The use of traditional medicine was found to be first implemented in Ancient Greece. According to Greek traditional knowledge, gods gave the knowledge of healing to man. Theophrastus (372–286 BC), a disciple of Aristotle, an ancient Greek philosopher, and a scientist, authored the first scientific system of plants [1]. Although not wholly aware of their exact physicochemical characteristics at the time, the human population has found additional health benefits from plants throughout history. The same components from plant sources that have a long medicinal history and are proven effective in the welfare of human health are indicated within traditional medicine. This traditional medicinal knowledge and colonial expansion through the progress of communication mediums have been transferred over the generations ^[1][2][1,2]. Currently, traditional medicines are becoming more popular for therapeutic use, specifically for self-treatment practices ^[3][4][5][3,4,5].

Calendula officinalis Linn. (CO), as an important plant within traditional medicine, has found application in the food industry [6] as well as the pharmaceutical industry [7] owing to the presence of secondary metabolites in the plant. The Calendula genus covers approximately 25 species, among which C. officinalis, C. arvensis, C. tripterocarpa, C. stellata, and C. suffruticose are the most common [8]. CO is the most studied species of Calendula. It has been used medicinally since the 12th century ^[9][10][9,10] and is known as English Marigold, Pot Marigold, Holigold, Mary Bud, Marybud, or Mary Gowles. The name Calendula originates from the Latin term “calends” denoting the first day of each month when the Calendula flower blooms. Along with this, Calendula has also been referred to as the “herb of the sun”, considering the efflorescence of Calendula flowers in the morning and their shriveling in the evening. For a long period, this traditional herb has been used to treat minor burns, wounds, and skin problems. Currently used CO medicines include pot marigold tincture and carophyllenic ointment, which both contain carotenoids derived from the flowers. It is one of the ingredients of the branded homeopathic drug Traumeel^®, which is intended to relieve the pain and swelling brought on by sudden musculoskeletal injuries [11]. Moreover, many sources suggest using Calendula petal powder as an economical substitute for saffron because its coloring and flavoring aided in food products in early times [10].

CO is a self-seeding, annual plant species that grows to a height of 12–18 inches and is found near warm and humid atmospheric conditions [12]. A 5 to 7 cm composite flower head rests on the plant’s stem. The flower head consists of an epicalyx of multiple tapered lanceolate sepals, compactly overlayed on each of the two sides by glandular hairs and yellow-orange tubular florets on the interior side ^[9][13][9,13]. CO powder is a yellowish-brown powder with a distinctive aromatic smell and a mildly bitter taste. It contains normocytic stomata in the outer epidermis’ apical region, fragments of the corolla, covering and glandular trichomes, elongated sclerenchymatous cells, fragments of the walls of the ovaries containing brown pigment, pollen grains, fragments of stigma, and fibrous fragments. CO plants are abundantly seen in Central Europe and the Mediterranean regions ^[14][15][14,15]. It is also found in Middle Eastern countries, specifically Cyprus, Turkey, and Iran. In addition, Calendula cultivation has also been observed in India and China on a larger scale ^[16][17][16,17].

It is considered a safe medication when considering its therapeutic potential with a proper dose and other pharmacological indications ^[9][18][9,18]. Some toxicological studies have even proven the safety of acute and subacute administration of Calendula in terms of biochemistry and physical parameters. According to the European Medicines Agency, CO oil is classified as a herbal medical product and has a claimed LD 50 (lethal dose 50) value of 20 mL/kg of body weight ^[10][19][10,19].

Many ailments have been treated with CO; a plant frequently used in homeopathic medicine. Additionally, it can be cytotoxic and inhibit tumor growth ^[20][95]. It functions as an antimicrobial ^[21][22][56,96], antioxidant ^[23][97], anti-inflammatory ^[24][25][89,98], antiseptic ^[26][99], anti-viral ^[24][89], hepatoprotective ^[21][56], and antidiabetic medicine ^[27][100]. It is also applied to the skin to treat various conditions, including inflammation of the skin, open wounds, and laceration wounds that bleed. Additionally, it is used to heal minor ailments such as razor burns and wind burns. The major parts of the CO plant and their therapeutic applications discussed in this resviearchw are represented in Figure 12 and Table 13.

CO is currently being investigated, as it exhibits excellent anti-inflammatory activity. Alkaloids, tannins, flavonoids, essential oils, sterols, saponins, carotenoids, triterpene alcohols, mucilage, polysaccharides, and resin are only a few of the categories of secondary metabolites that the plant has that are correlated with the anti-inflammatory characteristics ^[38][110]. Dried flower heads or dried ligulate flowers are plant components that are utilized in medicine and cosmetics. The ligulate flowers are rich in triterpene alcohols, triterpene saponins, fatty acid esters, flavonoids, carotenoids, coumarins, hydrocarbons, essential oils, and fatty acids ^[39][111]. Using in vivo pharmacological testing, it has been determined that the triterpenoid fatty acid esters are responsible for the anti-inflammatory effects of Calendula flowers. The lauryl, myristoyl, and palmitoyl esters of faradiol are the most prevalent of these ^[40][112], demonstrating that flower extract of CO was much more effective for treating both acute (caused by dextran and carrageenan) and chronic (caused by formalin) swelling in mice. They hypothesized that it may be attributed to the inhibition of the production of proinflammatory cytokines (IL-6, interleukin 6; IL-1β; TNF-α, tumor necrosis factor α; and IFN-γ, interferon γ) and COX-2 (cyclooxygenase 2), and subsequently, Refs. ^[40][41][112,113] demonstrated the anti-inflammatory activity of CO extract and investigated its effects on nitric oxide production. The results revealed that the CO extract inhibited nitric oxide production in a dose-dependent manner, with cytotoxicity only observed at 147 μL/mL concentrations or above.

Garrido-Suárez ^[25][98] studied the antinociceptive effects of CO cream on inflammatory hyper-nociception. Rats were subjected to several tests, and it was reported that CO cream (20% or 30% w/w), when applied topically, led to a significant decrease in TNF-α and suppression of COX-2. Pharmaceutical formulations such as nanoemulsion ^[42][114] have also been developed to achieve the anti-inflammatory effects of CO. Furthermore, the scientists discovered that all three samples of Calendula extract (3, 5, and 7%) had beneficial effects on healing and soothing wounds when applied to albino rats. The Calendula extract nanoemulsion has an anti-inflammatory impact on skin cells, according to the findings. The schematic representation of the anti-inflammatory effects of CO is shown in Figure 23. The aforementioned information reveals the potential uses of CO as an anti-inflammatory and analgesic agent. Considering this characteristic of CO, it was able to minimize dermatitis in newborns caused by diaper friction when compared to Aloe vera ^[28][101]. In the oral cavity, mouth rinsing with CO tincture reduced gingival inflammation ^[29][58].

Plant polyphenols such as flavonoids are among the most significant natural compounds with active antioxidant properties. The radical scavenging or chelating flavonoids are caused by their hydroxyl group content ^[43][44][115,116]. The family of antioxidants ^[43][115] as phenolic chemicals, on the other hand, operate as free radical terminators ^[45][117]. Hence, CO’s high flavonoid and phenolic phytochemical content contribute to its antioxidant activity, which can further promote its strong radical-scavenging capacity and confer protective effects ^[32][104]. The leaves and petals of the CO plant contain natural sources of antioxidants ^[21][56]. As a result of riboflavin’s photoreduction, it has been claimed that CO extract scavenges hydroxyl and superoxide radicals. Pandey et al. ^[46][118] examined the antioxidant properties of the leaves and flowers of CO by using TBA (thiobarbituric acid) and FTC (ferric thiocyanate) techniques. The FTC technique calculated the amount of peroxide produced during the initial stage of linoleic acid peroxidation. The results revealed that the antioxidant concentration decreases with decreasing absorbance value. When compared to regular Vitamins C and E, the aqueous extract of leaves and petals exhibited a high level of antioxidant effect based on absorption rates. The fact that the aqueous extract of the petals displayed lower absorbance with both the FTC and TBA techniques suggests that the petals possessed more antioxidant activity than the leaves.

Based on the evidence, it can be concluded that CO extracts may be extremely beneficial in treating several ailments such as AIDS (acquired immunodeficiency syndrome), heart disease, malaria, diabetes, stroke, cancer, and arteriosclerosis due to their potent antioxidant activity.

Saponin, one of the separated active compounds of CO, has been shown to exhibit antimutagenic action ^[47][119]. The interest in the purported anti-tumor activity of CO extracts and components has grown with the rise of complementary and alternative medicine based on herbs as cancer treatment. Cruceriu et al. ^[48][120] demonstrated the anti-tumor activity of methanolic extracts of CO using a cell line study. The authors reported that CO extracts could exert anti-cancer activity by inducing apoptosis, activating caspase 3 and caspase 7 at a protein level, and downregulating cyclin D1, D3, A, E, and several cyclin-dependent kinases. Furthermore, BAX (Bcl2 associated X protein) and BBC3 (Bcl2 binding component), two proapoptotic genes, were upregulated and NF-κB (nuclear factor kappa-light-chain enhancer of activated B cells) and STAT3 (signal transducer and activator of transcription factor 3) were downregulated after the treatment with CO extracts. Similarly, Hernández-Rosas et al. ^[49][121] demonstrated the in vitro cytotoxic effects of hydro-alcoholic extract of CO on human cancer cell lines. The authors found that the biological activities of high free-radical scavenging capacity (ABTS; 2,2-azino-bis (3-ethylbenzothiazoline-6sulfonic acid, DPPH; 2,2-diphenylpicrylhydrazyl), moderate ability to neutralize hydroxyl radicals, effective metal chelation, and strong reducing capacity are responsible for the anti-cancer effect.

Clinical studies have shown the use of CO in different presentations. At the beginning of the 20th century, the clinical study conducted by Pommier et al. ^[30][102] showed the efficacy of Calendula ointment as adjuvant therapy when compared to trolamine for acute dermatitis during irradiation in the treatment of breast cancer. In another study, promising results showed the use of CO gel on oral leukoplakia when compared to lycopene gel ^[31][103]. In oral mucositis, the 2% CO mouthwash was able to decrease oral mucositis when compared to the placebo group ^[32][104].

In conclusion, there are encouraging findings about CO’s prospective usage in cancer management, particularly in cancer prevention, treatment of cancer, and palliative care for cancer patients. However, progress to pertinent preclinical studies is impeded without understanding the bioactive components responsible for the in vitro and in vivo selective cytotoxicity and for preventing radiotherapy-induced adverse effects. As a result, further study is required to find novel components of CO that have the potential to become useful bioactive components in the treatment of cancer.

Chronic wounds and delayed wound healing are major medical issues that provide difficult clinical challenges for doctors and have profound socioeconomic consequences. Since ancient times, herbs and their preparations have been utilized in addition to traditional medicines to expedite the healing of wounds. In this context, preparations (alcoholic and lipophilic) made from the flowers of CO have received stellar reviews for treating mild skin inflammations and slow-healing wounds. This is accomplished by enhancing the amount of blood and oxygen delivered to the wound site, which encourages the body to produce new tissue. CO plants’ dried petals are used to make tinctures, ointments, and washes to cure mild infections, scrapes, bruises, and burns. CO also contributes to maintaining calmed, hydrated skin by encouraging the development of collagen, a necessary protein for radiant skin.

Deka et al. ^[26][99] stated that CO could dramatically increase wound angiogenesis and collagen metabolism, which results in scar softening and emollient characteristics. The floral extract of CO, when applied topically and orally, has therapeutic properties for burns and wounds. An increase in collagen-hydroxyproline and hexosamine shows that the person or animal being treated is mending their wounds. Gunasekaran et al. ^[50][122] demonstrated the wound-healing activity of CO in the winter strain of albino rats. The results revealed that a herbal ointment containing CO could inhibit the activation of macrophages and speed up the migration and proliferation of keratinocytes and fibroblasts, which were responsible for wound healing. This was accomplished by preventing the release of proinflammatory cytokines and reducing oxidative stress at the wound site. The mechanism of action of CO for wound healing is shown in Figure 34.

Similarly, Rathod and co-workers ^[51][123] investigated the wound-healing efficacy of CO-loaded collagen films on wounds induced in Wistar rats. On day 21, the rate of wound contraction in the developed CO film was considerably higher than in the control group, the placebo-treated group, and the marketed-product-treated group. In a randomized controlled trial, the CO-containing ointment was studied on 72 qualified primiparous females for cesarean wound healing. According to the findings, applying CO ointment to the wound after a cesarean significantly boosted the rate of wound healing. It can be successfully employed to speed up the cesarean healing process ^[52][124].

It is important to note that clinical studies have already been conducted in order to evaluate the efficacy of the use of CO in the healing of hand and finger wounds by secondary intention. In this perspective, there is evidence showing that CO extract is favorable for the treatment of these wounds by reducing the epithelialization time and increasing the healing speed ^[33][105]. In chronic wounds, such as venous ulcers, the use of CO also obtained positive results, showing that the treatment with topical CO reduces the surface area of the lesion, achieves greater epithelialization in less time, and accelerates healing time ^[34][106]. In addition, this type of healing is advantageous because it reduces medical interventions and treatment costs ^[53][125]. Another important finding is that the use of CO ointment after episiotomy reduces pain, redness, and swelling and helps healing ^[35][107].

Most substances that enter the body are processed by the liver, which is also in charge of detoxification. Up to 83% of all pathological cases worldwide are hepatotoxic, making it the most prevalent disease. The main causes of liver toxicity include hepatitis, viral infections, dietary additives, alcohol, toxic industrial chemicals, air pollution, and water pollution. Researchers have shown that CO extracts can protect the liver from the cytotoxicity and oxidative stress caused by carbon tetrachloride. This results in a rise in the amount of total hemoglobin. Similarly, in vitro and in vivo models of the flowers’ hydro-alcoholic extract show decreased hepato-cytolysis and liver biomarkers. The treatment with ethanolic extract brought back normal levels of hepatic blood markers, increased the level of total thiols, decreased levels of total antioxidant status, decreased levels of antioxidant enzymes (CAT, catalase; SOD, superoxide dismutase; GPx, glutathione peroxidase; and GST, glutathione s-transferases) and decreased the levels of malondialdehyde and total oxidant status in both the blood and the hepatocytes. Furthermore, restoration of cellular antioxidant levels, specifically enhanced levels of reduced glutathione enzymatic components and total thiols of the antioxidant system, was also observed, which may be due to the polyphenolic chemicals in CO that protect the cells from chemically induced cellular damage. Moreover, in a dose-dependent manner, CO extract improved the histological picture of the liver, as well as the biochemical parameters and inflammatory cytokines ^[54][126].

In addition to being a major cause of illness in humans and animals, parasitic infections also negatively impact the economy. Due to increased resistance to conventional antihelminthic treatments, there has been a quantum leap toward investigating herbal medicines. Herbs such as CO have been used for centuries to combat parasitic illnesses, and they are still utilized for that purpose in many countries. In a study, Khursheed et al. ^[24][89] investigated the anthelmintic activity in adult Indian earthworms (Pheretima posthuma). It was observed that the ethanolic extracts of CO exhibited anthelmintic activity (paralysis of the worms followed by death) at 10 mg/mL concentration compared with the standard drug, albendazole. CO was also proven to show anthelminthic activity against Ascaris suum ^[55][127] and 50% efficacy on L1-2 larvae of Strongiloides papillosus ^[56][128].

Although antibiotics have played a significant part in the treatment of infectious diseases caused by bacteria and fungi for the past 60 years, it has been observed that the occurrence of dangerous bacteria that are resistant to antibiotics has increased in frequency over the course of the past several decades ^[57][129]. Because there are a number of different mechanisms by which drug resistance can be manifested, finding a solution to this issue is not likely to be an easy challenge. Because of the growing prevalence of drug-resistant pathogens, there is an immediate and pressing requirement to discover and isolate new bioactive compounds derived from medicinal plants using standardized and contemporary analytical methods. Compounds obtained from medicinal plants might provide unique and relatively simple techniques to treat pathogenic microbes. CO extracts have also proven to be effective as antimicrobial agents ^[58][36].