the layers, the flattening of the dermal-epidermal junction, the reduction in natural hydration, the decrease in lipids and their oxidation, and increased transepidermal water loss (TEWL). In the dermis, the following are observed: the reduction of fibroblasts and the production of collagen and elastin, fiber degradation, and the loss of skin elasticity, associated with a decrease in hyaluronic acid [160,161].

Over time, research into anti-aging solutions has constantly evolved. The bioactive substances in moisturizers support the skin barrier and reduce skin damage through hydration and lipid protection [155]. Anti-aging ingredients inhibit enzymes that degrade collagen and elastin. Products with natural ingredients are popular for caring for dry and mature skin, improving hydration, and protecting skin structure, but their effectiveness in vivo requires further research [160,162,163].

5.1. BV—Beneficial Actions for the Skin

BV has been studied and found to be used in the treatment of various skin conditions, including atopic dermatitis, acne vulgaris, alopecia, morphea, melanoma, vitiligo, psoriasis, and for wound healing, but it is also widely used in cosmetics in the form of topical preparations [164] (Figure 1).

Thus, BV is included as an active ingredient in various cosmetic products such as face creams, balms, masks, and serums, and is used due to its astringent, anti-inflammatory, anti-aging, and antibacterial properties [165,166,167].

5.1.1. Healing and Regenerative Properties

BV has been shown to stimulate tissue regeneration and wound healing, being used in various formulations to improve the healing process [168]. Amen et al. studied a wound dressing with a content of 4% BV, 10% polyvinyl alcohol, and 0.6% chitosan on diabetic rat models, which, after application, demonstrated an improvement in wound healing, and also an anti-inflammatory effect like other natural preparations [169,170].

Another group of researchers focused on developing a hydrogel-based on PVA (polyvinyl alcohol) and chitosan (promising excipient for retard dosage forms) [171], with BV incorporated. The study showed that the integration of BV significantly improved the morphological, physical, and mechanical properties of the hydrogel. In addition, the antioxidant and anti-inflammatory activities of this formulation accelerated the wound healing process, especially in skin regeneration in patients with diabetes. The use of topical preparations reduced systemic side effects, suggesting that hydrogel-based formulations may provide good patient compliance due to their safety and efficacy profile [172].

The results of research on mice concluded that the use of BV significantly increased wound closure in diabetic animal models by improving collagen production and restoring the inflammatory cytokines TGF-β and VEGF [173].

5.1.2. Anti-Inflammatory and Soothing Properties

BV can reduce redness and inflammation, making it beneficial for sensitive or irritated skin from various dermatological conditions.

Acne

Currently, there are numerous studies demonstrating the effectiveness of BV in the treatment of acne: A double-blind randomized control trial was conducted by Han et al. on 12 subjects for 14 days to observe the effects of purified BV in this condition. The mechanism was examined by scanning electron microscopy and transmission electron microscopy. It was found that participants who used products containing BV had a 57.5% reduction in ATP (adenosine triphosphate) levels. There was a significant difference in gradation levels based on the number of inflammatory and non-inflammatory lesions in favor of subjects treated with venom compared to the control group. Researchers have also observed and reported that BV has concentration-dependent antimicrobial activity [174].

Another prospective, non-comparative study was conducted by Han et al. on 30 acne subjects who used a purified serum (purified BV diluted in cold sterile water) twice daily for 6 weeks. A clinical evaluation of the lesions was performed at weeks 0, 3, and 6, with a percentage improvement in acne of 52.3% after 6 weeks. Marked therapeutic effects were obtained, and 77% of the volunteers showed a visual improvement at the end of the research [175].

An et al. studied the effects of BV on skin inflammation caused by Propionibacterium acnes (responsible for the appearance of inflammation in acne). P. acnes was injected intradermally into the ears of mice and BV (in concentrations of 1, 10, and 100 μg, mixed with 0.05 g of petroleum jelly) was applied only to the right ear. A decrease in inflammatory cell infiltration and a reduction in IL-1β and TNF-α have been observed in the ear treated with BV [176].

Lee et al. studied the therapeutic effects of melittin on P. acnes-induced inflammation. The thickness of the ears of mice injected with melittin showed a 1.3-fold reduction compared to those in which P. acnes alone was injected and significantly decreased the expression in TNF-α and IL-1β, the results demonstrating that melittin has the potential to be used as an alternative treatment in inflammatory skin diseases caused by P. acnes [177].

Atopic dermatitis

The anti-inflammatory effect of BV has also been demonstrated in the treatment of atopic dermatitis. Patients who used emollient topically with BV had a lower eczema area, severity index, and visual analog scale value than patients who used emollient without BV [43].

The anti-inflammatory activity of apamin has been investigated in the context of TNF-α- and IFN-γ-induced inflammatory responses in human keratinocytes, specific to atopic dermatitis. The results indicate that apamin has a significant role in atopic dermatitis due to its anti-inflammatory properties [178].

Vitiligo

BV has been shown in an in vitro study to stimulate melanocyte proliferation in a dose-dependent manner at concentrations of 10 μg/mL or higher for 7 days, resulting in an approximately two-fold increase in melanocyte counts compared to the control group. Research results suggest that BV may be a potential ingredient in various formulations designed to treat vitiligo [179].

Psoriasis

BV has the potential to become a new therapy for localized plaque psoriasis. Administered intradermally either alone or in combination with oral propolis, BV has proven to be an effective treatment for this condition. BV decreases the levels of IL-1β, TNF-α, and IL-6, due to the presence of melittin, which inhibits the expression of inflammatory genes. Venom also reduces COX-2 expression, thereby decreasing the production of prostaglandins involved in inflammation [180].

In a randomized double-blind clinical trial, 25 patients aged 18 to 60 years who suffered from recalcitrant localized plaque psoriasis (RLPP) were treated with BV. Treatment was administered once a week for 3 months, starting with a dose of 0.05–0.1 mL, which gradually increased to 1 mL per injection. A complete response was observed in 92% of the patients treated with BV. The side effects were minor, including erythema, moderate pain, and mild swelling at the injection site, all of which were manageable [181].

5.1.3. Anti-Aging/Anti-Wrinkle Properties

BV stimulates the synthesis of collagen and elastin, improving skin firmness and elasticity and reducing wrinkles, making it particularly suitable as an ingredient in mature skincare formulas. Often compared to the effects of botox, this substance influences the mechanisms of cutaneous neurotransmission, relaxing the muscles responsible for facial expressions [182].

The first clinical trial investigating the effect of cosmetics containing BV on human facial wrinkles was led by Han and his collaborators. In this study, 22 South Korean women, aged 30 to 49, applied a facial serum with a concentration of 0.006% BV, using 4 mL of the product twice a day for 12 weeks. The wrinkle changes were assessed by visual examinations by a dermatologist, by analyzing photographs, and by imaging analysis of skin replicas. The results indicated a clinical improvement in facial wrinkles, evidenced by reducing the total surface area, number, and average depth of wrinkles, without causing side effects. Thus, the serum containing BV is effective and safe for reducing wrinkles [183].

A clinical evaluation of the efficacy of a face cream containing BV involved 30 volunteers selected after an irritation test and exclusion criteria. BV was added as an active ingredient and the melittin content was previously measured. Skin condition was assessed at 14 and 28 days, using specific indices and a 9-point scale for 15 skin attributes. During the 28 days of care, improvements were observed in the superficial layers of the skin, consistent with the volunteers’ tolerance and satisfaction assessments. Good tolerance and high satisfaction suggest the potential for long-term continued application, with possible anti-aging effects. The study concluded that BV is an effective active ingredient that, after 14 days of use, demonstrated visible improvements in skin condition, with the potential for better results through extensive use [184].

A group of researchers obtained PLA2-free bee venom (PBV) by removing PLA2 using ultrafiltration of natural bee venom and evaluated its effectiveness as an ingredient in skincare products compared to the original BV. They then investigated its potential cosmetic properties, focusing on its benefits (anti-wrinkle effect) as well as possible adverse effects (cytotoxicity). The results showed that both BV and PBV restore cellular integrity, stimulate collagen production, and inhibit the activity of MMP-1 and -13 in HaCaT cells, as well as MMP-1, -2, and -3 in UVB-exposed HDF cells. However, BV has an adverse cytotoxic effect, while PBV could offer advantages in preventing wrinkle formation without inducing cytotoxicity. Thus, the use of PBV in cosmetics appears to be a promising strategy for preventing wrinkles and protecting the skin from UVB exposure [185].

5.1.4. Moisturizing and Regenerating Properties of the Skin

BV has been shown to contribute to skin regeneration and improved skin texture. A group of researchers formulated a skincare prototype with a content of 0.1% BV, 0.3% propolis extract, 0.45% honey, and 1.0% royal jelly. The prototype body cream was analyzed for stability, activity, antioxidant, dermatological response, and cytotoxicity. The results showed stability at room temperature and +40 °C for up to 90 days, a high antioxidant capacity (85.45%), a lack of cytotoxicity, and an absence of irritation or side effects. The prototype was observed to brighten and moisturize the skin, reduce the visibility of wrinkles, and improve skin elasticity [186].

5.1.5. Hair Growth Stimulating Properties

BV demonstrated significant potential in stimulating hair growth, according to a study in which various concentrations of BV (0.001%, 0.005%, and 0.01%) were used, compared to the effects of applying 2% minoxidil [187].

5.2. CV- Beneficial Actions for the Skin

One of the compounds commonly used in cosmetic products is bioactive peptides, which comprises chains of amino acids with specific sequences that give them biologically active properties, capable of influencing various functions of the body. Even in low concentrations, these peptides can exert a wide range of activities, including moisturizing, antibacterial action, and regenerating or nourishing the skin. The effectiveness of peptides is directly related to their amino acid sequence [188]. Proteins and peptides derived from natural sources are particularly appreciated, being extracted from both animal and plant sources. For example, animal-derived peptides can be obtained from BV or snake venom [189]. Peptides in snake venom have demonstrated anti-aging properties and are protected by patents, an example being snake venom-derived pentapeptide-3 (GPRPA) which has demonstrated a reduction in wrinkles and skin roughness [190].

Healing and Regenerative Properties

CV in small and controlled doses can promote tissue regeneration through its effects on cells and blood vessels, promoting healing and proving that it can be a potential ingredient in various pharmaceutical and cosmetic formulations with beneficial effects on the skin [191] (Figure 2).

5.3. Ficus carica—Beneficial Actions for the Skin

Plant extracts and phytochemical compounds with antioxidant, anti-inflammatory, and immunomodulatory properties play an essential role in skin protection. They can neutralize free radicals, stimulate antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX), and reduce inflammation by regulating cytokines and inhibiting pro-inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) [192,193,194]. Traditional medicine has mainly focused on the use of figs to treat dermatological problems [149]. Clinical studies have shown that extracts from Ficus carica improve skin hydration, reduce transepidermal water loss, and normalize sebum production, thus contributing to maintaining skin health under conditions of psychological stress [195]. The main constituents of fig and their effects on the skin are presented in

Table 3. The main phytochemicals in Ficus carica and their effects on the skin.

Phytochemical Substances	Effects	Reference
Myricetin	Reduces sebum secretion	[196,197]
Luteolin	Anti-inflammatory, anti-allergic, eczema treatment	[198,199]
Quercetin	Anti-inflammatory, anti-allergic, eczema treatment, reduces sebum secretion	[196,197,199]
Kaempherol	Reduces sebum secretion	[150]
Gallic acid	Reduces transdermal water loss, reduces melanin secretion, reduces sebum secretion	[196,197]
Syringic acid	Reduces transdermal water loss, reduces melanin secretion, reduces sebum secretion	[150,196,197]
Ficin	Antioxidant activity Preserves the integrity of the skin, prevents premature aging, reduces oxidative stress	[200,201,202]
Vitamin C	Stimulation and acceleration of collagen synthesis in the dermis, antioxidant action Reduction of transdermal water loss, hydration of the dermis, stimulation of collagen synthesis, decrease of sebum secretion Anti-wrinkle and anti-acne effect	[150,203]
Catechines	Reduces melanin secretion, reduces transdermal water loss Antioxidant effect	[150,204]
Epicatechin	Antioxidant effect Reduces melanin secretion, reduces transdermal water loss	[150,204]
Chlorogenic acid	Reduces melanin secretion	[150]

.

5.3.1. Anti-Aging/Anti-Wrinkle Properties

Ficus carica has significant potential in the field of cosmetics, especially due to its content of ficin and phenolic compounds. These substances help protect skin cells against oxidative stress caused by psychological stress. Ficus carica extract is effective in reducing oxidative damage to lipids and proteins, thereby protecting skin integrity and preventing premature aging [202].

Ficin, a proteolytic enzyme, plays a key role in the antioxidant activity of the extract, especially at normal skin pH (4.5–5.0), reducing the markers of oxidative stress such as lipid peroxides and carbonyl proteins [200,201].

A study conducted by researchers demonstrated that water-soluble extract from Ficus carica cultures (FcHEx) has significant antioxidant and anti-inflammatory properties, protecting the skin from oxidative damage caused by psychological stress. By reducing oxidative stress, inflammation, and transepidermal water loss, FcHEx helped restore the skin barrier, regulate sebum production, and maintain optimal skin pH. Clinical trials have confirmed the effectiveness of the extract in improving the health and appearance of the skin under stress, preventing collagen degradation, the appearance of wrinkles, and skin color changes. These results suggest that FcHEx has considerable potential to be integrated into skincare products, especially for dry and stressed skin [205].

Plant extracts rich in compounds such as flavonoids, phenolic acids, tocopherols, alkaloids, and monoterpenes, recognized for their antioxidant and anti-inflammatory properties, are commonly used in the development of topical cosmetics [206]. Studies show that blends of plant extracts offer superior efficacy in herbal medicine compared to products containing single extracts [207]. A group of researchers evaluated the antioxidant, anti-collagenase (in vitro) and anti-wrinkle (in vivo) properties of a formulation combining the extracts of Ginkgo biloba, Punica granatum, Ficus carica, and Morus alba [208].

Ginkgo biloba (Ginkgoaceae family), known for its flavonoids and terpenoids, was chosen for its demonstrated photoprotective effects [209]. The fruit extract of Punica granatum (Punicaceae family) was selected because it is used extensively in cosmetics and therapy for protection against UV damage and inhibition of matrix metalloproteinases, thus preventing collagen degradation [210,211]. The other two products in the formulation were Ficus carica (due to the content of phenolics and organic acids that contribute to antioxidant and anti-inflammatory protection), and Morus alba (Moraceae family) which is distinguished by its content of polyphenols and flavonoids, having antioxidant and antimicrobial effects [212,213,214]. Collagenase is a metalloproteinase that breaks down essential proteins such as collagen and elastin, and inhibiting this enzyme can help maintain the integrity of the dermal matrix and prevent skin degradation [215]. The randomized, open-label, simple-blind, placebo-controlled, observer-blind study was conducted on 21 women aged 45 to 65 years. Participants applied twice a day, for 56 days, a cream with 2% fruit extract on one side of the face and on the other side a placebo. After 28 days, no significant differences were observed, but at the end of the 56 days there was a significant decrease in the depth, length, and surface of the wrinkles on the treated side. Antioxidant tests evaluated the ability to capture free radicals (DPPH, H₂O₂, and O₂⁻), and the extracts showed strong antioxidant activity, comparable to or above reference standards. The inhibition of oxygen radicals has also been shown to be dose-dependent. Anti-collagenase activity was measured by in vitro inhibition of the collagenase enzyme, with significant results at a concentration of 5 μg/mL (67.45% inhibition) and variable effects at lower doses (between 12.03% and 55.61%). The results showed that the synergistic formula of these plant extracts provides significant protection against collagen degradation and oxidative stress, while also having a notable impact on reducing wrinkles on human skin [208].

5.3.2. Anti-Inflammatory and Soothing Properties

The phenolic compounds in Ficus carica help reduce inflammation and improve skin-barrier function by inhibiting pro-inflammatory cytokines, such as interleukin-6, and reducing the effects of stress hormones, such as epinephrine. They have gained popularity in skin care due to their properties to combat dryness, eczema, and acne, neutralize free radicals, prevent aging, and protect the skin [216,217]. Myricetin, quercetin, kampferol, gallic acid, syringic acid, and rutin are substances detected in Ficus carica that can inhibit the activity of the enzyme 5-alpha-reductase, resulting in a reduction in sebum levels when applied [197].

Khan et al. aimed to evaluate the effects of a cream containing Ficus carica L. fruit extract on various skin features, including melanin, erythema, hydration levels, transepidermal water loss, and sebum production. For this research, a formulation was designed with a concentrated extract of 4% of Ficus carica fruits, along with an extract-free base, used as a control. Both products were applied to the cheeks of male volunteers for 8 weeks twice a day, using non-invasive bioengineering tools to analyze the impact on different skin parameters. These included the Mexameter reflection spectrophotometer for measuring melanin and erythema, the Tewameter MPA 5 timer for analyzing water loss from the dermis and the water content of the stratum corneum, and the MPA 5 sebometer for assessing sebum secretion. To test a possible irritative action, patches were applied to both forearms of the participants, each having either the base or the forms, and after 48 h, a specialist doctor analyzed the presence of irritations. After applying the base, minor oscillations in melanin levels were observed, while the use of the extract demonstrated a steady decrease in melanin content, due to the action of substances that inhibit the activity of tyrosinase, known for their depigmenting activity. Analyses have shown that the antioxidants and vitamin C in fig extract help reduce transepidermal water loss and stimulate collagen synthesis. A significant decrease in sebum production has also been observed, indicating that a stable local cream containing F. carica fruit extract may have anti-wrinkle and anti-acne potential [150].

Research has also focused on the benefits of fig extracts in other skin conditions: relieving the symptoms of atopic dermatitis (suggesting that they may be an alternative to corticosteroids), melasma (as an alternative to hydroquinone in topical preparations), psoriasis, and wound healing [164]. It has also been shown that the juice obtained from fig leaves can be beneficial in vitiligo due to the presence of furanocoumarins such as psoralen and daidzein [218].

5.3.3. Skin Moisturizing Properties

Fig fruits are an important source of ascorbic acid (vitamin C), recognized for their role in stimulating and accelerating collagen synthesis in the dermis, and by increasing collagen production, the hydration of the dermis is improved [203]. The fruits also contain phenolic compounds and flavonoids that can reduce skin melanosis by inhibiting tyrosinase, a key enzyme in melanin synthesis. These properties make Ficus carica fruit extract useful in skin depigmentation and moisturizing products. Additionally, fig fruit extract has demonstrated a significant reduction in transepidermal water loss and an increase in hydration, making it a promising ingredient for skincare products [150]. Research results highlight the potential of Ficus carica extract as an essential natural ingredient in skin treatment, protection, and regeneration products, with possibilities for use in various conditions [219,220] (Figure 3).

6. Safety Profile

Looking back at ancient times, we discover that some of the natural ingredients are still used today, and this shows us the importance of rigorous testing for their efficacy and toxicity, as not all natural ingredients are automatically safe [221,222,223].

The use of venom or venom-derived products always carries a risk, as they can cause severe side effects. These products contain extremely potent toxins or modified molecules derived from venom toxins, which can alter normal physiological functions. Compared to raw venom, toxicological studies and evaluations of side effects are relatively less complex for isolated or modified toxins [224].

6.1. BV—Safety Profile

BV therapy can be administered in the following various ways: by direct puncture at specific points, injections with pure and sterile homeopathic preparations, using ointments, gels, creams, lotions, capsules, drops, as well as intravaginal suppositories containing BV [225]. BV is considered an alternative to synthetic topical treatments but can sometimes cause allergic and anaphylactic reactions depending on the dose administered and the individual immune system, so clinical application is limited [226].

It has been found that an average of 140–150 μg of venom is delivered by a bee sting, and the average lethal dose (LD50) of bee venom is between 2.8 and 3.5 mg of venom per kg of human body weight [19,227]. The occurrence of allergic reactions is the main challenge to the approval and routine use of BV. Hypersensitivity to venom can lead to a severe systemic allergic reaction, which can sometimes be fatal [228]. Phospholipase is the main allergen, and implicitly, the most toxic component of bee venom. It acts aggressively on the cell membrane, causing cytolysis. This effect is amplified by the presence of melittin and lysolecitin, which are generated by the action of phospholipase [30]. Studies have shown that BV is dual, with compounds such as amine and melittin providing anti-inflammatory and analgesic properties, but which can also cause irritation and allergic reactions in sensitized individuals [226]. Topical administration of BV is well-tolerated in human skin, as it has shown no risk of dermal irritation in animal studies [229].

To assess the skin tolerance of cosmetic products with BV, a patch test was performed on volunteers under medical supervision. A 0.1 mL BV solution at a concentration of 0.001% was applied to a 1 cm² piece of filter paper, placed on the volunteer’s forearm and fixed with a hypoallergenic occlusive tape. The patch was maintained for 48 h, after which it was removed, and the area was evaluated after 30 min and then at 96 h (according to current guidelines, the evaluation of adverse reactions is performed at 48 h and 72 h, and if any adverse reaction occurs, an additional evaluation is performed at 96 h) [184].

To minimize adverse effects, research is currently underway to discover safer practices combined with innovative delivery systems [230].

The researchers’ interest is to discover various solutions for the transdermal administration of BV primarily safely, but also with satisfactory therapeutic effect, which has led to the use of the product embedded in nanoparticles as a delivery vehicle [16].

6.2. CV—Safety Profile

In 1986, LD ₅₀ was determined for snake venom for the first time, using mouse models. Research has shown that venom obtained from the same species of the snake here but from different geographical areas may have different LD ₅₀ values, and the approximate LD ₅₀ for the snake Naja naja was determined in mice to be equal to 0.05 μg/g body weight [231]. A study conducted many years ago in vitro and in vivo by Angeletti concluded that NGF in Naja naja showed no toxic effects [232].

Other more recent research suggests that the clinical use of Naja atra venom (NAV) and cobrotoxin (the neurotoxin in NAV) would be safe. Thus, experiments on mice, using Bliss tests, established that the LD ₅₀ of NAV venom was 102.3 mg/kg for oral administration, 996.6 μg/kg for intraperitoneal injection, and 623.9 μg/kg for intravenous injection. The researchers also measured the LD ₅₀ for cobrotoxin and concluded that by subcutaneous injections it was 59.991 μg/kg, and by oral administration, it was about 90 μg/kg [107].

6.3. Ficus carica—Safety Profile

Ficus carica, in general, has a favorable safety profile, being used in various conditions without showing significant toxicity at controlled doses. In vitro and in vivo studies have shown that Ficus carica leaf extracts did not exhibit cell toxicity or hepatotoxic and nephrotoxic effects at certain doses [151,233,234,235,236].

In one study, to assess the irritating potential of a cream with Ficus carica fruit extract, patch tests were performed on both forearms of each volunteer on the first day of skin evaluation. An area of 5x4 cm was marked on each forearm, where 1.0 g of base was applied on the left forearm and the formulated cream on the right one, covered with surgical dressing. After 48 h, the patches were removed, and an experienced dermatologist examined the skin and found that there were no signs of irritation [150].

However, certain compounds such as furocoumarins and triterpenoids, can cause irritation and phototoxic reactions to topical application, which underscores the need for caution and further research to ensure safe use [237].

7. Modern Approaches to Delivering Bioactive Compounds to the Skin

Recent discoveries on controlled drug delivery systems and nanotechnology-based delivery methods can improve the targeted delivery of an exact amount of ingredient to the desired location, increase bioavailability, and reduce side effects occurring by routine administration [238].

The easy penetration through the skin of various natural or non-natural products has been studied since ancient times; modern approaches consist of encapsulation in nanocarriers (nanoparticles, ethosomes, liposomes, aquasomes, niosomes, transfersomes, novasomes, cubosomes, ultrasomes, photosomes, polymerosomes, fullerenes, dendrimers), the use of stimulus-sensitive materials (wearable devices, patches, etc.), physical methods (thermal ablation, laser microporation, iontophoresis, sonophoresis, electroporation, thermophoresis, or microneedle patches), and the inclusion of chemical permeation enhancers (peptides, alcohols, glycols, fatty alcohols, fatty acids, surfactants) [239,240,241,242,243,244].

In the case of cosmetics, the introduction of nanotechnology was a very important step in improving the overall health of the skin (including pigmentation, dehydration, wrinkles, and fine lines) by improving the distribution of the active ingredient, thus achieving superior and long-lasting efficacy [245,246]. By using nanotechnology, personalized cosmetic products can be made, and the shelf life of the product can be extended [247].

Microneedles (MN) are currently very successful in the cosmetic field, the primary purpose being to deliver various molecules into the skin without causing injury or insignificant damage [248]. Recently, Lim and collaborators used DLP 3D printing technology to create a delivery system for acetyl hexapeptide 3, a small peptide known for its safety and effectiveness as an anti-aging molecule. The results showed a good skin penetration capacity of the developed MN patch and a future potential in the delivery of anti-wrinkle products [249].

Hyaluronic acid-based microneedles with a content of bioactive peptides were designed by Avcil and collaborators and applied to 20 volunteers. A 25.8% reduction in wrinkles was observed, and an improvement in skin hydration by 15.4%, without the occurrence of side effects [250].

Studying and developing suitable formulations for the topical treatment of acne through the use of nanotechnology is a strategy capable of overcoming some of the disadvantages that can occur using natural products [251]. In the treatment of acne, the target site of action is the hair follicle, thus, nanomaterial systems are made for the delivery of the trans-follicular and follicular drugs [252]. It has been concluded that silver and gold nanoparticles have the potential to be used in the treatment of acne, but further controlled studies are needed to demonstrate clinical efficacy [253].

Lipid-based nanosystems that include liposomes, transfersomes, niosomes, invazomes, ethosomes, cubosomes, sphingosomes, acvazomes, and ufasomes, have been studied and have shown promising results for the transport of various anti-acne agents [254].

7.1. BV—Nanoformulations and Delivery Systems for Topical Use

Bee-sting therapy is recognized as a traditional therapeutic approach, but it has a few drawbacks, including considerable discomfort for patients. Due to the short half-life of melittin, repeated injections are required to maintain effective concentrations. It can induce inflammation and make it difficult to maintain constant blood concentrations [255].

Discoveries in drug delivery have introduced more complex approaches to BV therapy, including the use of controlled-release systems.

7.1.1. Niosomes

A recent study investigated the potential of melittin-laden liposomal vesicles against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), and clinical isolates of the intermediate vancomycin Staphylococcus aureus (VISA). The liposomal vesicles were prepared for dermal and transdermal use, and surfactants (Tween 80 and Span 60) were used in different ratios. The effective inhibitory activity of melittin on skin pathogens has been demonstrated. Of the strains tested, VISA was more susceptible to melittin. This formulation also showed an excellent ability to improve drug distribution in the stratum corneum and was able to restrict the spread of bacterial infection in ex vivo pig-ear skin models. This observation suggests that melittin-laden niosomal vesicles have the potential to be further developed for skin treatment and may be candidates for topical application [256].

7.1.2. Nanoemulsions

To facilitate the passage of BV through the skin when used topically, a group of researchers used a nanoemulsion as a nanocarrier. The results of the study showed that the topical administration of water-in-oil nanoemulsion with a content of 18.75 or 9.37 μg/mL BV was able to significantly reduce inflammation in the paws of rat models with induced arthritis, compared to control groups, thus demonstrating the antirheumatic efficacy of the product [257].

7.1.3. Microneedles

With the help of polymeric microneedles made with hyaluronic acid, it has been demonstrated that the transdermal delivery of melittin could become a potential therapy with good results and high compliance in the treatment of rheumatoid arthritis. After modifying hyaluronic acid with methacrylate groups, microneedles with sustained-release properties were obtained [258].

7.2. Ficus carica—Nanoformulations and Delivery Systems for Topical Use

The researchers analyzed a combination of plant extracts, called 4HGF, which includes species such as Phellinus linteus grown on sprouted rice, Cordyceps militaris grown on sprouted soybeans, Polygonum multiflorum, Ficus carica, and coconut oil. The impact on hair growth of 4HGF encapsulated in nanoparticles composed of PGA and chitosan (PGA-4HGF) has been evaluated in both in vitro and in vivo experiments [259].

Previous studies have suggested that Polygonum multiflorum promotes hair regeneration, and coconut oil benefits skin and hair health [260,261,262,263]. Additionally, Phellinus linteus, Cordyceps militaris, and Ficus carica have been found to have anti-inflammatory properties, making them useful in stimulating hair growth [264,265,266,267].

PGA-4HGF nanoparticles can reach hair follicles in the basal layer of the skin, crossing the barrier of the stratum corneum, due to their size of about 400 nm, and improve blood circulation [268,269]. PGA-4HGF has been found to stimulate the β-catenin pathway, facilitating the transition from G1 to S phase by modulating cyclinD1 and CDK4 proteins, as well as increasing keratin II and melanin levels, thus contributing to sustainable hair growth. These results suggest that PGA nanocapsules for 4HGF delivery could represent a promising therapeutic solution for the treatment of hair growth problems [259].

Studies have been conducted with extracts of Ficus carica, embedded in an amphiphilic polymer matrix or gold and silver nanoparticles, their results offering promising prospects for wound treatment and tissue regeneration in diabetes [270,271].

Recent research has demonstrated that an advanced and effective approach to treating diabetes lesions is to use dressings containing polymers, nanoparticles, and various plant compounds [272,273].

Dressings containing Ficus carica extracts (FFE) have been reported to be effective in the treatment of diabetic wounds. A biomaterial composed of PXAG-PHB and FFE demonstrated complete wound healing within 72 h, without adverse reactions, and had strong antimicrobial activity (on Escherichia coli and Staphylococcus aureus). This compound stimulates cell proliferation, and the formation of new blood vessels, and has antioxidant and anti-inflammatory properties, making it a promising treatment for tissue regeneration in diabetic wounds [274].

Ultraviolet (UV) radiation generates reactive oxygen species (ROS) that affect DNA and collagen. Once on the surface of the skin, it contributes to the synthesis of vitamin D3, but can also cause immunosuppression, photoaging, and skin cancer [275,276,277].

Synthetic sunscreens are effective, but photostability and toxicity issues limit their use. In contrast, plants have developed, through evolution, natural mechanisms of protection against UV radiation. Natural antioxidants and sunblockers have proven to be increasingly valuable for cosmetic formulations [278]. The results of a study highlighted the significant effect of silver nanoparticles (AgNPs) stabilized with Ficus carica extract on the sun protection factor (SPF) of various natural extracts and commercial sunscreen products. The AgNPs, obtained by adding latex to the silver nitrate solution, were characterized as spherical, with an average size of 163.7 nm and a cubic structure of the fcc type, with a stability of six months. The incorporation of AgNPs at concentrations of 2% and 4% in sunscreens demonstrated a significant increase in the sun protection factor, with improvements ranging from 0.1% to 12.175% compared to the standard control. This synergistic effect suggests that silver nanoparticles synthesized using Ficus carica latex may enhance the efficacy of commercial sunscreens, providing improved sun protection [279].

8. Possible Synergies Between BV, CV and Ficus carica

Although this review is based on existing literature data, we also want to consider the synergistic potential of the natural products studied when used together in cosmetic formulations. The hypothesis of a synergy is based on the complementarity of the bioactive effects of each ingredient, which could provide significant cumulative benefits for skin health and beauty, maximizing regeneration, preventing ageing and protecting against oxidative stress (

Table 4. Common characteristics and synergistic potential of using BV, CV and Ficus carica for skin care.

Common Characteristics	BV	CV	Ficus carica	Synergistic Potential
Anti-inflammatory properties	Melittin, apamin, decrease inflammation [40,41].	Neurotoxins inhibit inflammation [84,101].	Phenolic compounds have an anti-inflammatory effect [216,217].	The combination could effectively reduce skin irritation and inflammation by providing a complex anti-inflammatory treatment.
Antioxidant properties	Antioxidant compounds neutralize free radicals [64].	Protection against oxidative stress [104].	Phenolic compounds with antioxidant role [150].	Together, they could provide amplified antioxidant protection, preventing skin damage caused by free radicals.
Immunomodulators properties	Stimulation of immune response [65,66].	Immune system modulation [107].	Bioactive compounds support skin immunity [195].	The potential to balance and regulate the skin’s immune responses, reducing the risk of infections and chronic inflammation.
Cosmetic properties	Skin regeneration and hydration [186]. Anti-wrinkle [182].	Lifting effect and anti-wrinkle [190]. Regeneration [191].	Regeneration [219,220]. Hydration [150,203]. Antirid [150].	The potential to create a complex formula that regenerates, hydrates, and prevents wrinkles.
Safety in use	Dose-influenced safety and individual sensitivity [19,226,227].	Variable safety depending on dose and method of administration [107,231].	Generally favorable safety profile [151,233,234,235,236].	Improved safety and optimized efficiency, with reduced risks of irritation and side effects.

).

9. Conclusions

In scientific literature, BV is recognized for its remarkable therapeutic potential, especially in the treatment of inflammatory, autoimmune, and oncological conditions. However, research is still at an early stage, and rigorous research through well-designed clinical trials, standardized protocols and strict safety assessments is needed to turn these findings into effective clinical treatments. As far as dermatology is concerned, BV has shown great benefits, especially for skin tissue regeneration and anti-aging therapies. Due to its antibacterial and anti-inflammatory properties, it is also used in the treatment of some skin conditions, such as acne. However, concerns about possible allergic reactions need to be seriously addressed, especially in the case of cosmetics. BV holds considerable potential in the pharmaceutical and cosmetic fields. And in this context, substantial efforts are being made to develop safe methods of administration, integrated with modern technologies aimed at minimizing the incidence of adverse effects and expanding clinical and therapeutic applicability.

In recent decades, only a small fraction of the components of CV have been identified, characterized, and approved for use in pharmaceuticals, while numerous other components are still in the preclinical or clinical trial phase for possible therapeutic application. It has recently been highlighted that cobra venom, due to its main components (neurotoxins, cardiotoxins, cobra venom factor, phospholipase A2, and nerve growth factor) has multiple therapeutic actions, demonstrating significant potential for the development of drugs intended to treat various conditions. The anticancer activities of CV represent one of the most promising therapeutic characteristics and have been intensively researched and reviewed in recent years. A recent discovery of scientific interest is the ability of CV to intervene in the prevention and treatment of COVID-19. Although it has a huge therapeutic value, CV is not yet fully exploited, and further studies are needed to investigate the mechanisms underlying different pharmacological actions and especially to study the safety profile.

In the current context of scientific research, Ficus carica continues to be a topic of interest due to its bioactive potential and its extensive applicability in various fields, including cosmetics and therapeutics. Preliminary studies have demonstrated a wide range of beneficial properties of compounds isolated from this species, but the need for further research is evident to optimize its use in clinical and commercial practices. In the cosmetic industry, Ficus carica is of considerable interest due to its antioxidant, anti-inflammatory, and photoprotective activities. Identifying and characterizing in more detail the compounds responsible for these effects, such as polyphenols and flavonoids, could lead to the development of new dermo-cosmetic products aimed at preventing premature skin aging, protecting against UV radiation and relieving various skin conditions, including acne and atopic dermatitis. In addition, exploring the synergy between Ficus carica extracts and other natural or synthetic substances can open new horizons in the formulation of products with increased efficacy and optimal tolerability. In addition to cosmetic applications, the possible therapeutic role of Ficus carica in the management of other conditions requires further investigation. Future research should focus on elucidating the molecular mechanisms by which Ficus carica extracts exert their biological effects, as well as conducting rigorous clinical trials to validate their efficacy and safety. These efforts will help strengthen the position of the fig tree as a valuable ingredient both in traditional medicine and in the development of innovative therapeutic and cosmetic solutions.

The use of nanoparticles has proven effective in delivering various bioactive compounds from BV and Ficus carica to the skin, thus improving stability, and bioavailability and allowing for targeted delivery.

Although the three products have different origins and chemical compositions, these natural sources of bioactive compounds share several common pharmacological elements (anti-inflammatory, antioxidant, immunomodulatory, healing, antimicrobial, and neuroprotective), which make them promising candidates for various applications in the cosmetic and pharmaceutical industries.

Ficus carica can amplify the effectiveness of BV and CV, helping to enhance their beneficial effects and reducing the risk of adverse effects due to its well-tolerated nature.

It would be interesting for future research directions to focus on exploring synergies between these ingredients and developing products that make the most of their combined potential. Rigorous clinical trials and research into the molecular mechanisms by which these substances interact will be essential to develop innovative solutions that not only treat the visible signs of aging but also improve skin health in the long term. By investigating these synergies and optimizing formulations, new perspectives will open in the pharmaceutical and cosmetics industry, offering more efficient and safer products.

Given the exciting challenges in the field of discovering natural ingredients for various uses, we are motivated to continue scientific explorations and end this journey with the confidence that new bioactive compounds are waiting to be discovered, ready to contribute to the advancement of medicine and skin care, and transforming natural resources into valuable allies for human health.