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Zimbro: History

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Zimbro or common juniper (Juniperus communis) is traditionally used to treat renal suppression, acute and chronic cystitis, bladder catarrh, albuminuria, leucorrhea, and amenorrhea. These uses are mainly attributed to its bioactive composition, which is very rich in phenolics, terpenoids, organic acids, alkaloids, and volatile compounds. In the last few years, several studies have analyzed the huge potential of this evergreen shrub, describing a wide range of activities with relevance in different biomedical discipline areas, namely antimicrobial potential against human pathogens and foodborne microorganisms, notorious antioxidant and anti-inflammatory activities, antidiabetic, antihypercholesterolemic and antihyperlipidemic effects, and neuroprotective action, as well as antiproliferative ability against cancer cells and the ability to activate inductive hepato-, renal- and gastroprotective mechanisms.

bioactive compounds
phenolic compounds
essential oils
biological potential
in vitro studies
in vivo studies
Juniperus communis L.

1. Introduction

Natural products have an important role in the research and development of new drugs. People have always extracted natural products from several natural sources, such as marine organisms, microorganisms, animals, and medicinal plants ^[1]. The main extracts from natural products come from medicinal plants. Plant-derived products and compounds have been used worldwide since ancient times in folk medicine as remedies for several diseases, such as tinctures, teas, poultices, maintaining high prevalence in public health ^[1]^[2]^[3]^[4]. Advances in clinical research and quality control have shown a greater value of herbal medicine in the treatment and overcoming of many diseases. Recent works report promising potential regarding the use of plants in the treatment and/or prevention of several hard-to-cure diseases, such as atherosclerosis ^[5]^[6], cancer ^[1]^[2]^[3]^[7]^[8], cardiovascular diseases ^[9]^[10]^[11]^[12], diabetes ^[8]^[13]^[14], and neurological disorders ^[4]^[15]^[16], among others.

The genus Juniperus includes roughly 68 species and 36 varieties and belongs to the Cupressaceae family ^[17]. The plant Juniperus communis L., named “zimbro” in Portugal, is a shrub or small evergreen tree; a perennial and long-lived coniferous, woody pioneer and colonizing plant, adapted to low nutrient availability in soil and having one the widest distribution ranges among the different plant species ^[18]. Its population is spread globally, being the only Juniperus species found in both hemispheres, with reports of this plant in Arctic regions of Asia and North America. In Europe, the largest population is found in some parts of the Alps, Scandinavia, Poland, northwest European lowlands, and Mediterranean mountain regions ^[19]^[20]. A significant population of “zimbro” is found in the Natural Park of Serra da Estrela, Portugal, where the var. alpina is mainly found at higher altitudes and the var. hemisphaerica at lower altitudes ^[21]. The wide geographical distribution is the principal reason for the remarkable variation in the morphological characteristics and secondary metabolites’ chemical composition ^[17].

On the other hand, J. communis seeds are too bitter due to their astringency. They are rarely consumed raw, usually being dried for use as a culinary component in different parts of the world. Together with juniper berries, they are commonly burnt in temples during religious ceremonies to purify the ambient air ^[22].

Relatively to their composition, “zimbro” plant parts are mostly composed of sugars, resins, organic acids, alkaloids, terpenic acids, leucoanthocyanins and flavonoids, gums, lignins, and wax. Their aromatic oils are rich in hydrocarbons of monoterpenes (α-pinene, β-pinene, sabinene, and myrcene), diterpenes, and sesquiterpenes ^[17]^[19]^[23]^[24]^[25]^[26].

2. Scientific Classification

J. communis species belongs to the Pinopsida class, Pinophyta division, Pinales order, Cupressaceae family, and Juniperus genus. Its binominal name is J. communis L.

The Juniperus genus is one of the most diverse within the conifers, being placed in the Cupressaceae family and including more than 60 species. It presents cosmopolitan distribution with a great capacity to develop in xerophytic and salinity conditions, although it is easier to find them in high-rainfall regions ^[27]^[28]. They are dioecious trees, producing seeds every 2 or 3 years that may have a globose or spherical morphology and be dispersed by zoocoria (e.g., frugivorous birds and small mammals), which allows them to colonize new territories quickly. In addition, they can be differentiated taxonomically into three well-differentiated sections, which represent different degrees of evolution within the genus, according to genetic analyses ^[27]^[29]. The Caryocedrus section, which is considered the most ancestral from an evolutionary point of view, is limited to areas of the Peloponnese, Anatolia, and Asia Minor and is only represented by the species J. drupacea, with acicular leaves, an anchor point to the stem, and woody cones ^[30]. The Juniperus (=Oxycedrus) section has a Holarctic distribution reaching the Mediterranean; it is represented by 14 species with acicular leaves, an anchoring point to the stem, and resiniferous cones. The third section, the Sabina section, is mainly found in the northern hemisphere and mountainous areas of the African continent. However, it also has some type of resin, and is distinguished from the other ones since it has decurrent needle-like or scale-shaped leaves and juicy cones ^[31]. According to these characteristics and with the fossil record, it is thought that the diffusion point of this genus occurred in the eastern Mediterranean region, first colonizing the northern regions of the Eurasian continent, and from there passing to the American continent at least 25 My ago ^[29].

All juniper species stand out for their high content of essential oils and phenolic compounds and are largely included in the traditional medicine of different cultures throughout the planet, exhibiting a wide range of biological activities and industrial applications ^[32]. Among them, it is worth highlighting the “zimbro” (J. communis) plant, since it shows the widest distribution, being practically circumboreal ^[29]^[33]. Another remarkable characteristic of this species is the ecological plasticity supported by great genetic variability, which translates into a substantially high number of varieties with phenotypes ranging from medium-sized trees (3–4 m high) to small creeping shrubs (Figure 1) ^[27]^[29]. The populations of the Iberian Peninsula are very diverse, and due to their position, their distribution is relegated to mountainous and more humid areas with a territorial occupation in islands, thus scaping from the thermophilic and xeric character of the nonmountainous lands of the Peninsula ^[30]^[33]. Indeed, it is believed that many years ago, this territory acted as a glacial refuge for many varieties that are currently found further north; even so, the populations of var. hemisphaerica show a high degree of genetic uniqueness, while the var. alpina (also known as var. nana) is mainly distributed in the upper areas of the mountains of the Iberian Peninsula, such as the Serra da Estrela mountains. These mountains are located in the middle interior of mainland Portugal and display an oromediterranean climatic island, being an isolated population from other populations of the Central System mountains or Cantabric System mountains ^[21]^[34].

Figure 1. Juniperus communis (A) main view of the plant growing in Serra da Estrela, (B) detail of leaves, and (C) details of berries. Images under Creative Commons licence, authorship: João Domingues Almeida and Paulo Ventura Araújo from www.flora-on.pt, accessed on 10 March 2022.

As well as other plants, J. communis also receives popular names. For example, Havusa or Matsyagandha (Sanskrit); Arar, Abahal oe Habbul (Assamese); Hayusha (Bengali); juniper berry, or common juniper (English); Palash (Gujrati); havuber or havubair (Hindi); zimbro (Portuguese); padma beeja (Kannada); hosh (Marathi); havulber (Punjabi); hapusha, abhal or arar (Urdu) ^[21]^[23].

For curiosity, and despite this plant not having a strong presence in ancient mythology, it is considered a symbol of fertility in Syria. On the other hand, in the Old Testament, it is described that the juniper has an angelic presence, which sheltered the prophet Elijah from Queen Jezebel’s pursuit. Moreover, a posteriorly biblical tale described that during their flight to Egypt, the infant Jesus and his parents used juniper to hide from King Herod’s soldiers ^[35].

3. Phytochemical Composition of Juniperus communis L.

As mentioned before, J. communis L. species are composed of a myriad of constituents, including nonessential substances, i.e., phytochemicals ^[36]. These compounds are secondary metabolites produced by plants to promote their normal cellular metabolism and offer protection against biotic and abiotic factors, and consequent oxidative injury ^[37]. Additionally, they are considered the key contributors to the organoleptic characteristics (e.g., aroma and color) and health benefits exhibited by plants ^[38]. They can be divided into five major categories (Figure 2). Although the plants’ genotype mainly influences their quantitative and qualitative composition, their levels also depend on the plant’s age, ripeness degree, cultivation techniques, geographical location, and meteorological conditions ^[39]^[40].

Figure 2. Main phytochemicals found in Juniperus communis L. ^[41].

3.1. Carotenoids and Chlorophylls

Although no studies have specifically reported the chlorophyll content of J. communis L. species, Rabska and colleagues ^[42] analyzed their total levels in fertilized and nonfertilized in both genders of this plant in autumn and winter (species not specified). The obtained data revealed nonfertilized plants had a lower concentration of total chlorophyll content than the fertilized ones (mean values of 5.0 versus (vs.) 7.4 mg/g in autumn and 3.6 vs. 4.8 mg/g in winter, respectively), and also lower amounts of total carotenoids (mean values of 0.64 and 0.95 mg/g for female and male, respectively, in autumn, and scores of 0.87 against 1.2 mg/g in winter). Focusing on gender, they observed that female plants had lower amounts of total chlorophyll compounds (values of 2.9 and 4.5 mg/g for female plants in autumn and winter, respectively, and 3.7 and 5.2 mg/g in autumn and winter, respectively, for the male ones) and carotenoid levels (values around 0.90 mg/g for female plants and around 1.0 mg/g for male, in autumn and winter, respectively). Without surprises, and regarding all the comparisons made, the authors also concluded that male and fertilized plants presented the highest levels of total chlorophyll and carotenoids (mean values of 4.3 and 1.3 mg/g, respectively).

This subclass of phytochemicals, highlighting carotenoids, possesses notable antioxidant potential and the ability to easily activate metabolic detoxification pathways, reducing the risk of appearance of several chronic and degenerative disorders ^[37]^[42].

3.2. Phenolic Compounds

Phenolics are the most predominant phytochemicals present in nature, and to date, about 10,000 different structures are currently described ^[43]. They are usually classified in (i) nonflavonoids and (ii) flavonoids ^[44]. The first ones can be further categorized into phenolic acids, including hydroxycinnamic and hydroxybenzoic acids, or in coumarins, lignans, or stilbenes ^[43]. On the other hand, flavonoids can be subdivided into isoflavones, coumestans, anthocyanidins, flavan-3-ols, flavanones, flavanonols (also called dihydroflavonols), flavones, or flavonols (Figure 2), depending on their structure ^[40]. This one comprises, at least, one phenol ring attached to one or more hydroxyl groups, and it is not only the main one responsible for dividing phenolics into different subclasses but also for conferring them a notable capacity to easily scavenge free radicals and reactive species; and to chelate metals, and in this way, counteract oxidative stress, diminish proinflammatory markers, and contribute to a healthy life state ^[43]^[45].

Focusing on phenolics found in J. communis L. species (Table 1), their levels depend on genotype, plant part, origin, age, gender, and solvent used to extract phenolics and perform the studies, but in a general way, they increase with latitude and plant age ^[42]^[46]^[47]. Additionally, male leaves and berries often present higher content in phenolic compounds than female ones ^[48].

Furthermore, and knowing the current interest in the biological potential of this plant, Brodowska et al. ^[49] conducted a study where they subjected J. communis (var. communis) L. berries to different ozone concentrations and time treatments. They verified that the treatment with ozone concentrations of 100 and 130 g/m³ for 30 min almost duplicated the phenolic content (15.47 and 12.91 mg catechin equivalent per g dry weight (dw), when compared to control (9.81 mg catechin equivalent per g dw), which consequently enhanced their antioxidant capacities positively.

Generally, the majority of phenolics reported in J. communis L. plant parts include 5-O-caffeoylquinic and quinic acids, catechin, epicatechin, amentoflavone, quercetin, luteolin, apigenin, and naringenin and their derivatives (Figure 3).

Table 1. Total phenolic, flavonoid, anthocyanin, and tannin content of different Juniperus communis L. plant parts extracts.

	Gender	Origin	Extract	Total Phenolic Compounds ^a	Total Flavonoid Content ^b	Total Anthocyanin Content ^c	Total Tannin Content ^b	References
Leaves
J. communis (var. alpina)	n.s.	Serra Da Estrela, Portugal	Methanolic (100%, v/v)	155.60			60.40	^[50]
J. communis (var. alpina)	n.s.	Yozgat, Turkey	Hydroethanolic (80% ethanol, v/v)	4.36	7.05			^[47]
J. communis (var. alpina)	n.s.	Yozgat, Turkey	Aqueous	169.27	24.30			^[47]
J. communis (var. communis)	Female	Rhodopes, Bulgaria	Methanolic (80% methanol, v/v)	132.00				^[46]
J. communis (var. communis)	Female	Mountain Ozren, near Sarajevo, Bosnia, and Herzegovina	Methanolic (80% methanol, v/v)	390.89	40.22 *			^[48]
J. communis (var. communis)	Male	Mountain Ozren, near Sarajevo, Bosnia, and Herzegovina	Methanolic (80% methanol, v/v)	544.09	48.06 *			^[48]
J. communis (var. communis)	n.s.	Nainital, India	Hydroethanolic (70% ethanol, v/v)	238.78				^[51]
J. communis (var. communis)	n.s.	Nainital, India	Hexane	189.65
J. communis (var. communis)	n.s.	Nainital, India	Ethyl acetate	315.33
J. communis (var. communis)	n.s.	Nainital, India	Aqueous	205.33
J. communis (var. oblonga pendula)	Male	North Carolina, USA	Methanolic (80% methanol, v/v)	91.00				^[46]
J. communis (var. saxatiles)	n.s.	Turkey	Hydroethanolic (80% ethanol, v/v)	212.10				^[52]
Berries
J. communis (var. alpina)	n.s.	Yozgat, Turkey	Hydroethanolic (80% ethanol, v/v)	Ripe berry: 11.92 Unripe berry: 130.92	Ripe berry: 2.56 Unripe berry: 17.57			^[47]
J. communis (var. alpina)	n.s.	Yozgat, Turkey	Aqueous	Ripe berry: 4.36	Ripe berry: 7.05			^[47]
J. communis (var. communis)		North-East Slovakia	Hydroethanolic (70% ethanol, v/v)	Ripe berry: 6.87–42.23				^[53]
J. communis (var. communis)	n.s.	Melbourne, Australia	Hydroethanolic (30% ethanol, v/v)	Ripe berry: 9.08	Ripe berry: 2.25		Ripe berry: 3.48 *	^[54]
J. communis (var. communis)	n.s.	Quebec, Canada	Hydroethanolic (80% ethanol, v/v)	Ripe berry: 99.20 ^b		Ripe berry: 0.47		^[55]
J. communis (var. communis)	n.s.	Serra Da Estrela, Portugal	Methanolic (100%, v/v)	Ripe berry: 44.70				^[50]
J. communis (var. communis)	n.s.	Ağrı, Turkey	Methanolic (100%, v/v)	Ripe berry: 59.17				^[56]
J. communis (var. n.s.)	n.s.	Pitesti hills, Romania	Hydroethanolic (50% ethanol, v/v)	Ripe berry: 0.19	Ripe berry: 51.09 ^d			^[57]
J. communis (var. saxatilis)	n.s.	Yozgat, Turkey	Hydroethanolic (80% ethanol, v/v)	Ripe berry: 21.00				^[52]
J. communis (var. saxatilis)	n.s.	Ankara, Turkey	Methanolic (100%, v/v)	Ripe berry: 17.64				^[56]
J. communis (n.s.)	n.s.	Šara mountain in south Serbia	Chloroformic	189.82	27.11 ^d			^[36]
J. communis (var. n.s.)	n.s.	Šara mountain in south Serbia	Ethanolic	189.82	42.85 ^d
J. communis (var. n.s.)	n.s.	Šara mountain in south Serbia	Ethyl acetate	144.21	38.40 ^d
Stems
J. communis (var. alpina)	n.s.	Serra Da Estrela, Portugal	Methanolic (100%, v/v)	221.30			79.30	^[50]

n.s.: not specified; ^a mg equivalent of gallic acid (GAE) per g dry weight (dw); ^b mg quercetin equivalents per g dw; ^c mg cyanidin 3-glucoside equivalents per g dw; ^d mg quercetin 3-O-rutinoside equivalents per g dw; * mg of catechin equivalents per g dw.

Figure 3. Main phenolic compounds found in Juniperus communis L. vegetal parts.

3.3. Volatile Organic Compounds (VOC’s)

J. communis L. parts, namely their essential oils, present many volatile organic compounds (VOCs) in their composition, particularly the presence of monoterpene hydrocarbons, oxygenated monoterpenes, sesquiterpene hydrocarbons, and oxygenated sesquiterpenes ^[57]^[39]. As well as other phytochemicals, their levels also depend on genotype, origin, cultivation methods, meteorological conditions, and extraction techniques. Even so, among the species, monoterpenes such as α-pinene, β-pinene, and β-myrcene are the most commonly found, followed by some sesquiterpenes compounds, namely germacrene D (Figure 4) ^[58]^[59]^[60].

Figure 4. The main volatile organic compound found in Juniperus communis L. parts.

A total of 57 different VOCs were detected in leaf ethanolic extracts (50:50, v/v), with pimaric acid being the predominant one (29.74% of total VOCs), followed by α-pinene (14.86% of total VOCs), β-myrcene (6.99% of total VOCs), bicyclosesquiphellandren (6.87% of total VOCs), and β-pinene (5.29% of total VOCs) ^[57]. On the other hand, extracts of var. communis exhibited higher percentages of limonene (26.12%), benzene (15.62%), β-myrcene (9.08%), and β-pinene (7.30%) ^[61]. Focusing on var. alpina, the predominant ones in their ethanolic extracts (50% ethanol, v/v) were δ-cadinene (12.80%), α-pinene (11.0%), germacrene D (9.30%), and borneol (8.60%) ^[62].

Regarding essential oils of their leaves, in the var. communis, α-pinene was also the most found (34.87% of total VOCs), followed by citronellyl acetate (14.26%), limonene (10.72%), and terpinolene (10.65%). Additionally, vestigial amounts (<6.21%) of ρ-cymene, elemene, cadinene, cyclohexane, cedrol, and caryophyllene were also reported ^[58]. α-Pinene was also the most abundant compound detected in different leaves of var. communis from different regions of the United States of America (USA) (66.6–75.2%) ^[63].

On the other hand, in leaves of var. communis from Serbia, sabinene was the main one reported (39.40%), followed by α-pinene (13.3%) and β-myrcene (4.70%) ^[64], whereas in var. alpina from France, limonene was clearly the most predominant (30.90%), followed by α-pinene (24.40%), β-phellandrene (12.60%), β-myrcene (3.60%), and α-phellandrene (3.60%) ^[65]. Similar percentages of α-pinene were reported on var. saxatilis (23.60%); additionally, this species was also shown to possess considerable percentages of α-cadinene (10.71%), sabinene (9.53%), germacrene D (7.25%), α-murolene (6.58%), and γ-cadinene (5.87%) ^[66]^[64].

The combination of all of these results is evidence that local origin influences the phytochemical profile. Additionally, Gonny et al. ^[65] determined the VOC profile of J. communis woods and roots of var. alpina. For woods, α-terpinyl acetate (9.10%) and α-terpineol (8.4%) were the predominant ones, while for roots, a high percentage of cedrol (37.70%) and cinnamyl acetate (11.50%) were found.

VOCs have been gaining great interest owing to their remarkable antimicrobial, antioxidant, anti-inflammatory, and anticancer properties, being able to attenuate, or even mitigate, the development of cardiovascular disorders and neuropathologies, and also ameliorate the mental state of individuals ^[67].

4. Biological Potential of Juniperus communis Linnaeus

Since ancient times, J. communis parts have been largely used as antiseptics, contraceptives, and diuretics, and as a remedy to treat colds, chest complaints, rheumatism, headaches, dermatological and respiratory ailments, and kidney and urinary infections ^[68]^[69]^[67]. Given the aforementioned, it is not surprising that this plant is a focus of continuous studies to discover its full potential.

To date, several reports have highlighted its antimicrobial, antifungal, antioxidant, anti-inflammatory, and antidiabetic potential, as well as its anticarcinogenic, hepatoprotective, neuronal, and renal effects, as described in Figure 5 and Table 2, Table 3 and Table 4 ^[70]^[68]^[57]^[52]^[71]^[72]^[73]. Next, a summary of the main studies already published concerning the health-promoting properties of this plant will be presented.

Figure 5. Main health-promoting properties attributed to Juniperus communis L. AST: aspartate aminotransferase; ALT: alanine aminotransferase; AChE: acetylcholinesterase; BChE): butyrylcholinesterase; Bax: Bcl-2-associated X protein; AIF: apoptosis-inducing factor; Fas: cell-surface death receptor; FasL: Fas ligand; Bcl-2: B-cell lymphoma 2; ↑: increase; ↓: reduction; T: inhibition.

Table 2. Antimicrobial and antiparasitic activity of different Juniperus communis extracts.

Part of the Plant	Origin	Subspecies/Variety	Method	Inhibited Species	References
Antimicrobial activity
Essential oils
Berries	Poland	n.s.	Disc diffusion	Staphyllococcus aureus, Serratia marcenscens, Enterobacter cloace, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumanii, Listeria monocytogenes, and Candida albicans	^[74]
Needles	Portugal	var. alpina	MIC and MLC	Epidermophyton floccosum, Microsporum canis, M. gypseum, Trichophyton mentagrophytes, T. mentagrophytes var. interdigitale, T. rubrum, and T. verrucosum	^[75]
Needles and berries	Italy	var. communis	MIC	C. albicans, S. aureus, and P. aeuroginosa	^[76]
Plant material (leaves and stems)	Iran	n.s.	Disc diffusion	S. aureus, P. aeruginosa, and E. coli	^[22]
Berries	Slovenia	n.s.	Biofims assay	Campylobacter jejuni, L. monocytogenes	^[77]
Plant material (undifferentiated)	Slovenia	n.s.	Disc diffusion	S. aureus and C. albicans	^[78]
Berries	Spain	n.s.	MIC	E. coli, Proteus mirabilis, K. pneumoniae, P. aeruginosa and Morganella morganii, MRSA, and L. monocytogenes	^[60]
Berries	Portugal	n.s.	MIC and MLC	B. cereus, B. subtilis, E. aerogenes, E. faecalis, E. coli, K. pneumoniae, Proteus mirabilis, P. aeruginosa, Salmonella typhimurium, S. aureus, and C. albicans	^[79]
Leaves	Croatia	n.s.	Disc diffusion, MIC, and MLC	16 species of bacteria and 14 species of fungus	^[80]
Berries	Serbia	n.s.	Disc diffusion, MIC, MLC, and in vivo adhesion assay	S. aureus, MRSA, E. faecalis, L. monocytogenes, E. coli, S. flexneri, S. enteritidis, P. aeruginosa, Aspergillus fumigatus, A. versicolor, A. ochraceus, A. niger, Trichoderma viride, Penicillium funiculosum, P. ochrochloron, and P. verrucosum var. cyclopium	^[81]
Plant material (leaves and branches)	Egypt	n.s.	MIC	S. aureus, E. coli, and C. albicans	^[82]
Plant material	Croatia	n.s.	MIC and biofilm assay	Mycobacterium avium, M. intracellulare, and M. gordonae	^[83]^[84]
Phenolic-rich extracts
Berries	Slovenia	n.s.	Biofilms assay	C. jejuni, L. monocytogenes	^[77]
Plant material	Italy	n.s.	Disc diffusion and MIC	Actinomyces viscosus, Lactobacillus casei, Streptococcus mutans, S. sobrinus, and general oral microbiota	^[85]
Berries	Turkey	n.s.	Disc diffusion and MIC	S. epidermidis, S. aureus, B. subtilis, P. aeruginosa, E. coli, and C. albicans	^[86]
Leaves	Turkey	var. communis and var. saxatilis	MIC	S. aureus	^[87]
Leaves	Poland	n.s.	Disc diffusion	K. pneumoniae, S. enteritidis, P. aeruginosa, A. baumannii, E. faecium, S. aureus, L. fermentum, Clostridium butyricum, L. monocytogenes, B. coagulans, C. utilis, Aspergillus spp., and Fusarium spp.	^[88]
Stem (branches)	Italy	var. communis and var. saxatilis	Biofilm formation	S. aureus	^[89]
Berries	Turkey	var. communis and var. saxatilis	MIC and MLC	S. aureus, S. epidermidis, E. hirae, B. subtilis, E. coli, P. mirabilis, P. aeruginosa, C. albicans, and C. parapsilosis	^[56]
Leaves	India	n.s.	MIC	E. coli, S. aureus, and K. pneumoniae	^[90]
Antiparasitic activity
Essential oils
Stems and leaves	France	n.s.	Radioactive micromethod	Two different strains of Plasmodium falciparum, which were chloroquine-resistant (FcBl) and chloroquine-sensitive (Nigerian) strains	^[91]

n.s.: not specified; MIC: Minimal inhibitory concentration; MLC: Minimal lethal concentration.

Table 3. In vitro and in vivo antioxidant effects of Juniperus communis extracts.

Part of the Plant	Origin	Extract	Subspecies/ Variety	Experimental Model	Effect	References
In vitro assay
Berries	Romania	Ethanolic (50% ethanol, v/v)	n.s.	Capacity to scavenge DPPH^●	IC₅₀ value of 1.42 µg/mL	^[24]^[57]^[36]^[47]^[53]
	Serbia	Ethanolic			IC₅₀ value of 28.55 µg/mL
		Ethyl acetate			IC₅₀ value of 106.44 µg/mL
		Chloroform			IC₅₀ value of 257.66 µg/mL
	Poland	Methanolic (70%, methanol v/v)			IC₅₀ values from 6.86 to 13.66 µg/L
	Poland	Essential oils			IC₅₀ varying from 1.27 to 4.25 µg/L
	Turkey	Methanolic	var. saxatilis		IC₅₀ value of 1.84 mg/mL
		Methanolic	var. communis		IC₅₀ value of 0.63 mg/mL
		Ethanolic (80% ethanol, v/v)	var. alpina		Inhibitory percentages of 33.25, 34.27, and 36.26% at 0.5, 1, and 2 mg/mL, respectively
		Aqueous	var. alpina		Inhibitory percentages of 48.40, 63.29, and 82.03% at 0.5, 1, and 2 mg/mL, respectively
	Poland	Methanolic (70% methanol, v/v)	n.s.	Reducing power potential	Values ranging 6.90 and 10.70 mM FeSO₄ × 7H₂O	^[47]^[49]^[53]^[56]
	Poland	Essential oils	n.s.		Values ranging from 0.47 and 1.11 mM FeSO₄ × 7H₂O
	Turkey	Methanolic	var. communis		IC₅₀ value of 12.82 mg/mL
			var. communis		12.82 ascorbic acid equivalent/mL
			var. saxatilis		IC₅₀ value of 64.14 mg/mL
			var. saxatilis		64.14 ascorbic acid equivalent//mL
		Ethanolic (80% ethanol, v/v)	var. alpina		Inhibitory percentages of 0.083, 0.095, and 0.203% at 0.5, 1, and 2 mg/mL, respectively
		Aqueous	var. alpina		Inhibitory percentages of 0.424, 0.689, and 1.371% at 0.5, 1, and 2 mg/mL, respectively
	Poland	Methanolic (70% methanol, v/v)	n.s.	β-carotene bleaching test	β-carotene inhibitory potential varying from 24.36 to 30.63%	^[49]
	Poland	Essential oils	n.s.	β-carotene bleaching test	β-carotene inhibitory potential varying from 1.19 to 2.39%	^[49]
	Turkey	Methanolic	var. saxatilis	Protect liposomes from lipid peroxidation	IC₅₀ value of 120.07 µg/mL	^[56]
	Turkey	Methanolic	var. communis	Protect liposomes from lipid peroxidation	IC₅₀ value of 4.44 µg/mL	^[56]
	Turkey	Methanolic	var. saxatilis	Ferrous ion (Fe²⁺)-chelating activity	Chelating ability around 30% at 2 mg/mL	^[24]^[47]^[55]
		Methanolic	var. communis		Chelating ability around 15% at 2 mg/mL
		Ethanolic (80% ethanol, v/v)	var. alpina		Inhibitory percentages of 4.88, 14.86, and 32.82% at 0.5, 1, and 2 mg/mL, respectively
		Aqueous	var. alpina		Inhibitory percentage of 0.83% at 2 mg/mL
	Canada	Ethanolic (80% ethanol, v/v)	var. communis	Capacity to scavenge peroxyl radicals	3876 µM Trolox equivalents at 1 mg/mL	^[24]^[52]
	n.s.	Essential oil	n.s.	Capacity to scavenge ABTS^•+ species	IC₅₀ value of 10.96 µg/mL
	Turkey	Ethanolic (80% ethanol, v/v)	var. saxatilis	Capacity to scavenge ABTS^•+ species	Inhibitory percentages of 42.5%, respectively at 3 mg/mL
	n.s.	Essential oil	n.s.	Capacity to scavenge hydroxyl radicals	IC₅₀ value of 0.0066 µg/mL	^[24]
	n.s.	Essential oil	n.s.	Capacity to scavenge superoxide anions	IC₅₀ of 0.822 µg/mL	^[24]^[47]
	Turkey	Ethanolic (80% ethanol, v/v)	var. alpina		Inhibitory percentages of 20.07, 21.97, and 17.80% at 0.5, 1, and 2 mg/mL, respectively
	Turkey	Aqueous	var. alpina		Inhibitory percentages of 5.49, 10.61, and 11.17% at 0.5, 1 and 2 mg/mL, respectively
Crushed berries	Slovakia	Ethanolic (70% ethanol, v/v)	n.s.	Capacity to scavenge hydroxyl radicals	Inhibitory values varying from 65.59 to 88.12% (recalculated by dry matter (DM), from 3.06 to 5.75%/g DM)	^[53]
Noncrushed berries	Slovakia	Ethanolic (70% ethanol, v/v)	n.s.	Capacity to scavenge hydroxyl radicals	Inhibitory values varying from 15.52 and 32.85% (recalculated by dry matter (DM), from 1.20 to 20.05%/g DM) for	^[53]
Unripe berries	Turkey	Ethanolic (80% ethanol, v/v)	var. alpina	Capacity to scavenge superoxide anions	Inhibitory percentages of 14.58, 10.99, and 18.37% at 0.5, 1, and 2 mg/mL, respectively	^[47]
				Capacity to scavenge DPPH^●	Inhibitory percentages of 46.21, 57.32, and 73.75% at 0.5, 1, and 2 mg/mL, respectively	^[24]^[47]
				Capacity to chelate metals	Inhibitory percentages of 6.32, 5.04, and 16.59% at 0.5, 1, and 2 mg/mL, respectively	^[47]
				Ferric-reducing antioxidant power	Inhibitory percentages of 0.288, 0.504, and 0.855% at 0.5, 1, and 2 mg/mL, respectively	^[47]
Leaves	India	Ethanolic (70% ethanol, v/v)	n.s.	Capacity to scavenge DPPH^●	IC₅₀ value of 213 µg/mL	^[46]^[47]^[51]^[64]^[92]
		Aqueous	var. communis		IC₅₀ value of 347 µg/mL
		Ethyl acetate	var. communis		IC₅₀ value of 177 µg/mL
	Turkey	Ethanolic (80% ethanol, v/v)	var. alpina		Inhibitory percentages of 66.62, 83.06, and 91.40% at 0.5, 1, and 2 mg/mL, respectively
	Turkey	Aqueous	var. alpina		Inhibitory percentages of 34.92, 35.56, and 37.29% at 0.5, 1, and 2 mg/mL, respectively
	Bulgaria	Methanolic (80% methanol, v/v)	var. Oblonga Pendula		IC₅₀ value of 258 µg/mL
	Serbia	Essential oil	var. communis		IC₅₀ value of 660 µg/mL
	Serbia	Essential oil	var. saxatilis	Potential to chelate metals	IC₅₀ value of 320 µg/mL	^[47]^[92]
	India	Ethyl acetate	var. communis		IC₅₀ value of 261 µg/ mL
	Turkey	Acetate	n.s.		Inhibitory effect of 6.05% at 1 mg/mL
	Turkey	Aqueous	var. alpina		Inhibitory percentages of 9.06, 12.39, and 38.40% at 0.5, 1, and 2 mg/mL, respectively
	Turkey	Ethanolic (80% ethanol, v/v)	var. alpina	Capacity to scavenge superoxide anions	Inhibitory percentages of 20.26, 25.00, and 25.38% at 0.5, 1, and 2 mg/mL, respectively	^[47]^[66]
	Turkey	Ethanolic (80%, ethanol v/v)	var. alpina	Ferric-reducing antioxidant power	Inhibitory percentages of 0.681, 1.278, and 1.971% at 0.5, 1, and 2 mg/mL, respectively
	Turkey	Aqueous	var. alpina		Inhibitory percentages of 0.121, 0.120, and 0.154% at 0.5, 1, and 2 mg/mL, respectively
	Serbia	Distilled extracts	var. saxatilis		Reduction capacity of 78.77 mg of ascorbic acid equivalents per g of dry matter
	Serbia	Distilled extracts	var. saxatilis	Lipid-peroxidation inhibitory potential	IC₅₀ value of 540 µg/mL	^[66]
	Serbia	Essential oils	var. saxatilis	Lipid-peroxidation inhibitory potential	IC₅₀ value of 2440 µg/mL	^[66]
	Turkey	Ethanolic (80% ethanol, v/v)	var. saxatilis	Capacity to scavenge ABTS^•+ species	Inhibitory percentage of 99.5 at 3 mg/mL	^[52]
Shoots	Poland	Crude extract	n.s.	Antioxidant-enzyme activity and reactive oxygen species in vitro assays	↑↑ the activity of intracellular antioxidant enzymes superoxide dismutase and catalase ↓↓ reactive oxygen species	^[42]
	Turkey	Acetone	n.s.	Capacity to chelate metals	Inhibitory percentage of 6.05% at 1 mg/mL	^[92]
		Ethyl acetate			Inhibitory percentage of 22.59 at 1 mg/mL
		Ethanolic (75% ethanol, v/v)			Inhibitory percentage of 12.31% at 1 mg/mL
Twigs	Spain	Essential oil	n.s.	Peroxy-radical-induced oxidation inhibition	120 µmol Trolox/gram of essential oil	^[39]
Hops	Australia	Ethanolic (30% ethanol, v/v)	n.s.	Ferric ion-reducing antioxidant power	4.17 mg of ascorbic acid equivalents per g	^[54]
				Capacity to scavenge DPPH^●	9.26 mg of ascorbic acid equivalents per g
				Capacity to scavenge ABTS^•+ species	49.54 mg of ascorbic acid equivalents per g
Plant material (twigs, leaves, and berries)	Spain	Essential oil	n.s.	Reducing power assay	IC₅₀ values from 135 to 970 µg/mL	^[60]
Plant material (twigs, leaves, and berries)	Spain	Essential oil	n.s.	Inhibition of oxidation process	IC₅₀ values from 324.76 to 1563.29 µg/mL	^[60]
In vivo assay
Leaves	India	Methanolic	n.s.	Effects on Wistar rats with induced Parkinson’s disease by chlorpromazine for 21 days at a dose of 200 mg/kg	↑↑ in reduced glutathione ↓↓ levels of TBARS	^[19]
Leaves	Romania	Essential oil	n.s.	Effects of juniper volatile oil (1% and 3%) daily inhalation on Amyloid Beta (1–42)-induced oxidative stress in Wistar rats	↑↑ superoxide dismutase and catalase enzymes, and glutathione peroxidase activity	^[67]

n.s.: not specified; IC50: half-maximal inhibitory concentration; TBARS: thiobarbituric acid-reactive substances, DPPH^●: 2,2-diphenyl-1-picrylhydrazyl radical; ABTS^•+: 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid; ↑↑: increase; ↓↓: reduction.

Table 4. In vitro and in vivo health benefits of Juniperus communis extracts.

Part of the Plant	Origin	Extract	Subspecies/ Variety	Experimental Model	Effect	References
Anti-inflammatory and antinociceptive properties
In vitro assay
Plant parts	Sweden	Aqueous	n.s.	Prostaglandin biosynthesis assay Platelet activating factor-induced exocytosis assay	↓↓ prostaglandins by 55% at 200 µg/mL ↓↓ platelet activating factor-induced exocytosis by 78% at 250 µg/mL	^[93]
Woods	Austria	Methylene chloride	n.s.	12(S)-lipoxygenase assay	↓↓ 12[S]-hydroxy-5,8,10,14-eicosatetraenoic acid by 54.0% at 100 µg/mL, 66.2 and 76.2%,	^[73]
Berries	Austria	Methylene chloride	n.s.		↓↓ 12[S]-hydroxy-5,8,10,14-eicosatetraenoic acid by 66.2% at 100 µg/mL
Berries	Austria	Ethyl acetate	n.s.		↓↓ 12[S]-hydroxy-5,8,10,14-eicosatetraenoic acid by 76.2% at 100 µg/mL
Plant material (twigs, leaves, and fruits)	Spain	Essential oil	n.s.	Inhibition of nitric oxide production in lipopolysaccharide-activated murine macrophage RAW 264.7 cells	IC₅₀ values from 23.98 to 84.80 µg/mL	^[60]
In vivo assays
Berries	Italia	Hydroethanolic (80% ethanol, v/v)	var. communis	Effects on the inhibition of writhing carrageenin foot edema in male Wistar rats after 7 days of treatment at doses of 100 and 200 mg/kg	↓↓ carrageenin-foot edema by 60% and 79% at 100 and 200 mg/kg, respectively	^[94]
Berries	Turkey	Aqueous	var. communis		12.8% inhibition (berries)	^[95]
Berries, leaves, and stems	Turkey	Methanolic	var. communis		18.5% inhibition (stems) 3.9% inhibition (berries) 18.5% inhibition (leaves)
		Aqueous	var. saxatilis		9.1% inhibition (berries) 7.8% inhibition (leaves)
		Methanolic	var. saxatilis		30.5% inhibition (berries) 35.2% inhibition (leaves)
		Aqueous	var. communis	Effects on stimulating response latency in male Swiss albino mice using a hot plate after administration of 100 mg/kg of extract	4.27% inhibition (stems) 5.36% inhibition (berries) 4.29% inhibition (leaves)
		Methanolic	var. communis		4.40% inhibition (stems) 4.11% inhibition (berries) 5.16% inhibition (leaves)
		Aqueous	var. saxatilis		3.26% inhibition (stems) 4.32% inhibition (berries) 5.13% inhibition (leaves)
		Methanolic	var. saxatilis		3.13% inhibition (stems) 4.05% inhibition (berries) 5.31% inhibition (leaves)
		Aqueous	var. communis	Effects on carrageenin-induced hind-paw edema in male Swiss albino mice after 360 min of 100 mg/kg extract administration	65.9% inhibition (stems) 65.1% inhibition (berries) 65.4% inhibition (leaves)
		Methanolic	var. communis		54.3% inhibition (stems) 65.8% inhibition (berries) 54.8% inhibition (leaves)
		Aqueous	var. saxatilis		69.6% inhibition (stems) 51.9% inhibition (berries) 53.6% inhibition (leaves)
		Methanolic	var. saxatilis		65.7% inhibition (stems) 43.4% inhibition (berries) 45.3% inhibition (leaves)
		Methanolic	var. saxatilis	Effects on PGE₂-induced hind-paw edema effects in male Swiss albino mice after 360 min of 100 mg/kg extract administration	17.6% inhibition (stems) 16.5% inhibition (berries) 16.8% inhibition (leaves)
Leaves	India	Methanolic	n.s.	In vivo study involving different nociceptive assays (acetic acid-induced writhing, formalin and tail-flick tests) in Swiss albino mice at 100 and 200 mg/kg	↓↓ writhing response and the late phase related with the formalin test Act centrally since the extract and pethidine effects were blocked by naloxone in the tail-flick test	^[96]
Berries	Romania	Hydroethanolic microemulsions	n.s.	Effects on paw edema in dextran-induced inflammation Wistar rats’ model	↓↓ paw edema	^[57]
Berries	Romania	Hydroethanolic microemulsions	n.s.	Kaolin-induced inflammation in Wistar rats’ model	↓↓ interleukins -1β and 6 expression ↓↓ tumor necrosis factor alfa	^[57]
Antidiabetic, antihypercholesterolemic and antihyperlipidemic effects
In vitro assays
Fruits	Turkey	Hydroethanolic (80% ethanol, v/v)	var. saxatilis	Capacity to inhibit α-amylase activity	Inhibitory value of 29.8% at 3 mg/mL	^[52]
Fruits	Turkey	Hydroethanolic (80% ethanol, v/v)	var. saxatilis	Capacity to inhibit α-glucosidase activity	IC₅₀ value of 4.4 µg/mL
Leaves	Turkey	Hydroethanolic (80% ethanol, v/v)	var. saxatilis	Capacity to inhibit the α-amylase activity	Inhibitory value of 84.3% at 3/mg/mL
Leaves	Turkey	Hydroethanolic (80% ethanol, v/v)	var. saxatilis	Capacity to inhibit the α-glucosidase activity	IC₅₀ value of 53.6 µg/mL
Plant material	United Kingdom	Aqueous	n.s.	Effects on glucose movement	↓↓ glucose diffusion by 6% at 50 g/L	^[97]
In vivo assays
Berries	United Kingdom		n.s.	Streptozotocin-induced diabetic mice models for 40 days at doses of 1 g/400 mL	↓↓ polydipsia Prevent weight losses	^[98]
	Spain	Aqueous	n.s.	Effects on streptozotocin-induced diabetic rat models after 24 days of treatment at doses of 250 and 500 mg/kg	↓↓ hypoglycemia in normoglycemic rats	^[99]
	Spain	Aqueous	n.s.	Effects on streptozotocin-induced diabetic rat models after 24 days of treatment at 125 mg/kg	↓↓ blood glucose levels and mortality index Prevent weight losses	^[99]
	Turkey	Oil dissolved in 0.5% of sodium carboxymethyl cellulose	n.s.	Effects on albino Wistar rats after 30 days of treatment at doses of 50, 100 and 200 mg/kg	↓↓ total cholesterol, oxidized low-density lipoprotein, alanine aminotransferase, and aspartate transaminase levels ↑↑ blood urea nitrogen and creatinine levels	^[100]
Plant	n.s.	Methanolic extracts	n.s.	Effects on streptozotocin-nicotinamide induced diabetic rats after 21 days of treatment at doses of 100 and 200 mg/kg	↓↓ blood glucose levels, total cholesterol, triglycerides, low-density lipoprotein, and very-low-density lipoprotein cholesterols ↑↑ high-density lipoprotein cholesterol	^[101]
Herbal preparation also composed of Juniperus. communis	Croatia	Hydroethanolic (60% ethanol, v/v)	n.s.	Effects on alloxan-induced nonobese diabetic NOD mice after 7 days of treatment at 20 mg/kg	↓↓ glucose and fructosamine levels	^[102]
Antiproliferative effects
In vitro assays
Berries	Nepal	Aqueous	n.s.	Effects on OECM-1 human gingival squamous cancer cells after 24 h of exposure	Induce apoptosis, exhibiting an IC₅₀ value of 46.20 µg/mL	^[103]
Plant material	n.s	Aqueous	n.s	Effects on CE81T/VGH human esophageal squamous cell carcinoma after 24, 48 and 72 h of exposure	Induce cell cycle arrest at the G0/G1 phase by regulating the expression of p53/p21 and CDKs/cyclins, triggering cell apoptosis by activating both the extrinsic (Fas/FasL/Caspase 8) and intrinsic (Bcl-2/Bax/Caspase 9) apoptosis pathways IC₅₀ values of 68.41, 64.33, and 60.07 µg/mL after 24, 48, and 72 h of exposure, respectively	^[69]
	n.s	Aqueous		Effects on CE48T/VGH human esophageal epidermoid carcinoma after 24, 48, and 72 h of exposure	Induce cell-cycle arrest at the G0/G1 phase, by regulating the expression of p53/p21 and CDKs/cyclins, triggering cell apoptosis by activating both the extrinsic (Fas/FasL/Caspase 8) and intrinsic (Bcl-2/Bax/Caspase 9) apoptosis pathways IC₅₀ values of 69.38, 56.96, and 36.10 µg/mL after 24, 48, and 72 h of exposure, respectively	^[69]
	USA	Distilled extracts		Effects on B16/F10 melanoma cells after 24 and 48 h of exposure	Induced apoptosis, decreased angiogenesis and metastasis, and diminished cancer stem-cell expression IC₅₀ values of 27 and 44 µg/mL, after 24 and 48 h of exposure, respectively	^[58]
Leaves	Turkey	Methanolic	n.s.	Effects on C6 rat brain tumor and HeLa human cervix carcinoma cells after 24 h of exposure	IC₅₀ value of 28.43 µg/mL (C6 rat brain tumor) IC₅₀ value of 32.96 µg/mL (HeLa cancer cells)	^[104]
Aerial parts	Egypt	Methanolic	n.s.	Effects on PC3 human prostate, HCT 116 human colon, and MCF7 breast cancer cells after 24 h of exposure	IC₅₀ value of 23.8 µg/mL (PC3 cancer cells) IC₅₀ value of 37.6 µg/mL (HCT 116 cancer cells) IC₅₀ value of 23.8 µg/mL (MCF7 cancer cells)	^[105]
Plant material	New Mexico, USA	Aqueous	n.s.	Effects on MCF-7/AZ breast cancer cells after 24 h of exposure	IC₅₀ value of 50 µg/mL	^[60]^[106]
Plant material	Spain	Essential oil	n.s.	Effects on NCI-H460 lung, MCF-7 breast, AGS gastric, and Caco-2 cancer cells after 24 h of exposure	IC₅₀ values varying from 41.99 to 44.87 µg/mL (NCI-H460 cancer cells) IC₅₀ values varying from 30.88 to 163.99 µg/mL (MCF-7 cancer cells) IC₅₀ values varying from 132.68 to 302.86 µg/mL (AGS cancer cells) IC₅₀ values varying from 107.65 to 230.79 µg/mL (Caco-2 cancer cells)	^[60]^[106]
Berries	Australia	Methanolic	n.s.	Effects on Caco-2 human colorectal and HeLa cervical cancer cells after 12 h of exposure	IC₅₀ value of 1383 µg/mL (Caco-2 cancer cells) IC₅₀ value of 2592 µg/mL (HeLa cancer cells)	^[107]
	Australia	Aqueous	n.s.	Effects on Caco-2 human colorectal and HeLa cervical cancer cells after 12 h of exposure	IC₅₀ value of 1516 µg/mL (Caco-2 cancer cells) IC₅₀ value of 2157 µg/mL (HeLa cancer cells)	^[107]
	Serbia	Essential oil and Distilled extracts	var. saxatilis	Effects on A549 human lung adenocarcinoma epithelial cells after 24 h of treatment after 24 h of exposure	Induced apoptosis and arrested cell cycle in G2/M IC₅₀ value of 69.4 µg/mL (essential oil) IC₅₀ value 1270 µg/mL (distilled extract)	^[66]
	USA	Distilled extracts	n.s.	Effects on HepG2 human hepatocellular cancer cells after 24, 48, and 72 h of exposure	IC₅₀ values of 48.9, 42.3, and 43.9 µg/mL, after 24, 48, and 72 h of exposure, respectively	^[108]^[109]
				Effects on Mahlavu human hepatocellular carcinoma cells after 24, 48, and 72 h of exposure	IC₅₀ values of 64.9, 58.5, and 59.4 µg/mL, after 24, 48, and 72 h of exposure, respectively
				Effects on J5 human hepatocellular carcinoma cells after 24, 48, and 72 h of exposure	IC₅₀ values of 74.2, 67.2, and 53.2 µg/mL, after 24, 48, and 72 h of exposure, respectively
				Effects on HT-29 colon cancer cells after 24, 48, and 72 h of exposure	Induced cell-cycle arrest at the G0/G1 phase via regulation of p53/p21 and CDK4/cyclin D1 Induced cell apoptosis via the extrinsic (FasL/Fas/caspase-8) and intrinsic (Bax/Bcl-2/caspase-9) apoptotic pathways IC₅₀ values of 66.71, 60.02, and 54.32 µg/mL, after 24, 48, and 72 h of exposure, respectively
				Effects on CT-26 colon cancer cells after 24, 48, and 72 h of exposure	Induced cell-cycle arrest at the G0/G1 phase via regulation of p53/p21 and CDK4/cyclin D1 Induced cell apoptosis via the extrinsic (FasL/Fas/caspase-8) and intrinsic (Bax/Bcl-2/caspase-9) apoptotic pathways IC₅₀ values of 27.8, 22.7, and 27.3 µg/mL, after 24, 48, and 72 h of exposure, respectively
Leaves and branches	Wyoming, USA	Essential oil	n.s.	Effects on SH-SY5Y human neuroblastoma cells after 24 h of exposure	IC₅₀ value of 53.7 µg/mL	^[110]
Seed cones	Serbia	Essential oil	var. saxatilis	Effects on HT-29 and HCT116 colon cancer cells after 24 h of exposure	IC₅₀ value 125 µg/mL (HT-29) IC₅₀ value of 62.5 µg/mL (HCT116)	^[81]
Seed cones	Serbia	Distilled extracts	var. saxatilis		IC₅₀ value 625 µg/mL (HT-29) IC₅₀ value of 1250 µg/mL (HCT116)	^[81]
Roots	China	Acetone	n.s.	Effects on N18 neuroblastoma cell lines after 24 and 48 h of exposure	Induced glioma cell-cycle arrest through intrinsic and extrinsic apoptotic pathways IC₅₀ values of 61.11 and 68.94 µg/mL, after 24 and 48 h of exposure, respectively	^[111]
				Effects on DBTRG-05MG, G5T/VGH, GBM8401, GBM8901, and RG2 glioblastoma cell lines after 24 h of exposure	Induced glioma cell-cycle arrest through intrinsic and extrinsic apoptotic pathways IC₅₀ value of 67.04 µg/mL (DBTRG-05MG glioblastoma cells) IC₅₀ value of 63.3 µg/mL (G5T/VGH glioblastoma cells) IC₅₀ value of 57.14 µg/mL (GBM8401glioblastoma cells) IC₅₀ value of 58.45 µg/mL (GBM8901 glioblastoma cells) IC₅₀ value of 69.97 µg/mL (RG2 glioblastoma cells)
				Effects on DBTRG-05MG, G5T/VGH, GBM8401, GBM8901, and RG2 glioblastoma cell lines after 48 h of exposure	Induced glioma cell-cycle arrest through intrinsic and extrinsic apoptotic pathways IC₅₀ value of 49.46 µg/mL (DBTRG-05MG glioblastoma cells) IC₅₀ value of 67.85 µg/mL (G5T/VGH glioblastoma cells) IC₅₀ value of 46.68 µg/mL (GBM8401glioblastoma cells) IC₅₀ value of 55.49 µg/mL (GBM8901 glioblastoma cells) IC₅₀ value of 53.8 µg/mL (RG2 glioblastoma cells)
In vivo assays
Plant	USA	Distilled extracts	n.s.	Effects on melanoma tumor model in C57BL/6 mice after 23 days of treatment at a dose of 200 mg/kg	Cell-cycle arrest at the G0/G1 phase ↓↓ tumor size by 45.2%, B-cell lymphoma-2 (Bcl-2), procaspases 8 and 9 and higher levels of Bcl-2-associated X protein, apoptosis-inducing factor, cell-surface death receptor Fas and Fas ligand when compared to untreated control	^[58]
Berries	USA	Distilled extracts	n.s.	Effects in BALB/c nude mice injected with HepG2 liver cancer cells at a dose of 200 mg/kg	↓↓ tumor size ↑↑ lifespan with no or low systemic and pathological toxicity	^[108]
Berries	USA	Distilled extracts	n.s.	Effects in female BALB/c mice injected with CT-16 colon cancer cells at a dose of 200 mg/kg	Inhibited proliferation Induced apoptosis No obvious change in body weight or histological morphology of normal organs after treatment	^[109]
Roots	China	Acetone	n.s.	Effects in male Foxn1 nu/nu mice injected with DBTRG-05MG human glioblastoma cells after 100 days of treatment at a dose of 200 mg/kg	Can penetrate the blood-brain barrier ↓↓ tumor size and the degree of neovascularization ↑↑ PCNA, VEGFR-1, and VEGFR-2 in 44.49%, 5.88%, and 5.85%, respectively, when compared to untreated control	^[111]
Neuronal effects and anticataleptic activity
In vitro assays
Leaves	Turkey	Hydroethanolic (80% ethanol, v/v)	var. alpina	Capacity to inhibit acetylcholinesterase activity	10.38% inhibition at 50 µg/mL 24.30% inhibition at 100 µg/mL 32.89% inhibition at 200 µg/mL	^[47]^[92]
Ripe Berries		Aqueous	var. alpina		5.47% inhibition at 100 µg/mL 28.17% inhibition at 200 µg/mL
Shoots		Ethyl acetate, ethanolic, and acetone extracts	n.s.		21.34% inhibition at 100 µg/mL (ethyl acetate extract) 13.46% inhibition at 100 µg/mL (ethanolic extract) 28.43% inhibition at 100 µg/mL (acetone extract)
Shoots		Ethyl acetate, ethanolic, and acetone extracts	n.s.		Inhibitory percentages varying from 32.34 to 41.97%% inhibition at 100 µg/mL (ethyl acetate extract) Inhibitory percentages varying from 22.29 to 45.45% inhibition at 100 µg/mL (ethanolic extract) Inhibitory percentages varying from 1.91 to 38.55% inhibition at 100 µg/mL (acetone extract)
Leaves		Ethyl acetate, ethanolic, and acetone extracts	n.s.		20.02% inhibition at 100 µg/mL (ethyl acetate extract) 10.56% inhibition at 100 µg/mL (ethanolic extract) 32.34% inhibition at 100 µg/mL (acetone extract)
Ripe berries and leaves	Turkey	Aqueous	var. alpina	Capacity to inhibit butyrylcholinesterase activity	25.87 (berries) and 25.33% (leaves) inhibition at 50 µg/mL 32.57 (berries) and 44.16% (leaves) inhibition at 100 µg/mL 36.97 (berries) and 62.01% (leaves) inhibition at 200 µg/mL	^[47]^[92]
Ripe berries and leaves		Hydroethanolic (80% ethanol, v/v)			43.68 (berries) and 30.31% (leaves) inhibition at 50 µg/mL 45.19 (berries) and 33.17% (leaves) inhibition at 100 µg/mL 47.55 (berries) and 35.33% (leaves) inhibition at 200 µg/mL
Unripe berries		Hydroethanolic (80% ethanol, v/v)			44.17% inhibition at 50 µg/mL 48.96% inhibition at 100 µg/mL 49.95% inhibition at 200 µg/mL
In vivo assays
Leaves	n.s.	Methanolic	n.s.	Effects on Wistar rats with induced Parkinson’s disease by chlorpromazine for 21 days at a dose of 200 mg/kg	↑↑ locomotor activity ↓↓ motor dysfunctions, including catalepsy and muscle rigidity	^[19]
Plant material	India	Methanolic		Effects on Wistar rats with induced catalepsy by reserpine 4 h after juniper treatment at a dose of 200 mg/kg	↓↓ catalepsy activity	^[70]
	Romania	Essential oil		Effects of juniper volatile oil (1% and 3%) daily inhalation on Amyloid Beta (1–42) male Wistar rat model of Alzheimer’s disease after 21 days of treatment	↑↑ working memory and reference memory errors within radial arm maze task ↓↓ spontaneous alternations percentage within Y-maze task	^[112]
	Romania	Essential oil		Effects of juniper volatile oil (1% and 3%) daily inhalation on Amyloid Beta (1–42)-induced oxidative stress in Wistar rats	↑↑ acetylcholinesterase, superoxide dismutase and catalase activities, and malondialdehyde and protein carbonyl levels ↓↓ glutathione peroxidase-specific activity and the total content of the reduced glutathione	^[67]
Hepatoprotective effects
In vivo assays
Leaves	India	Ethyl acetate	n.s.	Effects on Wistar albino rats with hepatic damage caused by paracetamol for 14 days at a dose of 200 mg/kg	↓↓ alkaline phosphatase (−57.41%), direct bilirubin (−30.33%) and total bilirubin (−38.41%), serum alanine aminotransferase (−34.17%), and serum aspartate aminotransferase (−27.58%) when compared to the untreated group Hepatoprotective effects with rearrangement promotion of portal triads and central veins	^[51]
Stems	n.s.	Petroleum ether, chloroform, and ethanol extracts	n.s.	Effects on rats with hepatic damage caused by carbon tetrachloride	Hepatoprotective activity	^[113]
Co-combination of berries from juniper and Solanum xanthocarpum	India	Ethanolic	n.s.	Effects on Wistar albino rats with liver toxicity induced by paracetamol and azithromycin for 14 days at a dose of 200 mg/kg	↓↓ serum glutamate oxaloacetate transaminase (−65.4%), serum glutamate pyruvate transaminase (−59.3%), alkaline phosphatase (66.8%), total bilirubin (62.1%), and liver inflammation Promoting liver tissue’s normal architecture	^[3]
Tyrosinase inhibitory activity
In vitro assays
Berries	Republic of Korea	Methanolic	n.s.	Capacity to inhibit tyrosinase activity	about 50% inhibition at 100 µg/mL	^[114]
Renal effects
In vivo assay
Berries	Croatia	Aqueous	n.s.	Daily intake of 10% aqueous infusion, 0.1% of oil (with 0.2% Tween 20 solubilizer) by healthy female Wistar rats	↑↑ diuresis and urine excretion without loss of electrolytes	^[71]
Antiurolithiasis effects
In vitro assay
Berries	Iran	Hydroethanolic (50% ethanol, v/v)	n.s.	Capacity to dissolve urinary stone brought out from human kidney at concentrations of 500, 1000, and 2000 µg/mL	Dissolve urinary stones ↓↓ dry powder weight of stones ↑↑ the ratio of calcium oxalate in normal saline aqueous solution plus stone	^[115]
Gastrointestinal effects
In vivo assays
Leaves	India	Methanolic (80% methanol, v/v)	n.s.	Effects on adult male Wistar albino rats with ulcers induced by aspirin, serotonin, indomethacin, alcohol, and stress at doses of 50 and 100 mg/kg	↓↓ aspirin, serotonin, indomethacin, alcohol, and stress-induced gastric ulcerations in rats ↑↑ healing rate of acetic acid-induced ulcers in rats	^[72]
Leaves	India	Methanolic (80% methanol, v/v)	n.s.	Effects on pigs with histamine-induced duodenal lesions at doses of 50 and 100 mg/kg	↓↓ histamine-induced duodenal lesions in pigs	^[72]
Vessels and trachea protective effects in passive smoking
In vitro assays
Berries	Romania	Aerosols	n.s.	Effects of 3-week juniper aerosols (40 min/day) on female Sprague-Dawley rats firstly exposed to daily passive smoking for 6 weeks	↓↓ acetylcholine endothelial-dependent relaxation	^[116]
Berries	Romania	Oil	n.s.	Effects of 3-week juniper nebulization (20 min/day) on the respiratory tract of rats which firstly exposed to 2 cigarettes per day, 5 days a week for 6 weeks	Bronchodilator effects mediated by nitric oxide	^[117]
Genotoxicity protective effects
In vitro assays
Berries	Romania	Hydroethanolic (50% ethanol, v/v)	n.s.	Capacity to exhibit genoprotective effects against aberrations and abnormalities induced by ethanol on root-tip cells of Allium cepa L.	Can effectively protect chromosomes aberrations	^[57]

n.s.: not specified; IC50: half-maximal inhibitory concentration ↑↑: increase; ↓↓: reduction.

This entry is adapted from the peer-reviewed paper 10.3390/ijms23063197

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