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Sources | Caffeine Range (mg) | References |
---|---|---|
Coffee | ||
Americano coffee | 91.7-213.3 | [40] |
Decaffeinated coffee (500 mL) | 0.0-13.9 | [41] |
Instant coffee | 8.7-120.0 | [29,39,40,42] |
Plain coffee | 68.4-136.9 | [40] |
Espresso | 66.0-276.0 | [29] |
Tea | ||
Black tea | 42.0 | [39] |
Green tea | 18.0 | [39] |
Yerba Mate | 40.0 | [39] |
Soft drinks | ||
Coca-Cola classic | 34.0 | [39] |
Diet coke | 46.0 | [39] |
Guarana | 47.0 | [39] |
Mountain Dew | 54.0-90.0 | [39] |
Pepsi-Cola | 38.0 | [39] |
Soda | 0.0-69.0 | [39] |
Sunkist | 19.0 | [39] |
Energy drinks | ||
Mountain Dew Amp | 142.0 | [39] |
Full Throttle | 160.0 | [39] |
Monster | 60.0-300.0 | [39] |
Red Bull | 80.0-106.0 | [39] |
Rockstar | 160.0-300.0 | [39] |
Juice | ||
Cranergy | 70.0-80.0 | [39] |
Energy shots | ||
Bang Shot | 300.0 | [39] |
5 Hour Energy | 200.0 | [39] |
TruBrain Extra | 100.0 | [39] |
Spike Energy Double Shot | 350.0 | [39] |
Chocolate | ||
Dark chocolate | 8.0 | [39] |
Others | ||
Water Joe | 70.0 | [39,43] |
Target Cancer | Study Type | Model | Caffeine concentration | Result | Reference |
---|---|---|---|---|---|
Carcinoma squamous cells | In vitro | HN5 and KYSE30 cells | 0.5 - 70 mmol | Caffeine at the concentrations of 20, 50 and 70 mmol presented an inhibitory effect and decreased the proliferation rate of both cell lines. | [58] |
Glioblastoma multiforme | In vitro | Human GBM cell line U87-MG | 1 mM | Pretreatment of cells with caffeine followed by combined treatment of Temozolomide + caffeine significantly decreased cell viability compared with the other groups. | [59] |
Glioblastoma multiforme | In vitro | human GBM cell line U87MG and T98G 101 cells | 0.5- 10 | In both cell lines, caffeine at a concentration of 2.5 mM was able to reduce cellular viability, which was more pronounced under hypoxia. | [60] |
Pancreatic ductal adenocarcinoma | In vitro | AsPC-1, BxPC-3, Capan-1, COLO-357, MiaPaCa-2, SU.86.86, PANC-1, and T3M4 pancreatic cancer cells | 100, 200 µM | Caffeine enhanced cell death induced by 5-Fluorouracil and Gemcitabine, and also decreased the IC50 of both chemotherapeutic agents. | [61] |
Prostate cancer | In vitro | PC-3 cells | 0.5 mM | The caffeine affected the cell viability in a dose-dependent manner. Cell migration and invasion ability was more affected by the combination of atorvastatin and caffeine than by caffeine alone. The same was true for the formation of tumor spheres. | [62] |
Melanoma | In vitro | Normal human melanocytes COLO829 and C32 cells | 0.01 - 1.0 μmol/mL | The results show the ability of caffeine to reduce the viability of COLO829 and C32 cells, by 5-35% and 1-16%, respectively. In addition, it also led to a decrease in thiol degradation and pro-apoptotic effect and did not affect normal melanocytes cells. | [63] |
Breast cancer | In vitro | MDA-MB-231, MCF7 and MCF10A cells | 125 nM | After treatment of MDA-MB-231 and MCF7 with caffein, there was a change in metabolism towards respiratory-chain phosphorylation with low ratio of free to bound NADH. In combination with cisplatin, there was a decrease in viability, and preference of cancer cells over normal breast cells. | [64] |
Colon and Breast cancer | In vitro | HCT116 and MCF7 cells | 0 to 60 mM | Apoptosis increased in both cell lines proliferative and senescent cells after treatment of the cells with caffeine at a concentration of 15 mM. | [53] |
Lung cancer | In vitro | NCI-H23 and MLC15 cells | 0–500 µM | After treatment of NCl-H23 cells with 250 and 500 µM caffeine, the size of colonies decreased by 78.1% and 63.9%, respectively. In addition, caffeine at the same concentrations also induced cell arrest in the G0/G1 phase, reduced the S phase of the cell cycle, and suppressed cell invasion. | [65] |
Melanoma | In vitro | B16F10 cells | 1–40 µM | Pre-treatment cells with caffeine enhanced the cytotoxic effects induced by dacarbazine. In addition, caffeine also increased oxidative-stress in a dose-dependent manner. | [66] |
Breast | In vitro | MCF-7 and MDA-MB-231cells | 1-10 mM | In MTT assay, caffeine reduced the cell viability in concentrations greater than 2.5 mM for MCF7 and for 5 and 10 mM for MDA-MB-231 cell line. At the last-mentioned concentrations caffeine induces apoptosis and necrosis in both cell lines. | [54] |
Endometrial cancer | In vitro | RL95-2, HEC-1-A and KLE cells | 0-40 mM | The therapeutic concentration of cisplatin decreased from 4.1 to 1.1 µM and from 163 to 6.6 µM, with caffeine concentrations of 1.1 and 5.3 Mm, respectively. | [67] |
Glioma | RT2 cells-induced glioma in male Fischer 344 inbred rat | 30 mg/kg/day | The combination of caffeine with temozolomide reduced tumor wrinkles compared between the control group and the group with temozolomide alone. | [68] | |
Hepatocellular carcinoma | In vitro and in vivo | SMMC-7721 and Hep3 cell lines and Male BALB/c nude mice | 0-32 mM (in vitro) 20mg/kg/day (in vivo) |
Caffeine decreased the viability of both cell lines and has a synergistic effect with 5-fluorouracil. In addition, tumor growth was suppressed, and tumor weight was reduced in mice treated with caffeine alone or in combination with 5-fluorouracil. | [69] |
Adult pleomorphic rhabdomyosarcoma | In vitro and in vivo | RMS cells, Athymic nu/nu nude mice and cells removed to the tumor tissue | 0.5 and 1 mM (in vitro) 100 mg/kg per day (in vivo) |
Caffeine has been shown to enhance the antiproliferative effects of valproic acid. In the in vivo studies, the group treated with caffeine and valproic acid showed a reduction in tumor volume compared to the control group. This was also confirmed in the group treated with Salmonella typhimurium A1 receptor in combination with caffeine and valproic acid. | [70] |
Osteossarcoma, fibrosarcoma | In vitro and in vivo | HOS, HT1080 and LM8 cells and athymic nude mice | 0.5 mM (in vitro) 100 mg/kg (in vivo) |
The combination of cisplatin and caffeine decreased ell viability compared with cisplatin alone. In vivo, after implantation of LM8 and HT1080 cells the combination of cisplatin + caffeine decreased tumor volume and weight. | [71] |
Melanoma | In vivo | Albino mice and C57BL/6J mice | 0.08% w/v, daily | The authors demonstrated that in the carcinogen-induced tumor model, the groups treated with caffeine alone decreased the tumor growth rate from 5.3 mm2/day to 2.6 mm2/day, in combination with anti-PD1 the decrease was more pronounced (0.9 mm2/day). | [72] |
Fibrosarcoma | In vivo | Adult albino mice | 0.02%, 0.04%, and 0.08% w/v | In caffeine-treated mice, tumor incidence, size and growth rate decreased with the increasing concentration. In addition, caffeine-treated mice had a higher percentage of cytotoxic T cells and higher TNF-α and IFN-γ levels. | [55] |
Synovial sarcoma | In vivo | Athymic nu/nu nude mice | 100 mg/kg/day | The combination of oral recombinant methioninase and caffeine reduced tumor volume. | [56] |
Osteosarcoma | In vivo | Athymic nu/nu nude mice | 100 kg/kg/day | After treatment the osteosarcoma model (patient-derived orthotopic xenograft) with cisplatinum + oral recombinant methioninase + caffeine, the decreased was most smarked compared with the other groups. | [73] |
Fibrosarcoma | In vivo | Adult Syrian golden hamsters | 100 mg/kg | Administration of metformin (500 mg/kg) and caffeine resulted in inhibition of fibrosarcoma growth. | [74] |
Colorectal cancer | In vivo and in silico | Swiss Webster mice | 50 mg/kg/day | Mice treated with caffeine alone or in combination with chlorogenic acid decreased the expression of IL-6, IL-17 and TNF-α. | [75] |
Renal cell carcinoma | In vitro and in vivo and in silico | ACHN and 786-O cells and BALB/c nude mice | 0–3200 μg/mL | The molecular docking studies demonstrated that caffeine was able to bind to G6PDH at the NADP+ binding site, which is a biomarker and potential therapeutic target for renal cell carcinoma. In addition, caffeine was able to decrease the viability and proliferation of both cell lines and in the in vivo studies. | [57] |
Target/Goal | Study Type | Model | Caffeine Concentration | Result | Reference | |
---|---|---|---|---|---|---|
Anti-inflammatory effect and immunomodulation | In vitro | Human peripheral blood mononuclear cells | 0.019 -1.16 mM | Caffeine reduced the levels of several cytokines (IL-8, MIP-1β, IL-6, IFN-γ, GM-CSF, TNF-α, IL-2, IL-4, MCP-1, and IL-10. It also inhibited STAT1 signaling. | [92] | |
Immunomodulation | In vitro | Monocytes and macrophage | 300–1000 µM | Caffeine suppressed TNF−α in both LPS-activated macrophage subtypes, altered adenosine receptor expression, Akt/AMPK/mTOR signaling and inhibited STAT/IL-10 signaling in macrophage colony-stimulating factor. | [105] | |
Immunomodulation | In vitro | Mesenchymal stem cells and neutrophiles | 0.1-1 mM | Caffeine-treated mesenchymal stem cells produced fewer reactive oxygen species and increased phagocytosis of neutrophils co-cultured with mesenchymal stem cells. | [106] | |
Immunomodulation | In vitro | Mesenchymal stem cells and neutrophiles | 0.1-1 mM | Caffeine treatment increased the viability of co-cultured neutrophils. | [107] | |
Bronchopulmonary dysplasia - NLRP3 inflammasome | In vitro | THP-1-derived macrophages | 100-800 μM | There was a decreased in NLRP3 inflammasome activation, ASC speck formation, and caspase 1 cleavage. In addition, IL-1β and IL-18 decreased secretion, and phosphorylation of MAPK and NF-kB pathway members | [108] | |
Melanoma |
In vitro in silico |
Mel1 and Mel3 cells | 1 and 2 mM | After caffeine treatment, there was a decrease in the levels of IL-1β, IP-10, macrophage inflammatory protein 1-α, and CCL4. On the other hand, the expression of regulated and normal T cells decreased in Mel3 cell line. | [109] | |
Rheumatoid arthritis | In vitro and in vivo | Mesenchymal stem cells and Wistar rats | 0-1 mM | Caffeine at a concentration of 0.5 Mm can promote lower levels of cytokines, such as IFN-γ, IL-6, and IL-1β and higher levels of IDO and TGF-β. In addition, cells treated with caffeine diminish the severity of rheumatoid arthritis and cause a decrease in serum levels of C-reactive protein, nitric oxide, myeloperoxidase, and TNF-α. | [87] | |
Infection | In vitro and in vivo | Peritoneal macrophages and Swiss mice | 0.05- 5 μg/mL (in vitro) 0.05-5 mg/Kg (in vivo) |
In mice, the leucocyte infiltration of the peritoneal cavity decreased after caffeine treatment. In addition, mRNA expressions of IL-1β, IL-6, and the enzyme inducible nitric oxide synthase were decreased, whereas IL-10 was increased. | [110] | |
Immunological and metabolic anomalies in obesity | In vitro and in vivo | Male Sprague-Dawley rat, RAW 264.7 macrophage and HepG2 cells | 50, 100, 150Μm (in vitro) 20mg/kg/day (in vivo) | In caffeine-treated mice, the profiles of TNF−α, MCP-1, IL-6, intercellular adhesion molecule, and nitrite were suppressed. In addition, live white adipose tissue and muscle macrophages and their cytokine levels also decreased. | [111] | |
Depression | In vitro and in vivo | CBA × C57BL/6 F1 mice and syngeneic splenocytes | 100 μg/15 × 106 cells | Immune cells treated with caffeine and transplanted into depressive-like mice resulted in an increase in neuronal density and anti-inflammatory cytokines (IL-10 and IL-4) and a decrease of proinflammatory cytokine (IL-1β, INF-γ, and TNF-α). | [112] | |
Autoimmune Encephalomyelitis | In vitro and in vivo | Primary microglia and BV2 cells C57BL/6 mice were immunized to induce autoimmune encephalomyelitis |
2mM (in vitro) 10-30 mg/kg/day (in vivo) |
Caffeine decreased clinical score, inflammatory cell infiltration degree of the demyelination, and microglia stimulation in mice. In addition, it increased LC3-II/LC3-I levels and decreased NLRP3 and P62 levels. | [86] | |
Neurotoxicity - antioxidant and anti-inflammatory | In vivo | Albino rats | 20 mg/kg | Reduced oxidative stress and restored TNF-α levels in cerebral tissues. | [113] | |
Neuroinflammation | In vivo | Sprague-Dawley rats | 60 mg/kg/day | Caffeine/modafinil increased levels of anti-inflammatory (IL-4 and IL-10) and decreased proinflammatory (TNF-α, IL-1β) cytokines in the hippocampus. Decreased the microglial immunoreactivity and improved inflammatory response and anxious behavior. | [114] | |
Hepatic fibrosis - antioxidant and anti-inflammatory | In vivo | Hepatic fibrosis Sprague-Dawley rats | 50 mg/kg | Decreased fibrosis and necro-inflammation; decreased LPAR1, TGF-β1, CTGF, α-SMA and LPAR1 expression; improved liver function | [115] | |
Oxygen-Induced Inflammatory Lung Injury | In vivo | Neonatal rats | 10 mg/kg | Under hyperoxia, caffeine decreased pro-inflammatory mediators (TNF-α, IL-1α, IL-1β, IFN-γ) and NF-kB, and decreased infiltrating cells in the lung. Opposite effects were observed in normotoxic conditions. | [104] | |
Inflammation and adenosinergic system in cerebellum | In vivo | Ethanol-induced inflammation in wistar and UChB rats | 3 g caffeine/L of ethanol | Caffeine modulated A1 and A2a receptors and attenuated the inflammation, demonstrating a neuroprotective role. | [116] | |
Choroidal neovascularization - anti-inflammatory and na |
In vitro in vivo |
Laser photocoagulation mice model | 200, 400 uM (in vitro); 10 and 20 mg/kg (in vivo) |
Significantly reduced the migration of retinal and choroidal endothelial cells (in vitro); Decreased choroidal neovascularization and inflammatory (mononuclear phagocytes) cells’ recruitment to the lesion area. | [93] | |
Neurotoxicity | In vivo | Tramadol-induced damage in cerebelum rat model | 37.5 mg/kg | Up-regulated autophagy-related genes; reduced the expression of inflammatory and apoptosis markers, demonstrating neuroprotective effects in the cerebellum. | [117] | |
Retinal inflammation |
In vitro in vivo |
Ischemia reperfusion (I/R) injury mice model | 1 - 100 uM (in vitro); 10uL at 1,9% (in vivo) | Caffeine reduced the secretion of IL-1β, IL-6, and TNF-α and restored the integrity of retinal cell monolayer (in vitro). Instilled caffeine reduced IL-6 mRNA levels and maintained BDNF physiological levels in the retina | [96] | |
Cognitive impairment |
In vivo | BALB/c mice | 0.05 and 0.1 mg | Intranasal administration of caffeine improved the behavior outcomes of ischemic mice and reduced the expression of proinflammatory biomarkers (TNF-α, IL-6) and improved anti-inflammatory cytokines' (IL-10). | [118] | |
Hydrocephalus | In vivo | Kaolin-induced hydrocephalus mice | 50 mg/kg by gavage (dams) | Administration of caffeine to dams reduced cell death, and increased the neurons dendritic arborization in the sensorimotor cortex and striatum of the mice neonates and improved hydrocephalic deficits and behavioral development | [119] | |
Anti-inflammatory effect | In vivo | Albino rats | 100mg/kg | Administration of 100 mg/kg/day alone or in combination with nicotine decreased the number of CD68+ve macrophages and the density of CD68 immunoexpression. In addition, combined administration of caffeine and nicotine decreased apoptosis compared with nicotine alone. | [120] | |
Immunomodulation and anti-inflammatory effect | In vivo | Nile tilapia | Diet containing 5 and 8% | Diets containing 5% and 8% caffeine prevented alterations caused by hypoxia, such as ATP hydrolysis and consequent accumulation in the extracellular environment. | [121] | |
Dental pain | Clinical Trial | Patients with acute postoperative dental pain | 100 mg | Caffeine improved the effect of ibuprofen in the treatment of moderate postoperative dental pain. | [122] |
Disease | Study Type | Model | Caffeine concentration | Result | Reference |
---|---|---|---|---|---|
Parkinson’s Disease | In vitro | Transgenic Caenorhabditis elegans | 10 mM | Caffeine was able to prevent neuronal cell loss in 96% of dopaminergic neurons. | [135] |
Alzheimer’s Disease | In vitro | SHSY5Y cells | 0.6 and 1 mM | Both concentrations were able to reduce beta-amyloid neurotoxicity. | [141] |
Alzheimer’s Disease | In vitro | SH-SY5Y wildtype and N2a cells | 100 µM | In the presence of caffeine, the level of ADAM10 protein increased to 138.5% ± 9.2%, and the levels of APP protein level and ROS decrease to 85.4% ± 3.6% and 48.8% ± 3.2%, respectively. | [142] |
Alzheimer’s Disease | In vitro | HEK293 cells | 0.1-10 mM | Caffeine induces conformational chances on muscle nicotinic acetylcholine receptors, which are molecular targets of Alzheimer’s disease. | [143] |
Parkinson’s Disease | In vitro and in vivo | Swiss mice and Wistar rats | 31.2 mg/kg | Caffeine administration reduced the catalepsy index and increased the number of ipsilateral rotations. | [144] |
Cd-induced neurodegeneration | In vitro and in vivo | HT-22 and BV-2 cells and Wild-type C57BL/6N male mice | 30 mg/kg/day | Caffeine reduced ROS, lipid peroxidation and 8-dihydro-8-oxoguanine levels. It also attenuated neuronal loss, synaptic dysfunction, and learning and cognitive deficits. | [145] |
Hypoxia Ischemia | In vivo | Spague-Dawley mice | 0.3 g/L | Pretreatments with caffeine reduced the brain infarct after hypoxia ischemia and also restored the brain activity. | [146] |
Acetaminophen induced neurotoxicity | In vivo | Swiss albino mice | 20 mg/kg | Treatment with Caffeine and acetaminophen reduced the formation of ROS, compared with the acetaminophen group. In addition, the survival time of caffeine- treated mice increased 33%. | [147] |
Parkinson’s Disease | In vivo | C57BL/6 mice with motor behavioral deficit induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine | 20 mg/kg | Caffeine improved behavioral and neurotransmitter recovery against the induced toxicity. It was also able to restore antioxidant levels and suppress neuroinflammation. | [148] |
Hypoxic-ischemic | In vivo | Wild type C57/bl6 specific pathogen-free mice | 5 mg/kg | Caffeine administration after hypoxia ischemic brain injury reduces the lesion in the grey and white matter, and the number of amoeboid microglia and apoptotic cells. The expression of pro-inflammatory cytokines also decreased. | [149] |
Apnea of prematurity | In vivo | infection-free pregnant Sprague Dawley rats | 100 mg/kg | Caffeine administration in normoxia, reduced the oxidative stress, hypermyelination and increase golgi bodies. | [150] |
Parkinson’s Disease | In vivo | C57BL/6 male mice | 1 g/L | Caffeine protected against synucleinpathy by modulating α-syn-induced apoptosis, microglial and astrocytic activation in the striatum. | [139] |
N/D | In vivo | male Swiss mice | 0.3 g/L | The amount of A2A receptors was decreased in hippocampus of mice that consumed caffeine. The aged mice treated with caffeine presented more pyknotic neurons in the hippocampus and reduced damage. | [151] |
LPS-Induced Oxidative Stress and Neuroinflammation | In vivo | C57BL/6N male mice | 3 mg/kg/day | The LPS-injected group had enhanced expression of Bax and caspase-3. On the other hand, these markers were reduced in the group treated with caffeine, this treatment also caused a restoration of the synaptic markers. | [152] |
Diabetes | In vivo | Male GK and Wistar-Hannover-Galas rats | 1 g/L | Caffeine prevented the GFAP, vimentin and SNAP25 alterations caused by diabetes, and also improved the memory deficits. | [153] |
N/D | In vivo | C57bl\6j mice and A2AR knockout mice | 50 μM | Caffeine increased synaptic transmission by 40%, decreased facilitation of paired-pulse and decreased the amplitude of long-term potentiation by 35%. | [15] |
Alzheimer Disease | In vivo | Wild-type N2 and CL2006 worms | 200 and 400 μM | Treatment prevented amyloid beta-peptide paralysis, decreased acetylcholinesterase activity, and decreased amyloid beta-peptides mRNA levels. | [154] |
Parkinson’s disease | In vivo | C57BL/6J mice | 50 mg/kg/day | Co-administration of caffeine and eicosanoyl-5-hydroxytryptamide resulted in decreased accumulation of phosphorylated α-synuclein, maintenance of neuronal integrity and function, reduction of neuroinflammation, and improvement of behavioral performance. | [140] |
Parkinson’s Disease | In silico | Molecular Docking Simulations | N/A | Caffeine was able to bind at position 28th in both wild-type and mutant parkin protein. | [136] |
Alzheimer’s Disease | In silico | Molecular Docking Simulations | N/A | The results revealed that in the presence of caffeine, the distances between the inter-residual increased, leading to the breakdown of hydrophobic contacts, and ultimately destabilizing the Aβ protofibrils. | [155] |
Parkinson’s Disease | Clinical trial | Parkinson’s Disease Patients | 100 mg | Caffeine treatment reduced the number of errors in patient and controls on the Stroop and Choice reaction time and enhanced dual item accuracy on the rapid visual serial presentation task. | [156] |
Study Type | Model | Result | Reference |
---|---|---|---|
Systematic review | Review of prospective studies | Regular and moderate coffee consumption (1-2 cups/day) is not associated with hypertension risk. Higher coffee consumption has a protective effect. | [165] |
Prospective | 347,077 volunteers (37–73 years old, UK Biobank) | Coffee consumption may lead to a slight increase in CVD risk. | [159] |
Prospective | 2278 volunteers (18-80 years old) | Caffeine metabolites are responsible for lowering the risk of hypertension. | [166] |
Prospective | 20,487 (35-94 years old) | Coffee moderate consumption (3–4 cups/day) has been associated with a lower CVD mortality. | [161] |
Prospective | >500 000 individuals (40-69 years old) | The consumption of 2-3 cups of coffee per day (121-182 mg caffeine/day) was associated with a low risk of coronary artery disease. | [162] |
Prospective | 23,878 individuals (> 20 years old) | Higher caffeine intake (>100 mg/day) was associated with lower CVD mortality. | [163] |
Prospective | 362,571 individuals (37-73 years old, UK Biobank) | High coffee consumption (> 6 cups/day) increases levels of low-density-lipoproteins cholesterol, total cholesterol and apolipoprotein B, thereby increasing the risk for CVD. | [160] |
Prospective | 1095 individuals (mean age 53±14 years old) | Moderate coffee consumption (> 3 cups/day) reduces CVD risk factors such as arterial stiffness and high blood pressure | [164] |
Randomized Controlled Trial | 12 volunteers (19-39 years old) | Administration of caffeine (200 mg, 12h intervals) during sleep deprivation reduced HR and increased HF-HRV. The concentration-effect was non-linear. No significant interaction between sleep deprivation and caffeine intake | [167] |
In vitro in vivo |
Primary human and mouse aortic VSMCs, immortalized mouse aortic VSMCs; restenosis mice model (apoe−/−C57BL/6 J) | Caffeine induced autophagy by inhibiting mTOR signaling; decreased proliferation of VMCs by inhibiting WNT signaling; decreased vascular restenosis | [168] |
In vivo | Zebrafish | Both concentrations tested caused a similar decrease of the HR. | [169] |
Nanosystem | Method | Composition | Application | Model | Result | Reference |
---|---|---|---|---|---|---|
Lipid-based nanosystems | ||||||
Liposome | Thin-film hydration | Lecithin, polysorbate 80, polysorbate 20 | Alopecia | Wistar rats | Improves skin delivery, weight, and hair length. | [190] |
Liposomes | Thin film hydration | Phospholipid, cholesterol | Skin drug delivery | abdominal skin of WBN/ILA-Ht hairless rats | DPPG liposomes enhanced skin penetration by disrupting the lipidic barrier of stratum corneum. | [186] |
Liposomes | High-pressure homogenization | Phosphatidylcholine, propylene glycol | Skin drug delivery | full-thickness abdominal human skin | Propylene glycol increased liposome deformability and improved skin permeation of caffeine. | [188] |
Lipidic nanosystem | High-pressure homogenization | Trilaurin, oleic acid, pluronic F68, imiquimod | Cancer | orthotopic breast cancer mice model | Caffeine slightly improved antitumor activity. | [192] |
Lipid nanocapsules | Phase inversion temperature | Miglyol 812 N, Kolliphor HS 15, Phospholipon 90G | Skin drug delivery | porcine skin | Caffeine was not successfully encapsulated. Nanocapsules improved the transdermal permeation of caffeine. | [187] |
Semi-solid nanostructured lipid carriers | Two-stage homogenization method, high shear homogenization, ultrasonication | Compritol® 888 ATO and Precirol® ATO 5, argan oil, Poloxamer 407 | Cosmetics, skin drug delivery | Wistar rat full-thickness dorsal skin | NLCs' exhibited a high capacity for deposition and permeation through the skin. | [189] |
Proniosomes | Coacervation phase separation | Cholesterol, span 60, lecithin | Brain delivery - migraine | Swiss albino mices' abdominal skin and albino rabbits' ear | Increased caffeine permeation through the skin and caffeine levels in blood and brain compared to orally administered caffeine. No evidence of skin irritation. | [181] |
Nanoemulsion | Low energy emulsification | Dicaprylyl ether, ethylhexyl isononanoate, potassium lauroyl wheat amino acids, palm glycerides and capryloyl glycine | Cosmetics, skin drug delivery | Abdominal human epidermis | Did not improve skin permeation of caffeine compared to emulsion. | [196] |
Nanoemulsion | Low energy emulsification | Volpo-N10, oleic acid or eucaliptol | Skin drug delivery | human full-thickness skin | Increased permeation and retention of caffeine in hair follicles and skin. | [197] |
Pickering emulsion stabilized by magnesium oxide NPs | High shear homogenization | Wheat german oil, magnesium oxide NPs | Oral drug delivery - hepatoprotective | Wistar rats intoxicated with CCl4 | Decreased proliferation of cancer cells, moderate reduction of oxidative stress and inflammatory markers, similar to caffeine solution. Increased catalase levels compared to caffeine. | [198] |
Polymer-based nanosystems | ||||||
Polymeric nanoparticles | Emulsion polimerization | Methyl methacrylate, CTAB or sodium dodecyl sulfate | antifungal | C. albicans | CTAB-caffeine nanoparticles inhibited the growth of C. albicans. | [199] |
Polymeric nanoparticles | Desolvation | Gelatin | cancer | B16F10, L929 cell lines | Inhibited the proliferation of murine melanoma cells (B16F10) and induced apoptosis without causing cytotoxic effects on normal fibroblast cells (L929). | [193] |
Metal-based nanosystems | ||||||
Silver complexes anchored to magnetic NPs | Covalent conjugation and complexation | Chloro-functionalized Fe3O4 magnetic NPs, caffeine N-heterocyclic carbene-silver complex | cancer | HepG2, WRL-68 cell lines | Enhanced cytotoxic effects against HepG2 cells and antibacterial activity against E. coli, S. aureus and B. cereus. Hyperthermia studies showed that the nanosystems reached a temperature of 47 °C, which is suitable for anticancer applications | [194] |
Silver nanoparticles | Chemical reduction | Silver nitrate, galic acid, (-)-epicatechin-3-gallate or caffeine | cancer | B16-F0, COLO 679 cell lines | EGCG- and caffeine-stabilized AgNPs were the most and less effective against the tested cancer cell lines. | [200] |
Gold nanoparticles | Chemical reduction | Gold (III) chloride trihydrate | antibacterial | E. Coli, P. aeruginosa, S. aureus, L. monocytogenes | Inhibition of biofilm formation and removal of mature biofilms. Antibacterial activity against resistant pathogenic bacteria. | [195] |
Crystal-based nanosystems | ||||||
Nanocrystals | Pearl-milling | Carbopol® 981, propylene glycol | skin drug delivery | Human volunteers, arm skin | The nanocrystals with a size of 694 nm showed a delayed but higher and longer delivery of caffeine, being detected in serum for at least 5 days | [201] |
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Submitted:
17 May 2023
Posted:
17 May 2023
You are already at the latest version
This version is not peer-reviewed
Submitted:
17 May 2023
Posted:
17 May 2023
You are already at the latest version
Sources | Caffeine Range (mg) | References |
---|---|---|
Coffee | ||
Americano coffee | 91.7-213.3 | [40] |
Decaffeinated coffee (500 mL) | 0.0-13.9 | [41] |
Instant coffee | 8.7-120.0 | [29,39,40,42] |
Plain coffee | 68.4-136.9 | [40] |
Espresso | 66.0-276.0 | [29] |
Tea | ||
Black tea | 42.0 | [39] |
Green tea | 18.0 | [39] |
Yerba Mate | 40.0 | [39] |
Soft drinks | ||
Coca-Cola classic | 34.0 | [39] |
Diet coke | 46.0 | [39] |
Guarana | 47.0 | [39] |
Mountain Dew | 54.0-90.0 | [39] |
Pepsi-Cola | 38.0 | [39] |
Soda | 0.0-69.0 | [39] |
Sunkist | 19.0 | [39] |
Energy drinks | ||
Mountain Dew Amp | 142.0 | [39] |
Full Throttle | 160.0 | [39] |
Monster | 60.0-300.0 | [39] |
Red Bull | 80.0-106.0 | [39] |
Rockstar | 160.0-300.0 | [39] |
Juice | ||
Cranergy | 70.0-80.0 | [39] |
Energy shots | ||
Bang Shot | 300.0 | [39] |
5 Hour Energy | 200.0 | [39] |
TruBrain Extra | 100.0 | [39] |
Spike Energy Double Shot | 350.0 | [39] |
Chocolate | ||
Dark chocolate | 8.0 | [39] |
Others | ||
Water Joe | 70.0 | [39,43] |
Target Cancer | Study Type | Model | Caffeine concentration | Result | Reference |
---|---|---|---|---|---|
Carcinoma squamous cells | In vitro | HN5 and KYSE30 cells | 0.5 - 70 mmol | Caffeine at the concentrations of 20, 50 and 70 mmol presented an inhibitory effect and decreased the proliferation rate of both cell lines. | [58] |
Glioblastoma multiforme | In vitro | Human GBM cell line U87-MG | 1 mM | Pretreatment of cells with caffeine followed by combined treatment of Temozolomide + caffeine significantly decreased cell viability compared with the other groups. | [59] |
Glioblastoma multiforme | In vitro | human GBM cell line U87MG and T98G 101 cells | 0.5- 10 | In both cell lines, caffeine at a concentration of 2.5 mM was able to reduce cellular viability, which was more pronounced under hypoxia. | [60] |
Pancreatic ductal adenocarcinoma | In vitro | AsPC-1, BxPC-3, Capan-1, COLO-357, MiaPaCa-2, SU.86.86, PANC-1, and T3M4 pancreatic cancer cells | 100, 200 µM | Caffeine enhanced cell death induced by 5-Fluorouracil and Gemcitabine, and also decreased the IC50 of both chemotherapeutic agents. | [61] |
Prostate cancer | In vitro | PC-3 cells | 0.5 mM | The caffeine affected the cell viability in a dose-dependent manner. Cell migration and invasion ability was more affected by the combination of atorvastatin and caffeine than by caffeine alone. The same was true for the formation of tumor spheres. | [62] |
Melanoma | In vitro | Normal human melanocytes COLO829 and C32 cells | 0.01 - 1.0 μmol/mL | The results show the ability of caffeine to reduce the viability of COLO829 and C32 cells, by 5-35% and 1-16%, respectively. In addition, it also led to a decrease in thiol degradation and pro-apoptotic effect and did not affect normal melanocytes cells. | [63] |
Breast cancer | In vitro | MDA-MB-231, MCF7 and MCF10A cells | 125 nM | After treatment of MDA-MB-231 and MCF7 with caffein, there was a change in metabolism towards respiratory-chain phosphorylation with low ratio of free to bound NADH. In combination with cisplatin, there was a decrease in viability, and preference of cancer cells over normal breast cells. | [64] |
Colon and Breast cancer | In vitro | HCT116 and MCF7 cells | 0 to 60 mM | Apoptosis increased in both cell lines proliferative and senescent cells after treatment of the cells with caffeine at a concentration of 15 mM. | [53] |
Lung cancer | In vitro | NCI-H23 and MLC15 cells | 0–500 µM | After treatment of NCl-H23 cells with 250 and 500 µM caffeine, the size of colonies decreased by 78.1% and 63.9%, respectively. In addition, caffeine at the same concentrations also induced cell arrest in the G0/G1 phase, reduced the S phase of the cell cycle, and suppressed cell invasion. | [65] |
Melanoma | In vitro | B16F10 cells | 1–40 µM | Pre-treatment cells with caffeine enhanced the cytotoxic effects induced by dacarbazine. In addition, caffeine also increased oxidative-stress in a dose-dependent manner. | [66] |
Breast | In vitro | MCF-7 and MDA-MB-231cells | 1-10 mM | In MTT assay, caffeine reduced the cell viability in concentrations greater than 2.5 mM for MCF7 and for 5 and 10 mM for MDA-MB-231 cell line. At the last-mentioned concentrations caffeine induces apoptosis and necrosis in both cell lines. | [54] |
Endometrial cancer | In vitro | RL95-2, HEC-1-A and KLE cells | 0-40 mM | The therapeutic concentration of cisplatin decreased from 4.1 to 1.1 µM and from 163 to 6.6 µM, with caffeine concentrations of 1.1 and 5.3 Mm, respectively. | [67] |
Glioma | RT2 cells-induced glioma in male Fischer 344 inbred rat | 30 mg/kg/day | The combination of caffeine with temozolomide reduced tumor wrinkles compared between the control group and the group with temozolomide alone. | [68] | |
Hepatocellular carcinoma | In vitro and in vivo | SMMC-7721 and Hep3 cell lines and Male BALB/c nude mice | 0-32 mM (in vitro) 20mg/kg/day (in vivo) |
Caffeine decreased the viability of both cell lines and has a synergistic effect with 5-fluorouracil. In addition, tumor growth was suppressed, and tumor weight was reduced in mice treated with caffeine alone or in combination with 5-fluorouracil. | [69] |
Adult pleomorphic rhabdomyosarcoma | In vitro and in vivo | RMS cells, Athymic nu/nu nude mice and cells removed to the tumor tissue | 0.5 and 1 mM (in vitro) 100 mg/kg per day (in vivo) |
Caffeine has been shown to enhance the antiproliferative effects of valproic acid. In the in vivo studies, the group treated with caffeine and valproic acid showed a reduction in tumor volume compared to the control group. This was also confirmed in the group treated with Salmonella typhimurium A1 receptor in combination with caffeine and valproic acid. | [70] |
Osteossarcoma, fibrosarcoma | In vitro and in vivo | HOS, HT1080 and LM8 cells and athymic nude mice | 0.5 mM (in vitro) 100 mg/kg (in vivo) |
The combination of cisplatin and caffeine decreased ell viability compared with cisplatin alone. In vivo, after implantation of LM8 and HT1080 cells the combination of cisplatin + caffeine decreased tumor volume and weight. | [71] |
Melanoma | In vivo | Albino mice and C57BL/6J mice | 0.08% w/v, daily | The authors demonstrated that in the carcinogen-induced tumor model, the groups treated with caffeine alone decreased the tumor growth rate from 5.3 mm2/day to 2.6 mm2/day, in combination with anti-PD1 the decrease was more pronounced (0.9 mm2/day). | [72] |
Fibrosarcoma | In vivo | Adult albino mice | 0.02%, 0.04%, and 0.08% w/v | In caffeine-treated mice, tumor incidence, size and growth rate decreased with the increasing concentration. In addition, caffeine-treated mice had a higher percentage of cytotoxic T cells and higher TNF-α and IFN-γ levels. | [55] |
Synovial sarcoma | In vivo | Athymic nu/nu nude mice | 100 mg/kg/day | The combination of oral recombinant methioninase and caffeine reduced tumor volume. | [56] |
Osteosarcoma | In vivo | Athymic nu/nu nude mice | 100 kg/kg/day | After treatment the osteosarcoma model (patient-derived orthotopic xenograft) with cisplatinum + oral recombinant methioninase + caffeine, the decreased was most smarked compared with the other groups. | [73] |
Fibrosarcoma | In vivo | Adult Syrian golden hamsters | 100 mg/kg | Administration of metformin (500 mg/kg) and caffeine resulted in inhibition of fibrosarcoma growth. | [74] |
Colorectal cancer | In vivo and in silico | Swiss Webster mice | 50 mg/kg/day | Mice treated with caffeine alone or in combination with chlorogenic acid decreased the expression of IL-6, IL-17 and TNF-α. | [75] |
Renal cell carcinoma | In vitro and in vivo and in silico | ACHN and 786-O cells and BALB/c nude mice | 0–3200 μg/mL | The molecular docking studies demonstrated that caffeine was able to bind to G6PDH at the NADP+ binding site, which is a biomarker and potential therapeutic target for renal cell carcinoma. In addition, caffeine was able to decrease the viability and proliferation of both cell lines and in the in vivo studies. | [57] |
Target/Goal | Study Type | Model | Caffeine Concentration | Result | Reference | |
---|---|---|---|---|---|---|
Anti-inflammatory effect and immunomodulation | In vitro | Human peripheral blood mononuclear cells | 0.019 -1.16 mM | Caffeine reduced the levels of several cytokines (IL-8, MIP-1β, IL-6, IFN-γ, GM-CSF, TNF-α, IL-2, IL-4, MCP-1, and IL-10. It also inhibited STAT1 signaling. | [92] | |
Immunomodulation | In vitro | Monocytes and macrophage | 300–1000 µM | Caffeine suppressed TNF−α in both LPS-activated macrophage subtypes, altered adenosine receptor expression, Akt/AMPK/mTOR signaling and inhibited STAT/IL-10 signaling in macrophage colony-stimulating factor. | [105] | |
Immunomodulation | In vitro | Mesenchymal stem cells and neutrophiles | 0.1-1 mM | Caffeine-treated mesenchymal stem cells produced fewer reactive oxygen species and increased phagocytosis of neutrophils co-cultured with mesenchymal stem cells. | [106] | |
Immunomodulation | In vitro | Mesenchymal stem cells and neutrophiles | 0.1-1 mM | Caffeine treatment increased the viability of co-cultured neutrophils. | [107] | |
Bronchopulmonary dysplasia - NLRP3 inflammasome | In vitro | THP-1-derived macrophages | 100-800 μM | There was a decreased in NLRP3 inflammasome activation, ASC speck formation, and caspase 1 cleavage. In addition, IL-1β and IL-18 decreased secretion, and phosphorylation of MAPK and NF-kB pathway members | [108] | |
Melanoma |
In vitro in silico |
Mel1 and Mel3 cells | 1 and 2 mM | After caffeine treatment, there was a decrease in the levels of IL-1β, IP-10, macrophage inflammatory protein 1-α, and CCL4. On the other hand, the expression of regulated and normal T cells decreased in Mel3 cell line. | [109] | |
Rheumatoid arthritis | In vitro and in vivo | Mesenchymal stem cells and Wistar rats | 0-1 mM | Caffeine at a concentration of 0.5 Mm can promote lower levels of cytokines, such as IFN-γ, IL-6, and IL-1β and higher levels of IDO and TGF-β. In addition, cells treated with caffeine diminish the severity of rheumatoid arthritis and cause a decrease in serum levels of C-reactive protein, nitric oxide, myeloperoxidase, and TNF-α. | [87] | |
Infection | In vitro and in vivo | Peritoneal macrophages and Swiss mice | 0.05- 5 μg/mL (in vitro) 0.05-5 mg/Kg (in vivo) |
In mice, the leucocyte infiltration of the peritoneal cavity decreased after caffeine treatment. In addition, mRNA expressions of IL-1β, IL-6, and the enzyme inducible nitric oxide synthase were decreased, whereas IL-10 was increased. | [110] | |
Immunological and metabolic anomalies in obesity | In vitro and in vivo | Male Sprague-Dawley rat, RAW 264.7 macrophage and HepG2 cells | 50, 100, 150Μm (in vitro) 20mg/kg/day (in vivo) | In caffeine-treated mice, the profiles of TNF−α, MCP-1, IL-6, intercellular adhesion molecule, and nitrite were suppressed. In addition, live white adipose tissue and muscle macrophages and their cytokine levels also decreased. | [111] | |
Depression | In vitro and in vivo | CBA × C57BL/6 F1 mice and syngeneic splenocytes | 100 μg/15 × 106 cells | Immune cells treated with caffeine and transplanted into depressive-like mice resulted in an increase in neuronal density and anti-inflammatory cytokines (IL-10 and IL-4) and a decrease of proinflammatory cytokine (IL-1β, INF-γ, and TNF-α). | [112] | |
Autoimmune Encephalomyelitis | In vitro and in vivo | Primary microglia and BV2 cells C57BL/6 mice were immunized to induce autoimmune encephalomyelitis |
2mM (in vitro) 10-30 mg/kg/day (in vivo) |
Caffeine decreased clinical score, inflammatory cell infiltration degree of the demyelination, and microglia stimulation in mice. In addition, it increased LC3-II/LC3-I levels and decreased NLRP3 and P62 levels. | [86] | |
Neurotoxicity - antioxidant and anti-inflammatory | In vivo | Albino rats | 20 mg/kg | Reduced oxidative stress and restored TNF-α levels in cerebral tissues. | [113] | |
Neuroinflammation | In vivo | Sprague-Dawley rats | 60 mg/kg/day | Caffeine/modafinil increased levels of anti-inflammatory (IL-4 and IL-10) and decreased proinflammatory (TNF-α, IL-1β) cytokines in the hippocampus. Decreased the microglial immunoreactivity and improved inflammatory response and anxious behavior. | [114] | |
Hepatic fibrosis - antioxidant and anti-inflammatory | In vivo | Hepatic fibrosis Sprague-Dawley rats | 50 mg/kg | Decreased fibrosis and necro-inflammation; decreased LPAR1, TGF-β1, CTGF, α-SMA and LPAR1 expression; improved liver function | [115] | |
Oxygen-Induced Inflammatory Lung Injury | In vivo | Neonatal rats | 10 mg/kg | Under hyperoxia, caffeine decreased pro-inflammatory mediators (TNF-α, IL-1α, IL-1β, IFN-γ) and NF-kB, and decreased infiltrating cells in the lung. Opposite effects were observed in normotoxic conditions. | [104] | |
Inflammation and adenosinergic system in cerebellum | In vivo | Ethanol-induced inflammation in wistar and UChB rats | 3 g caffeine/L of ethanol | Caffeine modulated A1 and A2a receptors and attenuated the inflammation, demonstrating a neuroprotective role. | [116] | |
Choroidal neovascularization - anti-inflammatory and na |
In vitro in vivo |
Laser photocoagulation mice model | 200, 400 uM (in vitro); 10 and 20 mg/kg (in vivo) |
Significantly reduced the migration of retinal and choroidal endothelial cells (in vitro); Decreased choroidal neovascularization and inflammatory (mononuclear phagocytes) cells’ recruitment to the lesion area. | [93] | |
Neurotoxicity | In vivo | Tramadol-induced damage in cerebelum rat model | 37.5 mg/kg | Up-regulated autophagy-related genes; reduced the expression of inflammatory and apoptosis markers, demonstrating neuroprotective effects in the cerebellum. | [117] | |
Retinal inflammation |
In vitro in vivo |
Ischemia reperfusion (I/R) injury mice model | 1 - 100 uM (in vitro); 10uL at 1,9% (in vivo) | Caffeine reduced the secretion of IL-1β, IL-6, and TNF-α and restored the integrity of retinal cell monolayer (in vitro). Instilled caffeine reduced IL-6 mRNA levels and maintained BDNF physiological levels in the retina | [96] | |
Cognitive impairment |
In vivo | BALB/c mice | 0.05 and 0.1 mg | Intranasal administration of caffeine improved the behavior outcomes of ischemic mice and reduced the expression of proinflammatory biomarkers (TNF-α, IL-6) and improved anti-inflammatory cytokines' (IL-10). | [118] | |
Hydrocephalus | In vivo | Kaolin-induced hydrocephalus mice | 50 mg/kg by gavage (dams) | Administration of caffeine to dams reduced cell death, and increased the neurons dendritic arborization in the sensorimotor cortex and striatum of the mice neonates and improved hydrocephalic deficits and behavioral development | [119] | |
Anti-inflammatory effect | In vivo | Albino rats | 100mg/kg | Administration of 100 mg/kg/day alone or in combination with nicotine decreased the number of CD68+ve macrophages and the density of CD68 immunoexpression. In addition, combined administration of caffeine and nicotine decreased apoptosis compared with nicotine alone. | [120] | |
Immunomodulation and anti-inflammatory effect | In vivo | Nile tilapia | Diet containing 5 and 8% | Diets containing 5% and 8% caffeine prevented alterations caused by hypoxia, such as ATP hydrolysis and consequent accumulation in the extracellular environment. | [121] | |
Dental pain | Clinical Trial | Patients with acute postoperative dental pain | 100 mg | Caffeine improved the effect of ibuprofen in the treatment of moderate postoperative dental pain. | [122] |
Disease | Study Type | Model | Caffeine concentration | Result | Reference |
---|---|---|---|---|---|
Parkinson’s Disease | In vitro | Transgenic Caenorhabditis elegans | 10 mM | Caffeine was able to prevent neuronal cell loss in 96% of dopaminergic neurons. | [135] |
Alzheimer’s Disease | In vitro | SHSY5Y cells | 0.6 and 1 mM | Both concentrations were able to reduce beta-amyloid neurotoxicity. | [141] |
Alzheimer’s Disease | In vitro | SH-SY5Y wildtype and N2a cells | 100 µM | In the presence of caffeine, the level of ADAM10 protein increased to 138.5% ± 9.2%, and the levels of APP protein level and ROS decrease to 85.4% ± 3.6% and 48.8% ± 3.2%, respectively. | [142] |
Alzheimer’s Disease | In vitro | HEK293 cells | 0.1-10 mM | Caffeine induces conformational chances on muscle nicotinic acetylcholine receptors, which are molecular targets of Alzheimer’s disease. | [143] |
Parkinson’s Disease | In vitro and in vivo | Swiss mice and Wistar rats | 31.2 mg/kg | Caffeine administration reduced the catalepsy index and increased the number of ipsilateral rotations. | [144] |
Cd-induced neurodegeneration | In vitro and in vivo | HT-22 and BV-2 cells and Wild-type C57BL/6N male mice | 30 mg/kg/day | Caffeine reduced ROS, lipid peroxidation and 8-dihydro-8-oxoguanine levels. It also attenuated neuronal loss, synaptic dysfunction, and learning and cognitive deficits. | [145] |
Hypoxia Ischemia | In vivo | Spague-Dawley mice | 0.3 g/L | Pretreatments with caffeine reduced the brain infarct after hypoxia ischemia and also restored the brain activity. | [146] |
Acetaminophen induced neurotoxicity | In vivo | Swiss albino mice | 20 mg/kg | Treatment with Caffeine and acetaminophen reduced the formation of ROS, compared with the acetaminophen group. In addition, the survival time of caffeine- treated mice increased 33%. | [147] |
Parkinson’s Disease | In vivo | C57BL/6 mice with motor behavioral deficit induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine | 20 mg/kg | Caffeine improved behavioral and neurotransmitter recovery against the induced toxicity. It was also able to restore antioxidant levels and suppress neuroinflammation. | [148] |
Hypoxic-ischemic | In vivo | Wild type C57/bl6 specific pathogen-free mice | 5 mg/kg | Caffeine administration after hypoxia ischemic brain injury reduces the lesion in the grey and white matter, and the number of amoeboid microglia and apoptotic cells. The expression of pro-inflammatory cytokines also decreased. | [149] |
Apnea of prematurity | In vivo | infection-free pregnant Sprague Dawley rats | 100 mg/kg | Caffeine administration in normoxia, reduced the oxidative stress, hypermyelination and increase golgi bodies. | [150] |
Parkinson’s Disease | In vivo | C57BL/6 male mice | 1 g/L | Caffeine protected against synucleinpathy by modulating α-syn-induced apoptosis, microglial and astrocytic activation in the striatum. | [139] |
N/D | In vivo | male Swiss mice | 0.3 g/L | The amount of A2A receptors was decreased in hippocampus of mice that consumed caffeine. The aged mice treated with caffeine presented more pyknotic neurons in the hippocampus and reduced damage. | [151] |
LPS-Induced Oxidative Stress and Neuroinflammation | In vivo | C57BL/6N male mice | 3 mg/kg/day | The LPS-injected group had enhanced expression of Bax and caspase-3. On the other hand, these markers were reduced in the group treated with caffeine, this treatment also caused a restoration of the synaptic markers. | [152] |
Diabetes | In vivo | Male GK and Wistar-Hannover-Galas rats | 1 g/L | Caffeine prevented the GFAP, vimentin and SNAP25 alterations caused by diabetes, and also improved the memory deficits. | [153] |
N/D | In vivo | C57bl\6j mice and A2AR knockout mice | 50 μM | Caffeine increased synaptic transmission by 40%, decreased facilitation of paired-pulse and decreased the amplitude of long-term potentiation by 35%. | [15] |
Alzheimer Disease | In vivo | Wild-type N2 and CL2006 worms | 200 and 400 μM | Treatment prevented amyloid beta-peptide paralysis, decreased acetylcholinesterase activity, and decreased amyloid beta-peptides mRNA levels. | [154] |
Parkinson’s disease | In vivo | C57BL/6J mice | 50 mg/kg/day | Co-administration of caffeine and eicosanoyl-5-hydroxytryptamide resulted in decreased accumulation of phosphorylated α-synuclein, maintenance of neuronal integrity and function, reduction of neuroinflammation, and improvement of behavioral performance. | [140] |
Parkinson’s Disease | In silico | Molecular Docking Simulations | N/A | Caffeine was able to bind at position 28th in both wild-type and mutant parkin protein. | [136] |
Alzheimer’s Disease | In silico | Molecular Docking Simulations | N/A | The results revealed that in the presence of caffeine, the distances between the inter-residual increased, leading to the breakdown of hydrophobic contacts, and ultimately destabilizing the Aβ protofibrils. | [155] |
Parkinson’s Disease | Clinical trial | Parkinson’s Disease Patients | 100 mg | Caffeine treatment reduced the number of errors in patient and controls on the Stroop and Choice reaction time and enhanced dual item accuracy on the rapid visual serial presentation task. | [156] |
Study Type | Model | Result | Reference |
---|---|---|---|
Systematic review | Review of prospective studies | Regular and moderate coffee consumption (1-2 cups/day) is not associated with hypertension risk. Higher coffee consumption has a protective effect. | [165] |
Prospective | 347,077 volunteers (37–73 years old, UK Biobank) | Coffee consumption may lead to a slight increase in CVD risk. | [159] |
Prospective | 2278 volunteers (18-80 years old) | Caffeine metabolites are responsible for lowering the risk of hypertension. | [166] |
Prospective | 20,487 (35-94 years old) | Coffee moderate consumption (3–4 cups/day) has been associated with a lower CVD mortality. | [161] |
Prospective | >500 000 individuals (40-69 years old) | The consumption of 2-3 cups of coffee per day (121-182 mg caffeine/day) was associated with a low risk of coronary artery disease. | [162] |
Prospective | 23,878 individuals (> 20 years old) | Higher caffeine intake (>100 mg/day) was associated with lower CVD mortality. | [163] |
Prospective | 362,571 individuals (37-73 years old, UK Biobank) | High coffee consumption (> 6 cups/day) increases levels of low-density-lipoproteins cholesterol, total cholesterol and apolipoprotein B, thereby increasing the risk for CVD. | [160] |
Prospective | 1095 individuals (mean age 53±14 years old) | Moderate coffee consumption (> 3 cups/day) reduces CVD risk factors such as arterial stiffness and high blood pressure | [164] |
Randomized Controlled Trial | 12 volunteers (19-39 years old) | Administration of caffeine (200 mg, 12h intervals) during sleep deprivation reduced HR and increased HF-HRV. The concentration-effect was non-linear. No significant interaction between sleep deprivation and caffeine intake | [167] |
In vitro in vivo |
Primary human and mouse aortic VSMCs, immortalized mouse aortic VSMCs; restenosis mice model (apoe−/−C57BL/6 J) | Caffeine induced autophagy by inhibiting mTOR signaling; decreased proliferation of VMCs by inhibiting WNT signaling; decreased vascular restenosis | [168] |
In vivo | Zebrafish | Both concentrations tested caused a similar decrease of the HR. | [169] |
Nanosystem | Method | Composition | Application | Model | Result | Reference |
---|---|---|---|---|---|---|
Lipid-based nanosystems | ||||||
Liposome | Thin-film hydration | Lecithin, polysorbate 80, polysorbate 20 | Alopecia | Wistar rats | Improves skin delivery, weight, and hair length. | [190] |
Liposomes | Thin film hydration | Phospholipid, cholesterol | Skin drug delivery | abdominal skin of WBN/ILA-Ht hairless rats | DPPG liposomes enhanced skin penetration by disrupting the lipidic barrier of stratum corneum. | [186] |
Liposomes | High-pressure homogenization | Phosphatidylcholine, propylene glycol | Skin drug delivery | full-thickness abdominal human skin | Propylene glycol increased liposome deformability and improved skin permeation of caffeine. | [188] |
Lipidic nanosystem | High-pressure homogenization | Trilaurin, oleic acid, pluronic F68, imiquimod | Cancer | orthotopic breast cancer mice model | Caffeine slightly improved antitumor activity. | [192] |
Lipid nanocapsules | Phase inversion temperature | Miglyol 812 N, Kolliphor HS 15, Phospholipon 90G | Skin drug delivery | porcine skin | Caffeine was not successfully encapsulated. Nanocapsules improved the transdermal permeation of caffeine. | [187] |
Semi-solid nanostructured lipid carriers | Two-stage homogenization method, high shear homogenization, ultrasonication | Compritol® 888 ATO and Precirol® ATO 5, argan oil, Poloxamer 407 | Cosmetics, skin drug delivery | Wistar rat full-thickness dorsal skin | NLCs' exhibited a high capacity for deposition and permeation through the skin. | [189] |
Proniosomes | Coacervation phase separation | Cholesterol, span 60, lecithin | Brain delivery - migraine | Swiss albino mices' abdominal skin and albino rabbits' ear | Increased caffeine permeation through the skin and caffeine levels in blood and brain compared to orally administered caffeine. No evidence of skin irritation. | [181] |
Nanoemulsion | Low energy emulsification | Dicaprylyl ether, ethylhexyl isononanoate, potassium lauroyl wheat amino acids, palm glycerides and capryloyl glycine | Cosmetics, skin drug delivery | Abdominal human epidermis | Did not improve skin permeation of caffeine compared to emulsion. | [196] |
Nanoemulsion | Low energy emulsification | Volpo-N10, oleic acid or eucaliptol | Skin drug delivery | human full-thickness skin | Increased permeation and retention of caffeine in hair follicles and skin. | [197] |
Pickering emulsion stabilized by magnesium oxide NPs | High shear homogenization | Wheat german oil, magnesium oxide NPs | Oral drug delivery - hepatoprotective | Wistar rats intoxicated with CCl4 | Decreased proliferation of cancer cells, moderate reduction of oxidative stress and inflammatory markers, similar to caffeine solution. Increased catalase levels compared to caffeine. | [198] |
Polymer-based nanosystems | ||||||
Polymeric nanoparticles | Emulsion polimerization | Methyl methacrylate, CTAB or sodium dodecyl sulfate | antifungal | C. albicans | CTAB-caffeine nanoparticles inhibited the growth of C. albicans. | [199] |
Polymeric nanoparticles | Desolvation | Gelatin | cancer | B16F10, L929 cell lines | Inhibited the proliferation of murine melanoma cells (B16F10) and induced apoptosis without causing cytotoxic effects on normal fibroblast cells (L929). | [193] |
Metal-based nanosystems | ||||||
Silver complexes anchored to magnetic NPs | Covalent conjugation and complexation | Chloro-functionalized Fe3O4 magnetic NPs, caffeine N-heterocyclic carbene-silver complex | cancer | HepG2, WRL-68 cell lines | Enhanced cytotoxic effects against HepG2 cells and antibacterial activity against E. coli, S. aureus and B. cereus. Hyperthermia studies showed that the nanosystems reached a temperature of 47 °C, which is suitable for anticancer applications | [194] |
Silver nanoparticles | Chemical reduction | Silver nitrate, galic acid, (-)-epicatechin-3-gallate or caffeine | cancer | B16-F0, COLO 679 cell lines | EGCG- and caffeine-stabilized AgNPs were the most and less effective against the tested cancer cell lines. | [200] |
Gold nanoparticles | Chemical reduction | Gold (III) chloride trihydrate | antibacterial | E. Coli, P. aeruginosa, S. aureus, L. monocytogenes | Inhibition of biofilm formation and removal of mature biofilms. Antibacterial activity against resistant pathogenic bacteria. | [195] |
Crystal-based nanosystems | ||||||
Nanocrystals | Pearl-milling | Carbopol® 981, propylene glycol | skin drug delivery | Human volunteers, arm skin | The nanocrystals with a size of 694 nm showed a delayed but higher and longer delivery of caffeine, being detected in serum for at least 5 days | [201] |
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