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	[25]
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%,	[88]
Berries	Austria	Methylene chloride	n.s.		↓↓ 12[S]-hydroxy-5,8,10,14-eicosatetraenoic acid by 66.2% at 100 µg/mL
		Ethyl acetate			↓↓ 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	[75]
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	[113]
	Turkey	Aqueous			12.8% inhibition (berries)	[114]
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			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			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			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			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			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	[29]
Berries	Romania	Hydroethanolic microemulsions	n.s.	Effects on paw edema in dextran-induced inflammation Wistar rats’ model	↓↓ paw edema	[40]
Berries	Romania	Hydroethanolic microemulsions	n.s.	Kaolin-induced inflammation in Wistar rats’ model	↓↓ interleukins -1β and 6 expression ↓↓ tumor necrosis factor alfa
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	[66]
				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
				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	[124]
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	[125]
	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	[126]
				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
	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	[33]
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	[31]
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	[127]
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	[128]
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	[39]
				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
	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	[73]
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)	[72]
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)	[129]
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	[75,130]
	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)
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)	[131]
		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)
	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)	[71]
	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	[132,133]
				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	[134]
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)	[93]
		Distilled extracts			IC50 value 625 µg/mL (HT-29) IC50 value of 1250 µg/mL (HCT116)
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	[135]
				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	[73]
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	[132]
				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	[133]
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	[135]
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	[61,107]
Ripe Berries		Aqueous			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)
					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	[61,107]
		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	[34]
	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	[136]
				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	[85]
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	[65]
Stems	n.s.	Petroleum ether, chloroform, and ethanol extracts	n.s.	Effects on rats with hepatic damage caused by carbon tetrachloride	Hepatoprotective activity	[30]
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	[137]
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	[86]
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	[138]
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	[87]
			n.s.	Effects on pigs with histamine-induced duodenal lesions at doses of 50 and 100 mg/kg	↓↓ histamine-induced duodenal lesions in pigs
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	[139]
		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	[140]
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	[40]

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