Pharmaceuticals 16 00611

pharmaceuticals
Review
An Updated Review on the Multifaceted Therapeutic Potential
of Calendula officinalis L.
Kiran Shahane 1,† , Madhuri Kshirsagar 1,† , Srushti Tambe 1,† , Divya Jain 1,† , Srutee Rout 2,† ,
Maria Karolina Martins Ferreira 3 , Suraj Mali 4 , Purnima Amin 1 , Prem Prakash Srivastav 2 , Jorddy Cruz 3
and Rafael Rodrigues Lima 3, *
1 Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology,

Mumbai 400019, India
2 Department of Agricultural and Food Engineering, Indian Institute of Technology, Kharagpur 721302, India
3 Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará,
Belém 66075-110, Brazil
4 Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra 835215, India
* Correspondence: rafalima@ufpa.br
† These authors contributed equally to this work.
Abstract: Calendula officinalis Linn. (CO) is a popular medicinal plant from the plant kingdom’s
Asteraceae family that has been used for millennia. This plant contains flavonoids, triterpenoids,
glycosides, saponins, carotenoids, volatile oil, amino acids, steroids, sterols, and quinines. These
chemical constituents confer multifaceted biological effects such as anti-inflammatory, anti-cancer,
antihelminthic, antidiabetes, wound healing, hepatoprotective, and antioxidant activities. Addi-
tionally, it is employed in cases of certain burns and gastrointestinal, gynecological, ocular, and
skin conditions. In this review, we have discussed recent research from the last five years on the
therapeutic applications of CO and emphasized its myriad capabilities as a traditional medicine. We
have also elucidated CO’s molecular mechanisms and recent clinical studies. Overall, this review
intends to summarize, fill in the gaps in the existing research, and provide a wealth of possibilities
for researchers working to validate traditional claims and advance the safe and effective use of CO in
treating various ailments.
Citation: Shahane, K.; Kshirsagar, M.;
Tambe, S.; Jain, D.; Rout, S.; Ferreira, Keywords: Calendula officinalis; traditional medicine; chemical composition; biological activities
M.K.M.; Mali, S.; Amin, P.; Srivastav,
P.P.; Cruz, J.; et al. An Updated
Review on the Multifaceted
Therapeutic Potential of Calendula 1. Introduction
officinalis L.. Pharmaceuticals 2023, 16,
The use of traditional medicine was found to be first implemented in Ancient Greece.
611. https://doi.org/10.3390/
According to Greek traditional knowledge, gods gave the knowledge of healing to man.
ph16040611
Theophrastus (372–286 BC), a disciple of Aristotle, an ancient Greek philosopher, and a
Received: 13 March 2023 scientist, authored the first scientific system of plants [1]. Although not wholly aware of
Revised: 27 March 2023 their exact physicochemical characteristics at the time, the human population has found
Accepted: 31 March 2023 additional health benefits from plants throughout history. The same components from plant
Published: 18 April 2023 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]. Currently, traditional medicines are becoming more popular for
Copyright: © 2023 by the authors.
therapeutic use, specifically for self-treatment practices [3–5].
Licensee MDPI, Basel, Switzerland.
This article is an open access article
Calendula officinalis Linn. (CO), as an important plant within traditional medicine,
distributed under the terms and
has found application in the food industry [6] as well as the pharmaceutical industry [7]
conditions of the Creative Commons owing to the presence of secondary metabolites in the plant. The Calendula genus covers
Attribution (CC BY) license (https:// approximately 25 species, among which C. officinalis, C. arvensis, C. tripterocarpa, C. stellata,
creativecommons.org/licenses/by/ and C. suffruticose are the most common [8]. CO is the most studied species of Calendula. It
4.0/). has been used medicinally since the 12th century [9,10] and is known as English Marigold,
Pharmaceuticals 2023, 16, 611. https://doi.org/10.3390/ph16040611 https://www.mdpi.com/journal/pharmaceuticals

Pharmaceuticals 2023, 16, 611 2 of 21
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]. 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]. 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].
It is considered a safe medication when considering its therapeutic potential with
a proper dose and other pharmacological indications [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].
This review congregates the hitherto scattered reports on the pharmacological activities
of CO from the last five years. Nonetheless, we aim to highlight the importance of CO
as a natural remedy for therapeutic purposes based on the positive data that has been
documented in the literature. In summary, the objective of this review is to provide a
summary, fill in the gaps in the existing research, and present a multitude of possibilities to
researchers already working on the validation of traditional claims and the development of
CO’s use in the safe and effective treatment of a variety of diseases.
2. Chemical Composition
Some of the important components in CO pharmacological activities belong to differ-
ent classes of chemical compounds, terpenoids, flavonoids, triterpeneol esters, steroids,
phenolic compounds, carotenes, triterpenoids, essential oils, quinones, fatty acids, min-
erals, saponins, carbohydrates, sterols, and tocopherols [20,21]. In various regions of
CO, the compounds ubiquinone, tocopherol, phylloquinone, and proto-quinone were
identified from quinones. From the petroleum ether extract of CO flowers, terpenoids
were extracted [22,23]. Some other phytoconstituents present in CO are paraffins, cal-
endin, and calendulin [12]. All these secondary metabolites increase the importance of
CO as traditional medicine. Carotenoids and triterpene alcohols, in both free and ester-
ified forms, are also present in CO [24]. Co-derived carotenoid pigments [25] and other
polyunsaturated fatty acids produced from CO, such as Calendric acid [26], have been
demonstrated to have anti-inflammatory activities in vitro and in vivo [27]. Nonetheless,
triterpene oligoglycosides and calendasaponins A, B, C, and D from CO have proven to
exhibit gastric-emptying-inhibitory, gastroprotective, and hypoglycemic properties [28].
CO leaf extract contains fatty acids, triterpenes, chloroform extracts, and sterols. In the
aqueous extract, flavonoids and saponins were identified, and alkaloids were also found in
the ethanolic extract. In various regions of CO, the compounds ubiquinone, tocopherol,
phylloquinone, and proto-quinone were identified from quinones. From the petroleum
ether extract of CO flowers, terpenoids were extracted [22,23]. CO was also used to extract
flavonoids such as quercetin, isorhamnetin, and isoquercetin. Some other phytoconstituents
present in CO are paraffins, calendin, and calendulin.
Table 1 represents the major constituents and percentages of various Calendula species,
and Table 2 represents the various chemical constituents present in CO.
Table 1. The major constituents and percentages of various Calendula species [29].
Species Major Component Percentage References

Calendula suffruticosa α-linolenic acid 24.20 [17,30]
Calendula arvensis d-cadinene (Sesquiterpines) 15.1 [16,31]
CO α-cadinol 64 [31–36]
Calendula stellata linalool 34.40 [30]
Calendula tripterocarpa Phenolic compounds 11.22 [37,38]
Table 2. Various chemical constituents are present in Calendula officinalis Linn.
Plant part Groups Active Ingredients Ref.

ψ-taraxasteol, Lupeol [39]
Erythrodiol [40]
Terpenoids Calenduloside [41]
Calendula glycoside A and B [42]
Cornulacic acid acetate [43]
Calendoflavoside Isoquercitrin, rutin [42]
Flower
Flavonoids Isorhamnetin, Quercetin [44]
Narcissin, Isorhamnetin-3-O-β-D glycoside [45]
Coumarins Scopoletin, umbelliferone, Esculetin [46]
Oplopanone, Cubenol, methyl linoleate [47]
Volatile oils Limonene, nerolidol, palustron p-cymene,

nonanal, Sabinene, carvacrol, α-pinene, [48]
t-muurolol, geraniol
α-tocopherol, plastoquinone, Phylloquinone,
Leaves Quinones [49]
ubiquinone
Root Terpenoid Calenduloside B [50]
2.1. Carotenoids
The flower of CO, which is primarily orange, has high levels of carotenoids. The num-
ber of carotenoids in CO inflorescences increased significantly. Orange CO species include
more hydrocarbons than yellow ones, which mainly contain oxygenated derivatives [25].
Carotenoids, which are pre-eminently found in plant flowers, majorly consist of ly-
copene, beta carotene, lutein, flavoxanthin, and zeaxanthin. Some of the other carotenoids
found in petals and pollens of CO are luteoxanthin, neoxanthin, violaxanthin, 9Z-Violaxanthin,
9Z-Neoxanthin, auroxanthin, 9Z-Anthroxanthin, mutatoxanthin, 13/130 Z-Lutein,
α-cryptoxanthin, z-cryptoxanthin, 9/90 Z-lutein, α-carotene, β-carotene, and β-cryptoxanthin.
In addition to this, carotenoids found in the stem and leaves of CO include violaxanthin,
9Z-Violaxanthin, 9Z-Neoxanthin, antheraxanthin, neoxanthin, mutatoxanthin epimer 1 and
2, 9/90 Z-Lutein, β-carotene, α-cryptoxanthin, lutein, luteoxanthin, β-cryptoxanthin, and

13Z-Violaxanthin [51,52]. Carotenoids are predominantly known for their antioxidant ac-
tivity through a radical scavenging mechanism, which makes them extremely useful in the
pharmacotherapy of oxidative disorders. The same antioxidant potential and their ability to
form artificial cross-linkage make them possess wound-healing action [25,53,54]. Zeaxanthin,
a non-provitamin A carotenoid belonging to the xanthophyll family, is known to have a
beneficiary therapeutic effect on age-related macular degeneration through its antioxidant
and blue-filtering potential [55].
2.2. Terpenoids
Terpenoids, which are primarily present in flowers and roots of CO, are majorly known
for their antioxidant activity. These sesquiterpenoids, entailing τ-cadinol, α-cadinol, and
τ-muurolol, bring out antioxidant action through a radical scavenging mechanism. Thus,
terpenoids have a significant role in the management of diseases and disorders involving ox-
idative reactions such as Alzheimer’s disease, skin hyperpigmentation, and diabetes-related
complications. In addition to this, terpenoids have extensive anti-inflammatory action.
This action is brought about by the inhibition of the COX-2 enzyme (Cyclo-oxygenase-2),
pro-inflammatory cytokines including Interleukins 1 and 6, tissue necrosis factor, and
synthesis of prostaglandins [22,23].
2.3. Flavonoids
Flavonoids present in CO, especially quercetin, have significant wound-healing ac-
tivity. There are several proposed mechanisms for this action. The basic mechanism of
action is the antioxidant activity brought about through radical scavenging action. Another
mechanism explains the adhesion and augmentation of fibroblasts, which additionally
cause an approbatory effect on the cellular activity in a given area [56,57]. Addition-
ally, flavonoids are known to have anti-plaque and anti-gingivitis action [58,59]. Quite
a few mechanisms are suggested for this action, including removal of plaque through
inhibition of lysosomal hydrolase, reduction in collagen degradation through inhibition
of recombinant human matrix metalloproteinases (MMPs), and subsequent increment in
collagen concentration. Furthermore, other constituents of CO belonging to the flavonoid
class such as rutin, apigenin, kaempferol, vitexin, and luteolin are known to have skin-
protective action through the antioxidant mechanism. In addition to this, flavonoid
compounds quercetin and rutin possess anti-depressant action. These compounds pro-
duce their action through the inhibition of Monoamine (MAO) oxidases and reduction in
GABA levels [60–62]. Isorhamnetin with quercetin derivatives such as 3-O-(200 -rhamnosyl)-
rhamnosides, 3-O-(200 -rhamnosyl)-glucosides, 3-O-(200 ,600 -di-rhamnosyl)-glucosides, 3-O-
(600 -rhamnosyl)-glucosides, 3-O-glucosides, and 3-O-(600 -acetyl)-glucosides are known to
have anti-acetylcholinesterase activity. This activity is chemically attributed to the pres-
ence of acetyl and rhamnosyl groups in flavonoid structure [27]. Hyperoside, another
flavonoid class compound, has a crucial effect on the management of osteosarcoma through
restraining multiplication and stimulation of osteogenic differentiation of sarcoma cells [63].
2.4. Coumarins
Coumarins, which are significantly found in flowers of CO, may prevent oxidative
damage to cells [54]. Some of the important coumarins present in CO are Umbelliferone,
Scopoletin, and Esculetin. Umbelliferone, using the antioxidant mechanism of action, acts
as a skin-protective agent, especially in sunscreen products. Scopoletin has spasmolytic
action: it acts by constraining the spastic contraction of muscles of the urogenital system
and gastrointestinal system. Esculetin, which is from the same class of coumarins, acts as
a phlebotonic and inflammatory agent by decreasing the permeability of capillaries and
rejuvenating venous tone. In addition to this, it is also known to have anti-thrombotic action
owing to its revelatory effect in the augmentation of the occlusion period for thrombotic
platelet plug formation [64,65].
2.5. Phenolic Acids

Phenolic acids found in CO such as caffeic acid, vanillic acid, chlorogenic acid, and
coumaric acid have proven scavenging activity because of their hydrogen-donating ten-
dency, which makes them useful in the treatment of oxidative disorders [66]. The same
mechanism of action explains the role of phenolic compounds from CO in the reduction in
exercise-instigated oxidative stress [67–69]. CO contains various fatty acids such as calendic
acid, linoleic acid, oleic acid, palmitic acids, and dimorphecolic acid. Among all fatty acids
with a crucial role in human bodily functions, calendic acid, a major fatty acid found in
CO, has additional predominant cytotoxic action. The mechanism of this action is lipid
peroxidation and downregulation of the gene lcf1, which is involved in the encoding of
long-chain fatty acyl-CoA synthetase [70–72].
Some of the fatty acid derivatives from CO are 28-O-β-D-glucopyranosyl ole-anolic acid 3-
O-β-D-galactopyranosyl (1→3)-β-D-glucuronopyranoside (calendulaglycoside C) [73], 28-O-β-
D-glucopyranosyl oleanolic acid 3-O-β-D-glucuronopyranoside (chikusetsusaponin or glyco-
side F) [74], oleanolic acid 3-O-β-D-galactopyranosyl (1→3)-β-D-glucuronopyranoside (calen-
duloside G) [75], 28-O-β-D-glucopyranosyl oleanolic acid 3-O-β-D-glucopyranosyl-(1→2)-
[β-D-galactopyranosyl-(1→3)]-β-D-glucuronopyranoside (calendulaglycoside A) [42], 28-
O-β-D-glucopyranosyl oleanolic acid 3-O-β-D-galactopyranosyl (1→3)-β-D-glucopyranoside
(calenduloside B) [73], oleanolic acid 3-O-β-D-glucopyranoside (Glucoside I) [76],
3-O-β-D-glucopyranosyl-(1→2)-[β-D-galactopyranosyl-(1→3)]-β-D-glucopyranosyl olea-nolic
acid (osteosaponin-I) [77], oleanolic acid, 3-O-β-D-galacto-pyranosyl-(1→3)-
β-D-glucopyranosyl oleanolic acid (arvensoside B) [78], stigmasterol and machaerinic acid
3-O-β-D-glucuronopyranoside [79].
2.6. Quinones
Quinones that are majorly found in the leaves of CO consist of phylloquinone, α-
tocopherol, ubiquinone, and plastoquinone. They have anti-cancer potential, and their
mechanism of action is alkylation and cleavage of DNA through DNA topoisomerase I and
II [80,81].
Other minor components of CO such as phenolics and tannins are known to have
antioxidant action as well as anti-ulcer action, which is rendered through maintenance as
well as regeneration of gastric mucosa [82].
2.7. Amino Acids

Threonine, glutamic asparagine, leucine, proline, acid, serine, histidine, phenylalanine,
tyrosine, arginine, lysine, aspartic alanine, methionine, and valine are some of the amino
acids that are present in CO that have been detected in its stems, leaves, and flowers.
Around 5% of amino acids were found to be present in the leaves, 3.5% in the stems, and
4.5% in the flowers [83].
Pharmaceuticals 2023, 16, x FOR PEER REVIEWThe chemical structures of some of the important chemical6 constituents
of 22 present in CO
are shown in Figure 1.
Figure 1. Chemical structures of constituents of CO. (1), isorhamnetin 3-O-β-glucoside (2), quercetin
Figure 1. Chemical structures of constituents of CO. (1), isorhamnetin 3-O-β-glucoside (2), quercetin 3-
3-O-β-neohesperidoside (3), quercetin 3-O-(2″-O-α-rhamnosyl-6″-O-malonyl)-β-glucoside (4),
quercetin 3-O-(6″-O-malonyl)-β-glucoside (5), quercetin 3-O-6″-O-methyl malonyl)-β-glucoside (6),
isorhamnetin 3-O-(6″-O-malonyl)-β-glucoside (7), chlorogenic acid (8), 3,4-dicaffeoylquinic acid (9),
and syringic acid (10). Adapted from [84] under Creative Commons CC BY license (CC BY 4.0)
For the extraction of CO, numerous conventional and novel techniques are available.
Conventional techniques used in past decades are hydrodistillation, solvent extraction,
steam distillation, acid-catalyzed extraction, maceration, expression, and soxhlet
O-β-neohesperidoside (3), quercetin 3-O-(200 -O-α-rhamnosyl-600 -O-malonyl)-β-glucoside (4),

quercetin 3-O-(600 -O-malonyl)-β-glucoside (5), quercetin 3-O-600 -O-methyl malonyl)-β-glucoside (6),
isorhamnetin 3-O-(600 -O-malonyl)-β-glucoside (7), chlorogenic acid (8), 3,4-dicaffeoylquinic acid (9),
and syringic acid (10). Adapted from [84] under Creative Commons CC BY license (CC BY 4.0).
For the extraction of CO, numerous conventional and novel techniques are available.
Conventional techniques used in past decades are hydrodistillation, solvent extraction,
steam distillation, acid-catalyzed extraction, maceration, expression, and soxhlet extrac-
tion [85–89]. The most common solvents used in these processes are methanol, ethanol,
acetone, and hexane. Here, due to the presence of high phenolic content, solvents with high
polarity are employed; for example, 80% methanol, when used in the extraction process,
leads to higher output in terms of the components yield [15,23,90]. Nevertheless, these
conventional techniques are challenging because of prolonged extraction time, temperature,
and pressure conditions. Here novel techniques such as ultrasound-assisted extraction,
microwave-assisted hydrodistillation, microwave distillation, headspace solid-phase mi-
croextraction, and headspace–cold finger extraction come into the picture, which support
numerous aspects such as enhanced extraction, in terms of yield and quality of extracts,
and economical as well as ecological advantages [86,91–94].
3. Therapeutic Applications of Calendula officinalis

Many ailments have been treated with CO; a plant frequently used in homeopathic
medicine. Additionally, it can be cytotoxic and inhibit tumor growth [95]. It functions as
an antimicrobial [56,96], antioxidant [97], anti-inflammatory [89,98], antiseptic [99], anti-
viral [89], hepatoprotective [56], and antidiabetic medicine [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
Pharmaceuticals 2023, 16, x FOR PEER REVIEW 7 of 22
burns and wind burns. The major parts of the CO plant and their therapeutic applications
discussed in this review are represented in Figure 2 and Table 3.
Figure 2. Pharmacological
Figure 2. Pharmacologicaleffects
effects of Calendulaofficinalis
of Calendula officinalis Linn.
Linn.
Table 3. Summary of clinical studies of the use of Calendula officinalis.
Author and Year Applicability Outcomes Reference

This study suggests that topical use of CO could be used effectively
Panahi et al., 2012 Diaper dermatitis [101]
for the treatment of diaper dermatitis in infants.
Dental plaque and The use of CO mouthwash was able to reduce dental plaque and
Khairnar et al., 2013 [58]
gingival inflammation gingivitis.
Topical use of CO prevented acute dermatitis grade 2 or higher in
Pommier et al., 2004 Acute dermatitis [102]
breast cancer patients given radiation therapy.
Homogeneous The use of CO extract gel was effective in reducing the size of the
Singh and Bagewadi, 2017 [103]
leukoplakia lesion.
Table 3. Summary of clinical studies of the use of Calendula officinalis.
Author and Year Applicability Outcomes Reference

This study suggests that topical use of CO
Panahi et al., 2012 Diaper dermatitis could be used effectively for the treatment of [101]
diaper dermatitis in infants.
Dental plaque and gingival The use of CO mouthwash was able to
Khairnar et al., 2013 [58]
inflammation reduce dental plaque and gingivitis.
Topical use of CO prevented acute dermatitis
Pommier et al., 2004 Acute dermatitis grade 2 or higher in breast cancer patients [102]
given radiation therapy.
The use of CO extract gel was effective in
Singh and Bagewadi, 2017 Homogeneous leukoplakia [103]
reducing the size of the lesion.
The use of CO extract gel was able to reduce
the intensity of oropharyngeal mucositis in
Babaee et al., 2013 Oropharyngeal mucositis [104]
patients undergoing radiotherapy during
treatment for head and neck cancer.
CO induced more rapid secondary intention
Giostri et al., 2022 Acute wounds on hand [105]
healing in hand and finger wounds
Patients with ulcers treated with CO extract
had a significant 4-fold increase in
Buzzi et al., 2016 Venous leg ulcer healing [106]
percentage healing velocity per week,
compared with the control group.
Women who used CO ointment after
episiotomy had significantly lower pain level
from the second day and during the entire
De Angelis et al., 2022 Episiotomy [107]
follow-up. In addition, CO ointment also
improves wound healing in terms of redness
and edema.
Treatment of vaginal candidiasis with CO
Saffari et al., 2017 Vaginal candidiasis [108]
vaginal lotion seems to be successful.
CO was used successfully and without any
Pazhohideh et al., 2018 Bacterial vaginosis negative side effects to treat bacterial [109]
vaginosis in women of reproductive age.
3.1. Anti-Inflammatory
CO is currently being investigated, as it exhibits excellent anti-inflammatory activity.
Alkaloids, tannins, flavonoids, essential oils, sterols, saponins, carotenoids, triterpene alco-
hols, 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 character-
istics [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 [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 [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. [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
inflammatory effects of Calendula flowers. The lauryl, myristoyl, and palmitoyl esters of
faradiol are the most prevalent of these [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-
Pharmaceuticals 2023, 16, 611 1β; TNF-α, tumor necrosis factor α; and IFN-γ, interferon γ) and COX-2 (cyclooxygenase 8 of 21
2), and subsequently, Refs. [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
nitric inhibited in
oxide production nitric oxide production
a dose-dependent manner,in with
a dose-dependent
cytotoxicity only manner,
observed withat
cytotoxicity only observed
147 µL/mL concentrations or above.at 147 µL/mL concentrations or above.
Garrido-Suárez[98]
Garrido-Suárez [98]studied
studiedthe the antinociceptive
antinociceptiveeffects
effects of of CO
CO cream
cream onon inflammatory
inflammatory
hyper-nociception.Rats
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weresubjected
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anditit was
was reported
reported that
that CO
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(20% or
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w/w), when applied topically,
topically, ledled to
to aa significant
significant decrease
decrease in TNF-α and
in TNF-α and
suppression of COX-2.
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Pharmaceuticalformulations
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suchas nanoemulsion
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developed the anti-inflammatory
to achieve the anti-inflammatoryeffects of CO. Furthermore,
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and soothing wounds when when applied
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newborns
dermatitiscaused by diaper
in newborns friction
caused when compared
by diaper to Aloe
friction when vera [101].
compared In the
to Aloe oral[101].
vera cavity,In
mouth
the oralrinsing
cavity,with COrinsing
mouth tincturewith
reduced gingivalreduced
CO tincture inflammation
gingival [58].
inflammation [58].
Figure 3.3. Anti-inflammatory

Figure Anti-inflammatory effects
effects of
of Calendula
Calendula officinalis
officinalis Linn
Linn by
by inhibiting
inhibiting pro-inflammatory
pro-inflammatory
cytokines (IL-6, IL-1β, TNF-α, and IFN-γ, etc.), COX-2, prostaglandin synthesis,
cytokines (IL-6, IL-1β, TNF-α, and IFN-γ, etc.), COX-2, prostaglandin synthesis, iNOS iNOS (inducible
(inducible
nitric oxide synthase), and CRP (C-Reactive Protein).
nitric oxide synthase), and CRP (C-Reactive Protein).
3.2.
3.2. Antioxidant
Antioxidant Activity
Activity
Plant
Plant polyphenols
polyphenolssuchsuchasas
flavonoids areare
flavonoids among
amongthe most significant
the most natural
significant com-
natural
pounds with active antioxidant properties. The radical scavenging or chelating
compounds with active antioxidant properties. The radical scavenging or chelating flavonoids
are caused by
flavonoids their
are hydroxyl
caused by group content [115,116].
their hydroxyl The family
group content of antioxidants
[115,116]. [115] as
The family of
phenolic chemicals,
antioxidants on phenolic
[115] as the otherchemicals,
hand, operate as free
on the radical
other terminators
hand, operate as[117].
free Hence,
radical
CO’s high flavonoid and phenolic phytochemical content contribute to its antioxidant activ-
ity, which can further promote its strong radical-scavenging capacity and confer protective
effects [104]. The leaves and petals of the CO plant contain natural sources of antioxi-
dants [56]. As a result of riboflavin’s photoreduction, it has been claimed that CO extract
scavenges hydroxyl and superoxide radicals. Pandey et al. [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 bene-
ficial in treating several ailments such as AIDS (acquired immunodeficiency syndrome),
heart disease, malaria, diabetes, stroke, cancer, and arteriosclerosis due to their potent
antioxidant activity.
3.3. Cytotoxic and Anti-Tumor Activity

Saponin, one of the separated active compounds of CO, has been shown to exhibit
antimutagenic action [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. [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. [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. [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 [103]. In
oral mucositis, the 2% CO mouthwash was able to decrease oral mucositis when compared
to the placebo group [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.
3.4. Wound-Healing Activity

Chronic wounds and delayed wound healing are major medical issues that provide dif-
ficult 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. [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. [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
Pharmaceuticals 2023, 16, x FOR PEERcytokines
REVIEW and reducing oxidative stress at the wound site. The mechanism of 11 action
of 22 of CO
for wound healing is shown in Figure 4.
Figure 4. (A). Mechanism of action of CO on Interleukin 6 (IL-6); (B) Mechanism of action of

Figure 4. (A). Mechanism of action of CO on Interleukin 6 (IL-6); (B) Mechanism of action of epidermal
epidermal growth factor (EGF) on wound healing. Adapted from [122] under Creative Commons
CC BY license (CC BY 4.0). NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells;
MPO, myeloperoxidase; IL-6, interleukin-6; TNF-α, tumor necrosis factor alpha; IL-1β, interleukin-
1-beta; BAX, BCL-2 associated x protein; Pol γ, DNA polymerase γ; SMAD, suppressor of mothers
against decapentaplegic; VEGF-c, vascular endothelial growth factor C; TGF-β, transforming
growth factor-beta; ATP, adenosine triphosphate; P2YR, purinergic G protein-coupled receptors;
HB-EGF, heparin-binding EGF-like growth factor; EGFR, epidermal growth factor receptor; RAS,
rat sarcoma; ERK1/2, extracellular signal-regulated kinase; Src, steroid receptor coactivator; Akt,
protein kinase B; PI3K, phosphoinositide 3-kinase.
Similarly, Rathod and co-workers [123] investigated the wound-healing efficacy of

CO-loaded collagen films on wounds induced in Wistar rats. On day 21, the rate of wound
growth factor (EGF) on wound healing. Adapted from [122] under Creative Commons CC BY
license (CC BY 4.0). NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; MPO,
myeloperoxidase; IL-6, interleukin-6; TNF-α, tumor necrosis factor alpha; IL-1β, interleukin-1-
beta; BAX, BCL-2 associated x protein; Pol γ, DNA polymerase γ; SMAD, suppressor of mothers
against decapentaplegic; VEGF-c, vascular endothelial growth factor C; TGF-β, transforming growth
factor-beta; ATP, adenosine triphosphate; P2YR, purinergic G protein-coupled receptors; HB-EGF,
heparin-binding EGF-like growth factor; EGFR, epidermal growth factor receptor; RAS, rat sarcoma;
ERK1/2, extracellular signal-regulated kinase; Src, steroid receptor coactivator; Akt, protein kinase B;
PI3K, phosphoinositide 3-kinase.
Similarly, Rathod and co-workers [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 [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 [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 [106].
In addition, this type of healing is advantageous because it reduces medical interventions
and treatment costs [125]. Another important finding is that the use of CO ointment after
episiotomy reduces pain, redness, and swelling and helps healing [107].
3.5. Hepatoprotective Activity

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 cyto-
toxicity 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 compo-
nents 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 [126].
3.6. Anthelmintic Activity

In addition to being a major cause of illness in humans and animals, parasitic infec-
tions 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. [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 [127] and 50% efficacy on L1-2 larvae of Strongiloides papillosus [128].
3.7. Antimicrobial Activity

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 [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 [36].
3.7.1. Antibacterial Activity

It is of the utmost significance to discover novel antibacterial medicines in view of the
research that shows the rapid global spread of clinical isolates that are resistant to antibiotic
treatment. A large variety of medicinal plants have been identified as useful sources of
natural antibacterial agents as alternative choices that have the potential to be successful in
the treatment of several bacterial diseases [130]. The antibacterial properties of a variety
of plants, which are caused by the production of phytochemicals during the secondary
metabolism of the plant, have led to their adoption in a wide range of fields. Tannins,
alkaloids, phenolic compounds, and flavonoids are just examples of the large range of
secondary metabolites that are abundant in plants. These metabolites have been shown to
exhibit antibacterial effects when tested in vitro [131–133].
CO has also been shown to possess potent antibacterial properties. Recently, Karn-
wal [134] studied the antibacterial potential of CO. It was observed that the minimum
inhibitory concentration (MIC) with CO aqueous extracts was 3.75 % for Clostridium perfrin-
gens, Staphylococcus aureus, Pseudomonas aeruginosa, and Listeria monocytogenes. For Listeria
monocytogenes, Clostridium perfringens, and Staphylococcus aureus, however, the lowest MBC
(1.87%) was observed. Ethanolic extract of CO showed the lowest MIC and MBC for just
one bacterial pathogen, and that was Pseudomonas aeruginosa, with 3.75% and 1.87%, respec-
tively. The antibacterial property of CO was also compared to sodium hypochlorite against
Streptococcus mutans as a root-canal-irrigating solution by Yalgi et al. [135]. It was observed
that CO showed a significant CFU reduction in S. mutans, i.e., from 15.85 CFU to 1.20 CFU.
The results were comparable to those of the group treated with sodium hypochlorite. The
authors reported that the antibacterial effect may be attributed to the presence of terpene
alcohols and terpene lactones in CO. Darekar et al. [136] also investigated the antibacterial
potential of CO against Bacillus subtilis, Klebsiella pneumonia, Staphylococcus aureus, and Ente-
rococcus faecalis using the disc diffusion method at a concentration of 10 mg/mL. The results
revealed strong antibacterial activity of CO against the tested strains as indicated by their
significant inhibition zones. Shahen and coworkers [137] studied chemical compounds with
bioactive properties from CO flowers and their antibacterial activity. The authors studied
paper-disc agar diffusion and tube-dilution techniques to test growth inhibition and to
calculate the minimum inhibitory concentration. Variable levels of antibacterial activity
were shown by the leaf extract against various microorganisms. The largest inhibitory zone
was generated by E. coli and K. pneumonia around the CO leaves, whereas B. subtilis and
S. lutea were shown to be more resistant bacteria. E. coli had the least inhibitory effects.
Calendula extracts in petroleum ether and chloroform showed antibacterial efficacy against
B. subtilis and E. coli. This finding shows that several pathogens are strongly inhibited by
leaf extracts of CO that were made using petroleum ether and chloroform.
3.7.2. Antiprotozoal Activity

An important global cause of death and morbidity is protozoal disease. Every year,
malaria infects between 200 and 500 million people, killing 2 million of them, mostly young
children under the age of 5 [138]. Future therapeutic agents must be found immediately,
and understanding traditional medicine can help to pave the path for future developments
in this area. However, due to the restricted availability and high cost of pharmaceutical
treatments, it is estimated that two-thirds of the global population relies on traditional
medicines. Additionally, it was discovered through global biological screens that many
natural compounds had antiparasitic activities, often with a surprising potency and high
selectivity. Samra et al. [139] studied the antiprotozoal activity of CO. The methanol extract
of CO included a novel phytoconstituent called (6Z,9Z)-heptadeca-6,9-diene-5,11-dione
(I). The structure of I was discovered by examining NMR spectra and HRESIMS data.
For both antibacterial and antiprotozoal properties, tests were conducted. Compound I
demonstrated mild antitrypanosomal activity with an IC50 of 37.6136 µM, leishmanicidal
activity against L. donovani amastigote with an IC50 of 16.4394 µM and IC90 of 28.9015 µM,
and leishmanicidal activity against L. donovani ecdysone. Standard experimental techniques
were used to test compound I cytotoxicity against THP1 cells; however, no cytotoxicity was
seen, demonstrating its selectivity and safety.
3.7.3. Antifungal Activity

According to the findings of the epidemiological studies, the incidence and prevalence
of major fungal infections are likely to continue to be a concern for public health. Antifungal
treatments have been used more often, which has resulted in the emergence of fungal strains
that are resistant to these medications. It is vital to identify new classes of antifungals from
natural products such as medicinal plants because of the rapid growth of drug-resistant
strains of fungus that are resistant to several treatments. CO has been found to possess
antifungal properties [140]. Vinola et al. [97] compared the antifungal activity of CO with
2% chlorhexidine against C. albicans. It was observed that compared to CO, chlorhexidine
exhibits much higher antifungal activity against C. albicans. CO does, however, have some
antifungal efficacy against C. albican. Nevertheless, CO also displayed volume-dependent
antifungal activity against C. albican to a considerable extent.
Recent findings shed light on the antifungal characteristics of CO that are utilized in
the treatment of infectious disorders. The bioactive chemicals from CO extracts will need
to be identified in further detail, as well as their pharmacological target or mechanism
of action. It is now essential to conduct more clinical trials to thoroughly investigate the
antimicrobial principles of CO and their numerous potential uses. It also has the potential to
be employed for the preservation of processed foods. Various other therapeutic applications
of CO are represented in Table 4.
Table 4. Various therapeutic applications of CO.
Therapeutic Application Model Results/Clinical Outcomes Ref

In endothelium-depleted rat aortic rings
pre-contracted with 60 mmol/L of KCl, the
Cardiovascular Wister rats [141]
experiment revealed that floral extract of CO caused
a concentration-dependent relaxation.
The results showed that feeding on CO had a
Hepatoprotective Albino rats protective effect on the liver against CCl4 and had [29]
improvement effect on liver.
Table 4. Cont.
Therapeutic Application Model Results/Clinical Outcomes Ref

Significant changes occurred in glucose and insulin
level (135.32 ± 2.43 and 88.42 ± 2.17, respectively) at
Antidiabetic Albino wister rats a dose of 200 mg/kg/day in a dose-dependent [142]
manner as compared to the control positive group
level (211.76 ± 3.95 and 134.82 ± 2.95) (p < 0.05).
In diabetic rats, the results revealed that CO was
able to normalize levels of creatine kinase (CK-MB
Antidiabetic Wister rats [143]
and total CK), amylase, and lipase. This allowed for
a reduction in the negative effects of diabetes.
After 21 days, the results demonstrated that rats
Polycystic ovary syndrome Sprague–Dawley rats given CO subcutaneous injections of DHEA were [144]
successfully induced with PCOS condition.
In a wound model including excision, mice that had
been treated with an extract of the leaves of CO
Wound healing Swiss albino mice [145]
showed a significant reduction in both the wound
area and the time it took to epithelize.
The application of 10% CO gel improves wound
Oral wound healing Wister rats [146]
contraction and enhances healing.
The healing percent of the lesion area ranged from
Wound healing Wister rats 7.69% to 87.01% with CO-flower-extract-loaded [147]
hydrogel sheet.
According to the findings, a pre-treatment with
GEO/CEO-encapsulated vesicular cream
Age-defying and
Albino rats formulations significantly reversed the detrimental [148]
photoprotective
biochemical alterations and protected the skin from
the deteriorating effects of UVB radiation.
According to the findings, CO essential oils and their
combination provide a significant advantage in
Antifungal Swiss albino rats [149]
terms of lowering the risk of fungal infection after
chemotherapy with cyclophosphamide.
4. Future Perspectives
For many centuries, CO has been utilized by humanity for diverse therapeutic applica-
tions. CO herb consist of terpenoids, steroids, phenolic compounds, carotenes, triterpenoids,
essential oils, quinones, fatty acids, minerals, saponins, carbohydrates, and tocopherols,
with α-cadinol (sesquiterpenoid) as a major component. Being rich in these secondary
metabolites, CO has been proven to have anti-inflammatory, antidiabetic, antioxidant, anti-
cancer, antibacterial, anti-ulcer, antifungal, anti-viral, anti-thrombogenic, neuroprotective,
antiprotozoal, skin-protective, and antifatigue activities. Considering that CO has these
multiple applications, it is crucial that extensive research on nonfloral components of the
plant, such as seeds, roots, leaves, and stems, be conducted in the future. In addition to
this, there is a vital need to focus on genus chemistry. Because of the limited amount of
literature available, other species of CO including C. arvensis, C. tripterocarpa, C. stellata,
and C. suffruticose should be explored further regarding their biochemical profiles and
pharmacological properties. In the same fashion, relative studies should be conducted to
understand variations in terms of the age of the plant, method of extraction, or processing
method. It is anticipated that as extraction methods become more advanced, previously
unidentified phytochemicals and an expansion of this plant’s pharmacological range of
activity will likely be found, posing fascinating research challenges. Moreover, the research
on developing novel drug delivery systems containing CO is still nascent; we anticipate
that research in this area will continue. Molecular docking and molecular dynamics are
two modern computational drug design techniques that hold great promise for developing
novel therapeutic candidates for various ailments.
Additionally, bioinformatics technologies have opened up new avenues for finding
the essential critical amino acids under almost comparable physiological settings, con-
siderably validating the outcomes of computational methods. However, based on the
chemical makeup of the medication and its target receptor, the therapeutic potential of
several bioactive compounds can be investigated, saving time and money [150]. In the
foreseeable future, CO-containing micro- and nano-formulations have excellent potential
for treating several ailments, and the future developments and applications are assured
to be astounding. Moreover, activity enhancement, combined with other available agents,
offers a promising strategy that may ultimately enhance pharmacological outcomes [3].
5. Conclusions
CO species have shown tremendous health advantages from prehistoric times to the
present. The present state-of-the-art CO in the health sciences realm has been rigorously
examined and briefly explained in this study with insights into their molecular processes.
Additionally, many CO-containing drug delivery methods and patents have been devel-
oped to improve solubility, targeting, and stability, and their active components have
been considered in this analysis. As a result, it is envisioned that this review will act as a
foundation for scientists, agronomists, and even small-scale herbal industries to integrate
the information that is currently available on CO and realize the full pharmacological,
agricultural, and industrial potential of this fascinating medicinal plant.
Author Contributions: Conceptualization, P.A. and S.T.; methodology, K.S., M.K., S.T., D.J. and S.R.;
data curation, K.S., M.K., S.T., D.J. and S.R.; writing—original draft preparation, K.S., M.K., S.T.,
D.J. and S.R.; writing—review and editing, R.R.L., M.K.M.F., K.S., M.K., S.T., D.J., S.R., S.M., P.A.,
P.P.S. and J.C.; visualization, R.R.L., M.K.M.F., P.A. and S.T.; supervision, P.A., P.P.S. and J.C.; project
administration, J.C.; funding acquisition, R.R.L. All authors have read and agreed to the published
version of the manuscript.
Funding: This research was funded by the CNPq (grant number 312275/2021-8).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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1 Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology,

Pharmaceuticals 2023, 16, 611. https://doi.org/10.3390/ph16040611 https://www.mdpi.com/journal/pharmaceuticals

Species Major Component Percentage References

Table 2. Various chemical constituents are present in Calendula officinalis Linn.

Plant part Groups Active Ingredients Ref.

Volatile oils Limonene, nerolidol, palustron p-cymene,

2, 9/90 Z-Lutein, β-carotene, α-cryptoxanthin, lutein, luteoxanthin, β-cryptoxanthin, and

2.5. Phenolic Acids

2.7. Amino Acids

O-β-neohesperidoside (3), quercetin 3-O-(200 -O-α-rhamnosyl-600 -O-malonyl)-β-glucoside (4),

3. Therapeutic Applications of Calendula officinalis

Table 3. Summary of clinical studies of the use of Calendula oﬃcinalis.

Author and Year Applicability Outcomes Reference

Table 3. Summary of clinical studies of the use of Calendula officinalis.

Author and Year Applicability Outcomes Reference

Figure 3.3. Anti-inflammatory

antioxidant concentration decreases with decreasing absorbance value. When compared to

3.3. Cytotoxic and Anti-Tumor Activity

3.4. Wound-Healing Activity

Figure 4. (A). Mechanism of action of CO on Interleukin 6 (IL-6); (B) Mechanism of action of

Similarly, Rathod and co-workers [123] investigated the wound-healing eﬃcacy of

Similarly, Rathod and co-workers [123] investigated the wound-healing efficacy of

3.5. Hepatoprotective Activity

3.6. Anthelmintic Activity

investigated the anthelmintic activity in adult Indian earthworms (Pheretima posthuma). It

3.7. Antimicrobial Activity

3.7.1. Antibacterial Activity

3.7.2. Antiprotozoal Activity

3.7.3. Antifungal Activity

Table 4. Various therapeutic applications of CO.

Therapeutic Application Model Results/Clinical Outcomes Ref

Therapeutic Application Model Results/Clinical Outcomes Ref

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