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Crocetin
Crocetin
Crocetin
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Crocetin[1]
Skeletal formula of crocetin
Skeletal formula of crocetin
Ball and stick model of crocetin
Ball and stick model of crocetin
Names
IUPAC name
8,8′-Diapocarotene-8,8′-dioic acid
Systematic IUPAC name
(2E,4E,6E,8E,10E,12E,14E)-2,6,11,15-Tetramethylhexadeca-2,4,6,8,10,12,14-heptaenedioic acid[2]
Other names
8,8'-Diapocarotenedioic acid;[1] Transcrocetinate
Identifiers
3D model (JSmol)
1715455
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.044.265 Edit this at Wikidata
EC Number
  • 248-708-0
KEGG
MeSH crocetin
UNII
  • InChI=1S/C20H24O4/c1-15(11-7-13-17(3)19(21)22)9-5-6-10-16(2)12-8-14-18(4)20(23)24/h5-14H,1-4H3,(H,21,22)(H,23,24)/b6-5+,11-7+,12-8+,15-9+,16-10+,17-13+,18-14+ checkY
    Key: PANKHBYNKQNAHN-MQQNZMFNSA-N checkY
  • InChI=1/C20H24O4/c1-15(11-7-13-17(3)19(21)22)9-5-6-10-16(2)12-8-14-18(4)20(23)24/h5-14H,1-4H3,(H,21,22)(H,23,24)/b6-5+,11-7+,12-8+,15-9+,16-10+,17-13+,18-14+
    Key: PANKHBYNKQNAHN-MQQNZMFNBY
  • CC(C=CC=C(C)C(O)=O)=CC=CC=C(C)C=CC=C(C)C(O)=O
Properties
C20H24O4
Molar mass 328.408 g·mol−1
Appearance Red crystals
Melting point 285 °C (545 °F; 558 K)
log P 4.312
Acidity (pKa) 4.39
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Crocetin is a natural apocarotenoid dicarboxylic acid, a diterpenoid, and a branched-chain dicarboxylic acid. It was the first plant carotenoid to be recognized as early as 1818 while the history of saffron cultivation reaches back more than 3,000 years. The major active ingredient of saffron is the yellow pigment crocin 2 (three other derivatives with different glycosylations are known) containing a gentiobiose (disaccharide) group at each end of the molecule. It is found in the crocus flower together with its glycoside, crocin, and Gardenia jasminoides fruits. It is also known as crocetic acid.[3][4] It forms brick red crystals with a melting point of 285 °C.

The chemical structure of crocetin forms the central core of crocin, the compound responsible for the color of saffron. Crocetin is usually extracted commercially from gardenia fruit, due to the high cost of saffron.

A simple and specific HPLC-UV method has been developed to quantify the five major biologically active ingredients of saffron, namely the four crocins and crocetin.[5]

Cell studies

[edit]

Crocin and crocetin may provide neuroprotection in rats by reducing the production of various neurotoxic molecules, based on an in-vitro cell study.[6]

Physiological effects

[edit]

A 2009 study involving 14 individuals indicated that oral administration of crocetin may decrease the effects of physical fatigue in healthy men.[7]

A 2010 pilot study investigated the effect of crocetin on sleep. The clinical trial comprised a double-blind, placebo-controlled, crossover trial of 21 healthy adult men with a mild sleep complaint. It concluded that crocetin may (p=0.025) contribute to improving the quality of sleep.[8]

In high concentrations, it has protective effects against retinal damage in vitro and in vivo.[9]

Transcrocetinate sodium

[edit]

The sodium salt of crocetin, transcrocetinate sodium (INN, also known as trans sodium crocetinate or TSC) is an experimental drug that increases the movement of oxygen from red blood cells into hypoxic (oxygen-starved) tissues.[10] Transcrocetinate sodium belongs to a group of substances known as bipolar trans carotenoid salts, which constitute a subclass of oxygen diffusion-enhancing compounds.[11] Transcrocetinate sodium was one of the first such compounds discovered.[10][12]

Transcrocetinate sodium

Transcrocetinate sodium can be prepared by reacting saffron with sodium hydroxide and extracting the salt of the trans crocetin isomer from the solution.[12] John L. Gainer and colleagues have investigated the effects of transcrocetinate sodium in animal models.[12][13] They discovered that the drug could reverse the potentially fatal decrease in blood pressure produced by the loss of large volumes of blood in severe hemorrhage, and thereby improve survival.[13]

Early investigations of transcrocetinate sodium suggested that it had potential applications in battlefield medicine, specifically in treatment of the many combat casualties with hemorrhagic shock.[10][13] Additional studies, carried out in animal models, and in clinical trials in humans, indicated that transcrocetinate sodium might prove beneficial in the treatment of a variety of conditions associated with hypoxia and ischemia (a lack of oxygen reaching the tissues, usually due to a disruption in the circulatory system), including cancer, myocardial infarction (heart attack), and stroke.[10][11][14][15][16]

Transcrocetinate sodium has shown promise of effectiveness in restoring tissue oxygen levels and improving the ability to walk in a clinical trial of patients with peripheral artery disease (PAD)[15] in which reduced delivery of oxygen-rich blood to tissues can cause severe leg pain and impair mobility. The drug has also been under investigation in a clinical trial sponsored by drug developer Diffusion Pharmaceuticals for potential use as a radiosensitizer, increasing the susceptibility of hypoxic cancer cells to radiation therapy, in patients with a form of brain cancer known as glioblastoma.[16] The drug is currently under investigation for its possible use in enhancing the oxygenation status of COVID-19 patients at risk for developing multiple organ failure due to severe respiratory distress.[17]

Mechanism of action

[edit]

Similar to other oxygen diffusion-enhancing compounds, transcrocetinate sodium appears to improve oxygenation in hypoxic tissues by exerting hydrophobic effects on water molecules in blood plasma and thereby increasing the hydrogen bonding between the water molecules.[18] This in turn causes the overall organization of water molecules in plasma to become more structured, which facilitates the diffusion of oxygen through plasma and promotes the movement of oxygen into tissues.[18][19][20]

Trans-crocetin has been found to act as an NMDA receptor antagonist with high affinity, and has been implicated in the psychoactivity of saffron.[21][22][23]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Crocetin

View on Grokipedia
from Grokipedia
Crocetin is a natural that acts as the aglycone of , the primary water-soluble pigment responsible for the color of stigmas. With the molecular formula C₂₀H₂₄O₄ and a molecular weight of 328.4 g/mol, it consists of a 20-carbon polyunsaturated chain featuring seven conjugated double bonds, four side-chain methyl groups, and two terminal carboxyl groups, existing in both cis and trans isomeric forms. Naturally occurring in the stigmas of L. (saffron) and the fruit of J. Ellis, crocetin can be obtained through the enzymatic of and exhibits a bright red crystalline appearance with a of 285 °C. Crocetin's confers lipophilic properties, rendering it poorly soluble in water and most organic solvents but soluble in and (DMSO); it is sensitive to heat, light, and pH changes, which can lead to degradation unless stabilized through esterification. The compound's enables strong activity by scavenging free radicals and modulating pathways. In , crocetin is biosynthesized via the pathway, involving oxidative cleavage of and subsequent to form crocins, with yields enhanced through bioengineering in microbial hosts like . Pharmacologically, crocetin has demonstrated a range of bioactivities, including , anticancer, cardioprotective, neuroprotective, and antidiabetic effects in preclinical models, attributed to its ability to inhibit tumor growth, improve oxygen , and regulate . Recent studies (as of 2025) have further explored its potential in anti-aging and alleviating . Clinical studies have shown promise in treating (e.g., 10 mg daily for 60 days improving endothelial function) and preventing progression in children (using 7.5 mg/day), with doses up to 22.5 mg/day deemed safe and well-tolerated in adults, exhibiting low (LD₅₀ > 20 g/kg in rats) and no significant adverse effects. Despite its therapeutic potential, crocetin's poor limits oral efficacy, prompting research into derivatized forms for improved delivery.

Chemical Properties

Molecular Structure

Crocetin is an apocarotenoid with the molecular formula C20H24O4 and a molecular weight of 328.40 g/mol. It consists of a linear 20-carbon chain featuring seven conjugated double bonds, which contribute to its characteristic red color, and terminal carboxylic acid groups at both ends, classifying it as a dicarboxylic acid. This structure arises from the oxidative cleavage of carotenoid precursors such as zeaxanthin, where a carotenoid cleavage dioxygenase (CCD2) enzyme symmetrically cleaves the 7,8 and 7',8' bonds of zeaxanthin to yield crocetin dialdehyde, the immediate precursor to crocetin via subsequent oxidation. In textual representation, the structure can be depicted as a symmetrical chain with alternating single and double bonds between carbons 8-12 and 12'-8', flanked by methyl groups at positions 13, 13', 9, and 9', and terminating in -COOH groups. Natural crocetin predominantly exhibits the all-trans configuration across its double bonds, which is the thermodynamically stable isomer responsible for its biological activity and solubility properties. Crocetin serves as the aglycone core of crocin, the primary pigment in saffron, where crocin is formed by esterification of crocetin's two carboxyl groups with the disaccharide gentiobiose (β-D-gentiobiosyl units).

Physical and Chemical Characteristics

Crocetin appears as an orange-red crystalline powder, often described as brick-red orthorhombic crystals in its pure form. It exhibits poor in , with reported values around 1.23 mg/L (0.00123 mg/mL), attributed to its non-polar polyene chain, but shows good in organic solvents such as (up to 31.25 mg/mL) and , as well as in alkaline solutions where the carboxylic groups ionize. Crocetin is sensitive to environmental factors, demonstrating low stability under exposure to , , and oxygen, which can lead to degradation through of its conjugated double bonds or oxidative cleavage. To mitigate this, it is typically stored desiccated at -70°C. In terms of spectroscopic properties, crocetin displays characteristic UV-Vis absorption maxima at approximately 422 nm, 447 nm, and 474 nm in or , reflecting its extended typical of . Identification via NMR shows distinct olefinic proton signals, with trans-isomer peaks around 6.0-7.0 ppm for the polyene chain, while IR reveals carboxyl group absorptions near 1700 cm⁻¹ for C=O stretching and 2500-3300 cm⁻¹ for O-H. The pKa values for its two carboxylic groups are approximately 5.35, indicating moderate acidity suitable for ionization in physiological or alkaline conditions.

Occurrence and Production

Natural Sources

Crocetin is primarily found in the stigmas of L., the saffron crocus, where it exists predominantly as the glycosylated form , an ester of crocetin with gentiobiose. constitutes 10-15% of the dry weight of stigmas and serves as the main precursor to free crocetin through . Free crocetin occurs in at low concentrations, typically up to 0.2-0.4% of the dry weight. In addition to , crocetin is present in trace amounts in the flowers and fruits of Ellis, a plant in the family commonly known as cape jasmine. The fruits of contain crocin derivatives that yield crocetin upon , making it a secondary natural source valued for industrial extraction due to higher yield potential compared to . Historically, crocetin has been associated with since ancient times, originating from cultivation and trade in regions like and later spreading to through Arab influences, where it was prized for its coloring and medicinal properties.

Biosynthesis

Crocetin is biosynthesized in plants through the pathway, where it arises from the oxidative cleavage of , a C40 , by specific cleavage dioxygenase (CCD) enzymes. In , the enzyme CsCCD2 catalyzes this cleavage at the 7,8 and 7',8' positions of , producing crocetin dialdehyde as the initial product. The subsequent step involves the oxidation of crocetin dialdehyde to crocetin, mediated by (ALDH) enzymes, such as CsALDH3I1, which are localized in the plastids of C. sativus stigmas. This two-step process—cleavage followed by oxidation—constitutes the core of crocetin production, with CsCCD2 and ALDH acting in concert within chromoplasts. Gene expression of key enzymes like CsCCD2 and associated ALDHs is upregulated during stigma development in C. sativus, peaking in mature stigmas to support apocarotenoid accumulation. Following crocetin formation, crocetin glucosyltransferase (UGT) enzymes, such as UGT91P3 or UGT709G1, glycosylate crocetin to yield crocins, enhancing stability and solubility. Heterologous production of crocetin has been achieved in microbial systems, including engineered , , and Yarrowia lipolytica, by introducing the CsCCD2 and ALDH genes alongside upstream pathway components to enable from simple carbon sources like . As of 2025, these approaches have reached yields up to 30.17 mg/L in Y. lipolytica, offering potential for scalable industrial production and bypassing plant extraction limitations.

Extraction Methods

Crocetin is primarily isolated from natural sources such as the stigmas of (saffron), where it occurs as the aglycone of crocin glycosides, and the fruits of . Traditional extraction methods begin with solvent extraction of crocin from saffron stigmas using (typically 80%) or methanol-water mixtures to achieve high recovery rates. The extract is then subjected to to liberate free crocetin; alkaline hydrolysis with (NaOH) is commonly employed, followed by acidification with to precipitate the crocetin, which is subsequently purified via silica gel chromatography or recrystallization from solvents like or . These methods yield analytical-grade crocetin on a small scale from saffron, though overall recovery from raw material remains low (around 0.1-0.5% dry weight) due to the limited crocin content in stigmas. Modern techniques have improved efficiency and purity, particularly through enzymatic , which avoids harsh chemical conditions that can cause degradation. For instance, extracted from fruit waste using 50% (yielding 8.61 mg/g ) is hydrolyzed with Celluclast® 1.5 L (a cellulase-β-glucosidase mixture) at pH 5.0 and 50°C for 16 hours, achieving a 75% conversion to trans-crocetin. Purification follows via adsorption on HPD-100 and centrifugal (CPC) with an ethyl acetate/n-butanol/water system, resulting in 96.8% purity and 95% overall yield from the hydrolyzed extract (total 5.03 mg/g from raw fruit). Another advancement involves one-step extraction and hydrolysis using recyclable deep eutectic solvents, such as benzyltriethylammonium chloride- dihydrate (1:1.5 mol/mol), at 80°C for 30 minutes with a 1:20 solid-to-liquid ratio from gardenia fruit, yielding 8.485 mg/g crocetin at 94% purity after separation. Recent optimizations as of 2025 include ultrasound-assisted and microwave-assisted extractions, as well as antisolvent precipitation with for selective crocin-I enrichment from , enhancing recovery and reducing use. Supercritical CO₂ extraction has also been adapted for initial isolation from , followed by enzymatic or , enhancing purity by minimizing residues, though it requires high-pressure equipment. Yield optimization focuses on hydrolysis efficiency, with (RSM) enabling up to 90% recovery of crocetin from through tuned parameters like NaOH concentration (0.5-1 M), temperature (60-80°C), and reaction time (1-2 hours). Challenges include crocetin's sensitivity to heat, light, and extreme pH, leading to or oxidation during processing, as well as its poor in and most organic solvents, which complicates precipitation and scaling. From , optimized enzymatic methods achieve higher overall yields (1-8 mg/g) compared to due to greater precursor abundance, but saffron remains preferred for premium, trace-authenticated crocetin. Synthetic production of crocetin, though less common due to high costs and complexity relative to natural extraction, involves chemical synthesis from precursors like β-ionone or via multi-step reactions including Wittig olefination and . One established route uses 3,7-dimethyloctatrienal and methyl 2-bromopropionate to form crocetin dimethyl , followed by to the free acid, yielding gram-scale quantities with >95% purity after , but economic viability is limited for commercial use. Microbial in engineered yeasts offers a promising alternative, with yields up to 30.17 mg/L as of 2025, though it is still emerging and not yet scaled industrially.

Pharmacological Profile

Pharmacokinetics

Crocetin exhibits rapid oral following ingestion, with peak plasma concentrations typically reached within 4 to 4.8 hours in humans after administration of extracts containing s. It is primarily derived from the hydrolysis of crocin in the by enzymes produced by intestinal or mucosal cells, occurring before or during absorption in the via passive transcellular . Its poor can limit absorption efficiency, though this is mitigated in natural contexts by co-administration with crocins or lipid-rich matrices that enhance and uptake. Due to its lipophilic nature as a carotenoid derivative, crocetin distributes widely in the body, accumulating preferentially in the liver, kidneys, brain, and adipose tissues. It readily crosses the blood-brain barrier, enabling central nervous system exposure, as demonstrated in both in vitro models and animal studies. In the liver, crocetin undergoes phase II metabolism primarily through conjugation to form glucuronide and sulfate metabolites, which facilitate its elimination. The elimination half-life in humans is approximately 6 to 7.5 hours, reflecting moderate metabolic stability. Excretion occurs mainly via through enterohepatic recirculation of conjugated metabolites, with smaller amounts eliminated in as glucuronides and sulfates; systemic clearance remains low, consistent with its tissue accumulation. and excretion can be influenced by factors such as composition, which affects rates, and co-ingestion with or precursors that promote sustained release and reduced first-pass metabolism.

Physiological Effects

Crocetin exerts beneficial effects on by promoting and enhancing endothelial function. In animal models, it improves endothelium-dependent relaxation of vascular through increased endothelial (eNOS) activity, facilitating better blood flow regulation. Additionally, crocetin demonstrates vasomodulatory properties that support normal , as evidenced by its ability to attenuate hypertensive responses in hypertensive rat strains via pathways. In metabolic processes, crocetin enhances insulin sensitivity and supports lipid homeostasis. Administration in high-fat diet-fed rats regulates genes involved in , accelerating hepatic uptake and oxidation of non-esterified fatty acids, thereby improving . It also lowers serum levels by inducing low-density lipoprotein receptor (LDLR) expression and inhibiting proprotein convertase subtilisin/kexin type 9 (), contributing to efficient clearance in the liver. Furthermore, crocetin reduces accumulation, promoting balanced profiles in experimental settings. Crocetin supports ocular by protecting retinal cells from baseline oxidative challenges. In retinal epithelial cells, it suppresses oxidative stress-induced damage, preserving cellular and function. Oral administration in animal models prevents retinal and degeneration triggered by environmental stressors, maintaining retinal barrier through anti- modulation. Overall, crocetin modulates associated with enzymes in hepatic cells, upregulating pathways to support physiological clearance processes. It exhibits no major at dietary doses, with high tolerability in where 50% (LD50) values for related components exceed 20 g/kg, indicating safety in normal physiological contexts. In animal models, physiological effects are observed at doses of 10-50 mg/kg, demonstrating a favorable dose-response profile for cardiovascular, metabolic, and ocular functions. Its pharmacokinetic profile enables these systemic impacts.

Biological Activities

Antioxidant and Anti-inflammatory Effects

Crocetin exhibits potent activity primarily through direct free radical scavenging and enhancement of endogenous defenses. studies demonstrate its ability to scavenge free radicals, as evidenced by positive results in assays where crocetin and its derivatives show inhibitory effects on radical formation. Additionally, crocetin upregulates the Nrf2 signaling pathway, promoting nuclear translocation of Nrf2 and expression of downstream targets such as oxygenase-1 (HO-1) and NAD(P)H 1 (NQO1), which bolster cellular capacity. This activation leads to increased levels of (SOD) and (GSH), mitigating oxidative damage in models of toxin-induced stress. In terms of effects, crocetin suppresses key inflammatory pathways by inhibiting activation, including blockade of IκB-α phosphorylation and p65 nuclear translocation, thereby reducing transcription of proinflammatory genes. This results in decreased production of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), with significant reductions observed in LPS-stimulated macrophages (e.g., TNF-α levels dropping from ~27,700 pg/mL to ~15,000 pg/mL at 100 μg/mL crocetin). Furthermore, crocetin blocks expression of (COX-2) and inducible (iNOS), lowering and levels in activated cells. In vitro evidence highlights crocetin's protective role against oxidative insults, such as H2O2-induced damage in H9c2 myocardial cells, where pretreatment (0.1–10 μM) improves cell viability, reduces , and restores SOD, , and GSH-Px activities while lowering and levels via mitophagy regulation. Similar protection extends to inhibition of , contributing to overall cellular resilience against . These mechanisms confer broader hepatoprotective implications, as crocetin attenuates ()-induced liver injury in mice by elevating GSH, , and activities, reducing serum ALT/AST levels, and preserving integrity through pathway activation.

Neuroprotective and Anticancer Effects

Crocetin exhibits neuroprotective effects primarily through its ability to mitigate amyloid-beta (Aβ) pathology in models of . In transgenic APP/PS1 mice, crocetin administration significantly reduced Aβ plaque accumulation in the hippocampus and cortex, while improving spatial learning and in the Morris water maze test. Furthermore, crocetin inhibits Aβ fibrillization and stabilizes Aβ oligomers , preventing their aggregation into toxic fibrils that contribute to neuronal damage. These actions are complemented by crocetin's enhancement of (BDNF) expression, which promotes neuronal survival and ; in models of chronic stress-induced depression, crocetin upregulated BDNF and its receptor TrkB, alleviating cognitive impairments via the BDNF/TrkB/CREB signaling pathway. In ischemia-reperfusion injury models, crocetin provides robust protection against neuronal loss. Oral administration of crocetin in mice subjected to occlusion reduced infarct volume and preserved neurological function by scavenging and inhibiting caspase-3 activation in affected brain regions. Similarly, in retinal ischemia-reperfusion models, crocetin prevented ganglion cell and maintained thickness by suppressing and . These neuroprotective mechanisms are partly linked to crocetin's mild properties, which curb microglial activation without directly overlapping with broader pathways. Turning to its anticancer properties, crocetin induces in various lines through caspase-dependent pathways. In human HL-60 cells, crocetin triggered intrinsic by activating caspase-3 and -9, increasing the Bax/ ratio, with an value of approximately 2 μM. It also promotes in esophageal cells via downregulation of the PI3K/Akt/ pathway, leading to reduced of Akt and subsequent inhibition of cell survival signals. Crocetin inhibits cancer cell proliferation by arresting the at the . In colon cancer HCT-116 cells, treatment with crocetin ( ~800 μM) upregulated p21 and expression, halting progression to and reducing colony formation. This effect extends to MDA-MB-231 cells, where crocetin similarly induced G0/G1 arrest and suppressed proliferation at concentrations of 20-100 μM. In models, crocetin exhibited comparable antiproliferative activity, though specific values vary between 10-100 μM across studies. Key anticancer mechanisms involve suppression of pro-survival and angiogenic pathways. Crocetin downregulates the PI3K/Akt pathway in multiple cancer types, inhibiting downstream effectors like to enhance and reduce . It also exerts anti-angiogenic effects by suppressing VEGF expression; in colon cancer cells, crocetin reduced VEGF mRNA levels by 50-70%, limiting endothelial tube formation in co-culture assays. In animal models, crocetin demonstrates significant antitumor efficacy. In pancreatic cancer xenografts, oral administration of crocetin at 4 mg/kg reduced tumor growth by approximately 45% compared to controls, accompanied by decreased microvessel density due to VEGF inhibition. Similar reductions in tumor burden were observed in gastric cancer rat models, where crocetin also lowered tumor incidence. These findings, confirmed in studies up to 2025, underscore crocetin's potential as a targeted therapeutic agent in preclinical settings.

Therapeutic Applications and Research

In Vitro and Animal Studies

In vitro studies have demonstrated crocetin's antiproliferative effects on various lines, including cells and cells. In cells, crocetin exhibited cytotoxicity with an ranging from 0.16 to 0.61 mM, inducing (ROS) production and reducing (LDHA) expression by approximately 34%, leading to inhibited in a concentration- and time-dependent manner. Similarly, in cells, crocetin suppressed growth by inhibiting activity and scavenging radicals, contributing to reduced cell viability without affecting non-malignant cells like human umbilical vein endothelial cells (HUVECs). These effects were more potent than those of its glycosylated form, , highlighting crocetin's direct role in targeting proliferation. Crocetin has also shown potential in enhancing oxygen diffusion in hypoxic environments, relevant to tumor and ischemic conditions. In biophysical models simulating hypoxia, crocetin increased the diffusivity of oxygen through plasma by altering its kosmotropic properties, facilitating better tissue oxygenation without altering binding. This mechanism was observed using oxygen-deprived cell systems, where crocetin at concentrations of 5–50 mg/L reduced in cells under oxygen-glucose deprivation by upregulating miR-145-5p and downregulating inflammatory pathways like TLR4/MyD88/. Animal studies have substantiated crocetin's neuroprotective effects in models. In rats subjected to middle cerebral artery occlusion (MCAO), intravenous administration of crocetin at 5–50 mg/kg dose-dependently reduced infarct volume and apoptotic cell numbers, improving neurological outcomes and tissue pathology through suppression of the TLR4/MyD88/ pathway. At 50 mg/kg, pretreatment significantly decreased and in myocardial ischemia-reperfusion injury models, leading to smaller infarct sizes compared to untreated controls. In antitumor evaluations, crocetin inhibited pancreatic tumor growth in mice, achieving significant regression in tumor volume and reduced proliferation as measured by (PCNA) staining, with oral doses demonstrating efficacy without systemic toxicity. Similarly, in glioma-bearing mice, crocetin reduced tumor progression by 40–60% through antiproliferative and anti-angiogenic actions. Toxicological assessments indicate crocetin has a favorable safety profile in preclinical models. No genotoxic effects were observed in standard assays, including those evaluating DNA damage in mammalian cells. In rodents, high oral doses up to 200 mg/kg elicited only mild gastrointestinal effects, such as transient irritation, with no mortality or organ damage reported across acute and subchronic studies from 2000 to 2020. These findings align with pharmacokinetic data showing rapid absorption and low accumulation, supporting its use in dosing regimens for ischemia and cancer models.

Clinical Trials and Potential Uses

Clinical trials involving crocetin and its related compounds, such as trans-sodium crocetinate (TSC) and (a of crocetin), have explored their therapeutic potential in various conditions, with a focus on studies translating preclinical findings. A Phase II randomized, double-blind, placebo-controlled trial (NCT03763929) evaluated intravenous TSC for acute ischemic and hemorrhagic , administering doses up to 2.9 mg/kg shortly after symptom onset to enhance oxygen in hypoxic brain tissue. However, the trial was terminated early in due to insufficient enrollment and logistical challenges, with no definitive demonstrated in improving neurological outcomes. Meta-analyses of randomized controlled trials have shown that saffron supplementation at 30 mg/day for 6–8 weeks is as effective as standard antidepressants such as (20 mg/day) or (100 mg/day) in reducing Hamilton Depression Rating Scale scores for mild to moderate depression, with fewer side effects such as dry mouth and anxiety. Adjunctive (15 mg twice daily) in patients with MDD on standard antidepressants further improved symptoms, as evidenced by significant reductions in depression scores compared to . For age-related macular degeneration (AMD), clinical trials support the use of and to preserve visual function. A randomized of 20 mg/day saffron in 48 patients with early AMD reported improvements in best-corrected and contrast sensitivity after 3 months, sustained at 12 months, independent of concurrent supplements. Doses of 5-15 mg/day crocin similarly enhanced retinal flicker sensitivity and electroretinogram responses in mild/moderate AMD cases, delaying disease progression without altering genetic risk factors. These effects are attributed to crocetin's properties, supported by preclinical models of . Ongoing research as of 2025 includes trials investigating crocin for metabolic syndrome and as an adjunct in cancer therapy. A double-blind, randomized trial (n=28) administering 30 mg/day crocin for 8 weeks in metabolic syndrome patients significantly reduced pro-inflammatory cytokines (IL-2, IL-10, VEGF, IFN-γ) and increased HDL cholesterol, suggesting anti-inflammatory benefits. In breast cancer, a randomized trial of 30 mg/day crocin during chemotherapy and radiotherapy demonstrated cardioprotective effects, reducing left ventricular ejection fraction decline by over 10% in treated patients compared to placebo, alongside improvements in anxiety and depression. Potential uses of crocetin extend to adjunctive therapy in to mitigate side effects and in , based on preliminary data. Crocin supplementation during esophageal (30 mg/day) reduced treatment-related fatigue and improved metrics. For Parkinson's, while human trials are lacking, preclinical evidence indicates crocetin attenuates motor deficits and loss in MPTP-induced models by improving mitochondrial function and reducing inflammation, warranting clinical exploration. Crocetin and exhibit a favorable safety profile, well-tolerated at doses up to 30 mg/day in clinical settings, with rare mild adverse events such as or gastrointestinal discomfort resolving without intervention. No serious toxicities were reported in trials up to 20 mg/day for one month, though higher doses exceeding 5 g/day of equivalents may pose risks. Allergic reactions are infrequent, primarily in saffron-sensitive individuals.

Derivatives

Crocins represent the primary glycosylated derivatives of crocetin, formed by esterification with moieties such as gentiobiose or , with crocin-I featuring gentiobiose at both ends of the crocetin backbone. These modifications confer significantly greater water solubility compared to the lipophilic parent compound crocetin, enabling their use as natural yellow-red food colorants derived from stigmas. Pharmacokinetically, crocins exhibit slower oral absorption than crocetin due to their hydrophilic nature, undergoing in the by esterases or β-glycosidases to yield free crocetin, which is then absorbed; this process results in lower peak plasma levels of intact crocins but sustains crocetin exposure. Despite these alterations, crocins retain core and anti-inflammatory activities akin to crocetin. Transcrocetinate sodium, the disodium salt of trans-crocetin, addresses crocetin's poor aqueous by achieving a solubility of 24.2 μg/mL in at 25°C, a 19.5-fold over the native compound. This derivative enhances oxygen diffusion in hypoxic tissues and has been developed specifically for ischemia therapies, including and myocardial reperfusion injury, by improving tissue oxygenation without altering blood oxygen content. Its pharmacokinetic profile supports intravenous administration, with rapid distribution and potential blood-brain barrier penetration, while preserving crocetin's oxygen-enhancing properties. Other semi-synthetic analogs include crocetin esters such as digentiobiosyl esters and dimethyl esters, which aim to optimize through targeted modifications to the groups. For instance, the dimethyl achieves high purity (98.8%) and improved stability, facilitating better absorption in environments, whereas diammonium salts offer moderate enhancements for specific formulations. These derivatives generally maintain crocetin's biological activities, including effects, but exhibit altered , such as extended half-lives or reduced renal clearance, depending on the or salt form.

References

  1. https://pmc.ncbi.nlm.nih.gov/articles/PMC8795768/
  2. https://pubchem.ncbi.nlm.nih.gov/compound/Crocetin
  3. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.745683/full
  4. https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/crocetin
  5. https://pubmed.ncbi.nlm.nih.gov/40555154/
  6. https://pubmed.ncbi.nlm.nih.gov/39416964/
  7. https://pmc.ncbi.nlm.nih.gov/articles/PMC6724222/
  8. https://pubmed.ncbi.nlm.nih.gov/21168209/
  9. https://www.chemspider.com/Chemical-Structure.4444644.html
  10. https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5780370.htm
  11. https://www.pnas.org/doi/10.1073/pnas.1404629111
  12. https://www.sigmaaldrich.com/US/en/product/sigma/sml3255
  13. https://www.mdpi.com/1999-4923/15/12/2790
  14. https://www.glpbio.com/gc35749.html
  15. https://pubs.acs.org/doi/10.1021/acsomega.4c02116
  16. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0289425
  17. https://www.sciencedirect.com/science/article/abs/pii/S2210271X13001175
  18. https://www.researchgate.net/figure/1-H-NMR-data-of-trans-and-cis-isomer-of-crocetin_tbl2_379391208
  19. https://pubs.acs.org/doi/abs/10.1021/jf9603487
  20. https://www.researchgate.net/figure/UV-vis-absorption-spectrum-of-crocetin-at-room-temperature-in-borate-buffer-pH-85_fig1_244241247
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC10740065/
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC9792498/
  23. https://daily.jstor.org/saffron-the-story-of-the-worlds-most-expensive-spice/
  24. https://nph.onlinelibrary.wiley.com/doi/10.1111/nph.13609
  25. https://www.sciencedirect.com/science/article/pii/S221138352300494X
  26. https://academic.oup.com/plphys/article/177/3/990/6117293
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC5983644/
  28. https://pubs.acs.org/doi/10.1021/acs.jafc.5c06555
  29. https://pmc.ncbi.nlm.nih.gov/articles/PMC4570256/
  30. https://www.nature.com/articles/s41598-018-21225-z
  31. https://academic.oup.com/bfg/article/16/6/336/3091754
  32. https://www.mdpi.com/1422-0067/22/16/8815
  33. https://microbialcellfactories.biomedcentral.com/articles/10.1186/s12934-023-02287-9
  34. https://biotechnologyforbiofuels.biomedcentral.com/articles/10.1186/s13068-024-02598-y
  35. https://pubmed.ncbi.nlm.nih.gov/21848061/
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC8839004/
  37. https://doi.org/10.1016/j.indcrop.2023.117969
  38. https://www.nature.com/articles/s41598-025-99695-1
  39. https://www.nature.com/articles/s41598-025-15176-5
  40. https://doi.org/10.3389/fbioe.2020.578005
  41. https://pubmed.ncbi.nlm.nih.gov/21112749/
  42. https://academic.oup.com/jpp/article/71/5/753/6122004
  43. https://www.sciencedirect.com/science/article/abs/pii/S094471131400364X
  44. https://pmc.ncbi.nlm.nih.gov/articles/PMC7692355/
  45. https://pubmed.ncbi.nlm.nih.gov/16876766/
  46. https://pubmed.ncbi.nlm.nih.gov/25531977/
  47. https://pubmed.ncbi.nlm.nih.gov/24550159/
  48. https://pubmed.ncbi.nlm.nih.gov/18469847/
  49. https://pubmed.ncbi.nlm.nih.gov/35093763/
  50. https://pubmed.ncbi.nlm.nih.gov/17109848/
  51. https://www.sciencedirect.com/science/article/abs/pii/S0014483522003864
  52. https://pubmed.ncbi.nlm.nih.gov/31908404/
  53. https://www.sciencedirect.com/science/article/abs/pii/S0014299910010071
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC8035019/
  55. https://pmc.ncbi.nlm.nih.gov/articles/PMC5339650/
  56. https://pubmed.ncbi.nlm.nih.gov/17263501/
  57. https://pmc.ncbi.nlm.nih.gov/articles/PMC8449229/
  58. https://www.tandfonline.com/doi/full/10.2147/DDDT.S247947
  59. https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.01341/full
  60. https://pubmed.ncbi.nlm.nih.gov/37306415/
  61. https://www.biomolther.org/journal/view.html?doi=10.4062/biomolther.2015.094
  62. https://immunityageing.biomedcentral.com/articles/10.1186/s12979-018-0132-9
  63. https://www.sciencedirect.com/science/article/abs/pii/S0378874120334966
  64. https://manu41.magtech.com.cn/Jweb_clyl/EN/abstract/abstract11752.shtml
  65. https://www.mdpi.com/1422-0067/20/17/4110
  66. https://pmc.ncbi.nlm.nih.gov/articles/PMC4315057/
  67. https://pmc.ncbi.nlm.nih.gov/articles/PMC8020854/
  68. https://www.mdpi.com/1420-3049/26/1/86
  69. https://journals.lww.com/rips/fulltext/2020/15060/crocetin_suppresses_the_growth_and_migration_in.9.aspx
  70. https://aacrjournals.org/mct/article/8/2/315/93383/Crocetin-inhibits-pancreatic-cancer-cell
  71. https://cdnsciencepub.com/doi/10.1139/bcb-2013-0014
  72. https://www.researchgate.net/publication/335226046_Comparative_anticancer_activity_analysis_of_saffron_extracts_and_a_principle_component_crocetin_for_prevention_and_treatment_of_human_malignancies
  73. https://pubmed.ncbi.nlm.nih.gov/32360463/
  74. https://pmc.ncbi.nlm.nih.gov/articles/PMC8273373/
  75. https://doi.org/10.5114/aoms/133886
  76. https://www.sciencedirect.com/science/article/abs/pii/S0014299914005925
  77. https://pubmed.ncbi.nlm.nih.gov/19208826/
  78. https://pubmed.ncbi.nlm.nih.gov/31936544/
  79. https://www.sciencedirect.com/science/article/abs/pii/S0278691519302844
  80. https://clinicaltrials.gov/study/NCT03763929
  81. https://pubmed.ncbi.nlm.nih.gov/30036891/
  82. https://pubmed.ncbi.nlm.nih.gov/25484177/
  83. https://pmc.ncbi.nlm.nih.gov/articles/PMC11537240/
  84. https://iovs.arvojournals.org/article.aspx?articleid=2126253
  85. https://www.nature.com/articles/s41598-025-15953-2
  86. https://www.sciencedirect.com/science/article/pii/S1043661825000556
  87. https://www.tandfonline.com/doi/abs/10.1080/07357907.2024.2319754
  88. https://pmc.ncbi.nlm.nih.gov/articles/PMC7569465/
  89. https://pmc.ncbi.nlm.nih.gov/articles/PMC3637903/
  90. https://www.researchgate.net/publication/352515345_Crocins_A_comprehensive_review_of_structural_characteristics_pharmacokinetics_and_therapeutic_effects
  91. https://journals.sagepub.com/doi/pdf/10.1177/1934578X0600100112
  92. https://www.smolecule.com/products/s545717
  93. https://pmc.ncbi.nlm.nih.gov/articles/PMC4170841/
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