Exploring the Potential of Saffron as a Therapeutic Agent in Depression Treatment: A Comparative Review.

Depression is a significant mental health challenge globally. While traditional antidepressants are effective, they often have unwanted side effects. Saffron, a natural spice derived from Crocus sativus L., has emerged as a potential alternative therapy for depression. Researchers have found that its components such as crocin, crocetin, and safranal have been found to mitigate depressive symptoms through neurotransmitter regulation, anti-inflammatory effects, and neuroprotection. Clinical trials suggest that the effectiveness of saffron in treating mild to moderate depression is comparable to that of standard medications, and animal studies support these results, showing behavioral improvements with saffron treatment. Saffron is particularly appealing due to its safety and lower incidence of side effects, making it suitable for those sensitive to conventional drugs. Additionally, its antioxidant properties may offer further health benefits. However, challenges such as determining the appropriate dosage, prohibitive cost, and the limited availability of quality saffron need to be addressed. Most research on saffron's efficacy is short-term; thus, long-term studies are essential to understand its full therapeutic potential and ongoing antidepressant effects. While saffron is safe in terms of its culinary value, higher therapeutic doses require careful monitoring for drug interactions and side effects. In summary, saffron represents a promising direction in depression treatment, with benefits potentially matching those of standard treatments and a better safety profile. However, further research is necessary to establish clear guidelines for its use, optimize dosing, and assess long-term outcomes. Saffron offers a natural treatment path for depression, but its use must be controlled and supported by scientific evidence.

Crocin-1 laden thermosensitive chitosan-based hydrogel with smart anti-inflammatory performance for severe full-thickness burn wound therapeutics.

Burns are the fourth most common type of civilian trauma worldwide, and the management of severe irregular scald wounds remains a significant challenge. Herein, crocin-1 laden hydroxybutyl chitosan (CRO-HBC) thermosensitive hydrogel with smart anti-inflammatory performance was developed for accelerating full-thickness burn healing. The injectable and shape adaptability of the CRO-HBC gel make it a promising candidate for effectively filling scald wounds with irregular shapes, while simultaneously providing protection against external pathogens. The CRO-HBC gel network formed by hydrophobic interactions exhibited an initial burst release of crocin-1, followed by a gradual and sustained release over time. The excessive release of ROS and pro-inflammatory cytokines should be effectively regulated in the early stage of wound healing. The controlled release of crocin-1 from the CRO-HBC gel adequately addresses this requirement for wound healing. The CRO-HBC hydrogel also exhibited an excellent biocompatibility, an appropriate biodegradability, keratinocyte migration facilitation properties, and a reactive oxygen species scavenging capability. The composite CRO-HBC hydrogel intelligently mitigated inflammatory responses, promoted angiogenesis, and exhibited a commendable efficacy for tissue regeneration in a full-thickness scalding model. Overall, this innovative temperature-sensitive CRO-HBC injectable hydrogel dressing with smart anti-inflammatory performance has enormous potential for managing severe scald wounds.

Protective effect of crocin-loaded nanoparticles in rats following epileptic seizures: Biochemical, behavioral and histopathological outcomes.

Epilepsy is a condition resulting from complex interactions involving excessive neuronal electrical activity and oxidative stress, which can lead to chronic neurological conditions. This study evaluates crocin encapsulated in SLNC for neuroprotective and countering pentylenetetrazole (PTZ) -induced oxidative damage. The rats were pre-treated with SLNC and FC (25, 50 mg/kg/day; P.O.) for 28 days before being induced with PTZ. Various standard tests were conducted to assess their behavioral functions, such as Y-maze, Open field test (OFT), and elevated plus maze (EPM) tests. ELISA measured brain tissue catalase activity (CAT) and nitric oxide status (NO). The expression of Nuclear factor kappa B (NF-κB) and the number of dendrite spines were examined through Immunohistochemical and Golgi-Cox staining, respectively. The Pretreating rats with SLNC plus PTZ significantly boosted memory and reduced anxiety levels in Y-maze, OFT, and EPM tests. In addition, it decreased NO levels and increased CAT levels. SLNC also showed a significant decrease in NF-κB expression and an increase in neurons and the number of spines. The positive effects of SLNC in improving memory and learning deficits after PTZ injection can be attributed to its anti-inflammatory and anti-oxidative effects.

Targeting Nrf2/HO-1 signaling by crocin: Role in attenuation of arsenic trioxide-induced neurotoxicity in mice.

ETHNOPHARMACOLOGY RELEVANCE: Saffron is a valued herb, obtained from the stigmas of the C.sativus Linn (Iridaceae). Pharmacopoeias have described it as having a variety of actions, such as stimulant, anti-carcinogen, and anti-depressant. As a folk medicine, crocin has been reported to have anti-cardiotoxicity and anti-hepatotoxicity effects. This paper focuses on crocin, one of the bioactive molecules found in saffron that are known to have therapeutic effects. Crocin has been shown in numerous experimental studies to be beneficial in treating depression, however, there aren't many studies on its neurotoxicity. AIM OF THE STUDY: Applications of arsenic trioxide (ATO) in medical settings is limited by its side effects. This study aims to examine crocin's protective effect against ATO-induced neurotoxicity and understand its potential molecular mechanism. Materialandmethods: A neurotoxicity model was created by administering ATO (4 mg/L/d). To counteract this, mice were intraperitoneally injected with crocin (100, 200 mg/kg/d). After 60 days, biochemical, histopathological, transmission electron microscopy, ELISA, and western blotting analyses were then performed. RESULTS: Our results indicated that crocin decreased neuronal death and loss caused by ATO, countered oxidative stress damage, and mitigated pro-inflammatory cytokines. Mice treated with crocin also displayed positive signs of brain tissue recovery. Additionally, crocin reduced the protein expressions of NLRP1, apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, GRP78, CHOP, and ATF4. CONCLUSIONS: This study attests that crocin can reduce ATO-induced neurotoxicity by safeguarding nerves from oxidative stress, inflammation, and apoptosis, possibly through the activation of the Nrf2/HO-1 signaling pathway.

The suppressive effects of crocin from saffron on allergic airway inflammation through Drp1/Nfr1/Mfn2/Pgc1-alpha signaling pathway in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Saffron is derived from the dried stigmas of Crocus sativus L., which was considered by ancient nations for food and medicinal purposes. In traditional medicine, the therapeutic use of Crocus sativus includes antispasmodic, antitussive and expectorant. AIM OF THE STUDY: Mitochondrial fusion, fission, biogenesis, and mitophagy are essential processes for maintaining mitochondrial dynamics in response to cellular stress. The primary objective of this research was to examine how crocin affected the levels of important mitochondrial regulators, including Drp1, Pgc1α, Nrf1, and Mfn2, in the lung tissue of ovalbumin-sensitized mice. MATERIALS AND METHODS: A total of fifty male BALB/C mice were randomly assigned to five unique groups (n = 10 for each group), including the control group, ovalbumin-sensitized group (OVA), OVA group treated with 30 mg/kg of crocin, OVA group treated with 60 mg/kg of crocin, and OVA group treated with 1 mg/kg of dexamethasone. Post-sensitization and ovalbumin challenge, mice lung tissues were evaluated for the expression of Drp1, Pgc1α, Nrf1, and Mfn2 mRNA levels using real-time PCR as well as histopathological assessments. RESULTS: In the OVA group, there was a significant elevated in inflammatory cells such as eosinophils, neutrophils, macrophages, and lymphocytes; however, crocin (both concentrations) and dexamethasone intervention showed significant inhibitory effects (P < 0.01 to P < 0.001). Moreover, an increase in the expression of Drp1, Pgc1α, and Nrf1 levels was seen in the OVA group, while crocin and dexamethasone showed protective benefits (P < 0.05 to P < 0.001). Furthermore, the levels of Mfn2 were reduced in the lung tissue of mice exposed to ovalbumin, but this decrease was reversed by crocin 60 (P < 0.05) and dexamethasone treatment (P < 0.001). CONCLUSION: In mice with OVA sensitization, the balance of mitochondrial dynamics in lung tissue was disrupted, but intervention of crocin identified to have a protective effect.

Crocin Protects the 661W Murine Photoreceptor Cell Line against the Toxic Effects of All-Trans-Retinal.

Age-related macular degeneration (AMD) is a common disease contributing to vision loss in the elderly. All-trans-retinal (atRAL) is a retinoid in the retina, and its abnormal accumulation exhibits toxicity to the retina and promotes oxidative stress-induced photoreceptor degeneration, which plays a crucial role in AMD progression. Crocin is a natural product extracted from saffron, which displays significant antioxidant and anti-inflammatory effects. The present study elucidates the protective effects of crocin on photoreceptor cell damage by atRAL and its potential mechanisms. The results revealed that crocin significantly attenuated cytotoxicity by repressing oxidative stress, mitochondrial injury, and DNA damage in atRAL-loaded photoreceptor cells. Moreover, crocin visibly inhibited DNA damage-induced apoptosis and gasdermin E (GSDME)-mediated pyroptosis in photoreceptor cells after exposure to atRAL. It was also observed that crocin distinctly prevented an increase in Fe2+ levels and lipid peroxidation caused by atRAL via suppressing the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor-erythroid 2-related factor 2 (NRF2)/heme oxygenase-1 (HO-1) signaling pathway, thereby ameliorating photoreceptor cell ferroptosis. In short, these findings provide new insights that crocin mitigates atRAL-induced toxicity to photoreceptor cells by inhibiting oxidative stress, apoptosis, pyroptosis, and ferroptosis.

Saffron (Crocus sativus) and its constituents in ovalbumin-induced asthma model: a preclinical systematic review and meta-analysis.

Background: Animal and human studies have demonstrated that the saffron and the active components of saffron, including crocin, crocetin, and safranal, possess anti-inflammatory, antioxidant, and immunomodulatory properties. In this meta-analysis, the preclinical evidence and potential mechanism of saffron were explored in an animal model of ovalbumin-induced asthma. Methods: Studies related to saffron and its constituents in an animal model of ovalbumin-induced asthma from the beginning to March 2024 were searched from Scopus, PubMed, and Web of Science databases. The methodological quality of the studies was evaluated using the 15-item CAMARADES checklist. Data analysis was performed using STATA software version 17. Results: Thirteen studies with 536 animals (268 animals in the intervention group and 268 animals in the ovalbumin-induced group) were analyzed. The meta-analysis findings demonstrated that saffron and its constituents played a significant role in reducing total WBC, eosinophil, lymphocyte, and monocyte counts. Moreover, saffron showed a significant decrease in the levels of IL-4, IL-5, IL-13, IgE, histamine, endothelin, nitric oxide, and nitrite. Moreover, saffron was found to elevate EC50 thresholds and lower maximum response rates in experimental animals. The analysis revealed a significant identification of modulation in endoplasmic reticulum (ER) stress markers and miRNAs pathways. Conclusion: Saffron and its components may impact ovalbumin-induced asthma model in animals through anti-inflammatory, antioxidant, and immunomodulatory pathways, as well as improving pulmonary function and modulating ER stress markers and miRNAs pathways. As a result, saffron should be considered for further clinical trials in individuals suffering from asthma.

Metabolomics to investigate the effect of preconditioned mesenchymal stem cells with crocin on pulmonary epithelial cells exposed to 2-chloroethyl ethyl sulfide.

Metabolomics significantly impacts drug discovery and precise disease management. This study meticulously assesses the metabolite profiles of cells treated with Crocin, Dexamethasone, and mesenchymal stem cells (MSCs) under oxidative stress induced by 2-chloroethyl ethyl sulfide (CEES). Gas chromatography/mass spectrometry (GC/MS) analysis unequivocally identified substantial changes in 37 metabolites across the treated groups. Notably, pronounced alterations were observed in pathways associated with aminoacyl-tRNA biosynthesis and the metabolism of aspartate, serine, proline, and glutamate. These findings demonstrate the potent capacity of the analyzed treatments to effectively reduce inflammation, mitigate reactive oxygen species production, and enhance cell survival rates. SIGNIFICANCE.

Investigation of the neuroprotective effect of crocin against electromagnetic field-induced cerebellar damage in male Balb/c mice.

Objective: Mobile devices are sources of electromagnetic fields (EMFs) that cause increasing concern among scientists about human health, especially with the long-term use of mobile phones. With regard to this issue, the potential adverse health effects, particularly on brain function have raised public concern. There is considerable evidence that natural compounds have neuro-protective effects due to their antioxidant and anti-inflammatory properties. Growing evidence suggests that crocin as a natural bioactive compound can be considered a potential therapeutic agent against various neurologic disorders. Therefore, the present study investigated the effects of crocin on the cerebellum after exposure to EMF. Materials and Methods: Twenty-four Male Balb/c mice were divided into control group, EMF group (2100 MHZ), EMF +Crocin group (2100 MHZ+50 mg/kg), and crocin group (50 mg/kg). The animals in the EMF and EMF+Crocin groups were exposed continuously for 30 days to an EMF 120 min/day. After 30 days, cerebellar cortex was evaluated by histomorphometric and immunohistochemical methods. Results: The results showed that 30 days of exposure to EMF had no significant effect on Purkinje cell size. However, EMF reduced significantly the diameter of astrocytes and increased Glial fibrillary acidic protein (GFAP) expression compared to the controls (p<0.05). Our findings also indicated that crocin treatment could improve the diameter of astrocytes and normalize GFAP expression (p<0.05). Conclusion: This study concluded that 2100-MHz EMF caused adverse effects on the cerebellum through astrocyte damage and crocin could partially reverse the EMF-related adverse effects.

Advances in the mechanisms of Gardenia jasminoides Ellis in improving diabetes and its complications.

Gardenia jasminoides Ellis (Zhi-zi), which belongs to the Rubiaceae family, has been used mainly with its fry fruit for thousands of years, and it is an herb with the homology of medicine and food. In traditional Chinese medicine (TCM) theory, Zhi-zi can be used for "Quench Xiaoke", meaning for therapying diabetes in modern medicine. Based on numerous pharmacological studies, Gardenia jasminoides Ellis (Zhi-zi), and its ingredients, mainly including iridoid glycosides and carotenoids (crocins), possess potent antioxidant and anti-inflammatory properties, and can promote insulin secretion and sensitization, stimulate GLP-1 pathway activity, and protect islet ß cells and the macro- and microvascular systems. These properties are the primary reasons why Zhi-zi and its ingredients are effective in reducing glucose levels, treating diabetes, and preventing its complications. This review aims to summarize the current situation and the advances of the studies on the mechanisms of Zhi-zi in improving diabetes and its complications, and it is expected to provide useful and systematic references for future research and clinical application of Zhi-zi and its active ingredients in the therapy of diabetes and complications.

Functional Mechanisms of Dietary Crocin Protection in Cardiovascular Models under Oxidative Stress.

It was previously reported that crocin, a water-soluble carotenoid isolated from the Crocus sativus L. (saffron), has protective effects on cardiac cells and may neutralize and even prevent the formation of excess number of free radicals; however, functional mechanisms of crocin activity have been poorly understood. In the present research, we aimed to study the functional mechanism of crocin in the heart exposed to oxidative stress. Accordingly, oxidative stress was modeled in vitro on human umbilical vein endothelial cells (HUVECs) and in vivo in mice using cellular stressors. The beneficial effects of crocin were investigated at cellular and molecular levels in HUVECs and mice hearts. Results indicated that oral administration of crocin could have protective effects on HUVECs. In addition, it protects cardiac cells and significantly inhibits inflammation via modulating molecular signaling pathways TLR4/PTEN/AKT/mTOR/NF-κB and microRNA (miR-21). Here we show that crocin not only acts as a direct free radical scavenger but also modifies the gene expression profiles of HUVECs and protects mice hearts with anti-inflammatory action under oxidative stress.

Intestinal Metabolism of Crocin and a Pharmacokinetics and Pharmacodynamics Study in the Chronic Social Defeat Stress Mouse Model.

Orally administered crocin rapidly and efficiently rescues depressive-like behaviors in depression models; however, crocin levels in the circulatory and central nervous systems are rather low. The underlying mechanism responsible for the inconsistency between pharmacokinetics and pharmacodynamics is unknown. To identify the active metabolites and clarify the underlying mechanisms, the pharmacokinetics and metabolic effects of the gut flora and hepatic and intestinal microsomes on crocin were examined, and the pharmacodynamics of crocin and its major metabolite, crocetin, were also evaluated in both normal and pseudo germ-free mice subjected to chronic social defeat stress. The results showed that oral administration of 300 mg/kg crocin significantly improved the depression-like behaviors of chronic social defeat stress mice, although the levels of crocin in the circulatory system were rather low (Cmax = 43.5 ± 8.6 µg/L; AUC = 151 ± 20.8 µg·h/L). However, the primary metabolite of crocetin was much more abundant in vivo (Cmax = 4662.5 ± 586.1 µg/L; AUC = 33,451.9 ± 3323.6 µg·h/L). Orally administered crocin was primarily metabolized into crocetin by the gut flora instead of hepatic or intestinal microsomal enzymes, and less than 10% of crocin was transformed into crocetin in the liver or intestinal microsomes. Inhibition of the gut flora dramatically reduced the production of and in vivo exposure to crocetin, and the rapid antidepressant effect of crocin disappeared. Moreover, crocetin showed rapid antidepressant effects similar to those of crocin, and the effects were independent of the gut flora. In conclusion, the metabolic transformation of crocin to crocetin primarily contributes to the rapid antidepressant effects of crocin and is dependent on the gut flora.

Crocin-Phospholipid Complex: Molecular Docking, Molecular Dynamics Simulation, Preparation, Characterization, and Antioxidant Activity.

Background: Crocin is a water-soluble carotenoid compound present in saffron (Crocus sativus L.), known for its wide range of pharmacological activities, including cardioprotective, hepatoprotective, anti-tumorigenic, anti-atherosclerosis, and anti-inflammatory effects. Objectives: The instability of crocin, its low miscibility with oils, and poor bioavailability pose challenges for its pharmaceutical applications. This study aimed to design and prepare a crocin-phospholipid complex (CPC) and assess its physicochemical properties. Methods: The study investigated the formation of the complex and its binding affinity through molecular docking. Molecular dynamics (MD) simulations were conducted to find the optimal molar ratio of crocin to phospholipid for the complex's preparation. The CPC was produced using the solvent evaporation method. Techniques such as X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), field-emission scanning electron microscopy (FE-SEM), nuclear magnetic resonance (NMR), and solubility studies were utilized to characterize and confirm the formation of CPC. Additionally, the in vitro antioxidant activity of crocin and CPC was evaluated. Results: Molecular dynamic simulations explored molar ratios of 1: 1, 1: 1.5, and 1: 2 for crocin to phospholipid. The ratio of 1: 2 was found to be the most stable, exhibiting the highest probability of hydrogen bond formation. Molecular docking, FTIR, and NMR studies indicated hydrogen bond interactions between crocin and phospholipid, confirming CPC's formation. XRD and FE-SEM analyses showed a decrease in crocin's crystallinity within the phospholipid complex. Furthermore, the solubility of crocin in n-octanol was enhanced post-complexation, indicating an increase in crocin's lipophilic nature. Conclusions: Phospholipid complexation emerges as a promising technique for enhancing the physicochemical characteristics of crocin.

Radioprotective Effect of Resveratrol, Crocin, and Their Combination on Cytogenetic Alterations in Human Lymphocytes.

Background: High-dose radiation altering the genetic material in patients' bone marrow cells can lead to hematopoietic radiation syndrome. Accordingly, the presence of radiation protections agents is critical to preventing these adverse effects. Objective: This study aimed to evaluate the radioprotection of the exclusive or combination effect of resveratrol and crocin extracts at various concentrations on irradiated human lymphocytes. Material and Methods: In this experimental study, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to evaluate the cell viability in pre-treatment with resveratrol, crocin, or a combination of both, using a concentration range of 5 to 4800 µM / ml in 24 h. The chromosomal aberration test was employed to determine the aberration frequency in 48 h. This study was performed on human peripheral blood lymphocytes treated with 2 Gy radiation and reliability of measurements performed by the triplicate repeat. Results: MTT results showed that the groups treated with either resveratrol or crocin at concentrations of 5 to 4800 µM had no significant reduction in cell viability. The cytogenetic analysis of irradiated lymphocytes with 2 Gy X-rays revealed a reduction in the frequency of dicentric chromosomes in all treated groups in contrast with the control group. The most significant reduction occurred in those treated with a single agent at the concentration of 100 µM and a combined drug at the concentration of 50 µM. Conclusion: The combination of resveratrol and crocin is considered a potential radioprotector and prophylactic for patients before radiation therapy.

The effect of crocin on movement disorders and oxidative DNA damage in Parkinson's disease: Insights from a randomized controlled trial.

BACKGROUND: Parkinson's disease (PD), the second most prevalent neurological disorder in the elderly, manifests with distinctive movement disorders, including bradykinesia, resting tremor, and stiffness. With a progressive course, current treatment strategies primarily target symptomatic relief. Crocin is a chemical compound isolated from the dry stigma of Crocus sativus, and has demonstrated neuroprotective properties. OBJECTIVES: This study explores the impact of crocin on movement disorders and neuronal oxidative DNA damage in PD patients. METHOD: Conducted as a randomized, blinded, and controlled trial, this research focused on patients aged 30 to 80 with idiopathic PD. Using the second and third parts of the movement disorder society-unified PD rating scale (MDS-UPDRS), aspects of daily life activity and movement disorders were assessed before and after an 8-week intervention. Patients in the crocin groups received capsules containing 30 mg of crocin twice daily. Additionally, the 8-hydroxy-2-deoxydiguanosine (8-OHdG) to urinary creatinine ratio (8-OHdG/uCr) was measured to evaluate neuronal oxidative DNA damage. RESULTS: Out of the initially evaluated 164 patients, 30 were randomly assigned to each group, with 53 subjects completing the study. Within-group analysis revealed a significant improvement in the second and third parts of MDS-UPDRS after 8 weeks of crocin intervention (P < 0.05). However, the 8-OHdG/uCr did not show significant changes. The well-tolerated daily dose of 60 mg of crocin demonstrated minimal side effects. CONCLUSION: This study establishes the efficacy of crocin in enhancing daily life activities and mitigating movement disorders, suggesting its potential as a supplementary intervention alongside conventional PD medications.

Construction of a high-efficiency GjCCD4a mutant and its application for de novo biosynthesis of five crocins in Escherichia coli.

Crocins are bioactive natural products that rarely exist in plants. High costs and resource shortage severely limit its development and application. Synthetic biology studies on crocins are of considerable global interest. However, the lack of high-efficiency genetic tools and complex cascade biocatalytic systems have substantially hindered progress in crocin biosynthesis-related research. Based on mutagenesis, a high-efficiency GjCCD4a mutant (N212m) was constructed with a catalytic efficiency that was 25.08-fold higher than that of the wild-type. Solubilized GjCCD4a was expressed via fusion with an MBP tag. Moreover, N212m and ten other genes were introduced into Escherichia coli for the de novo biosynthesis of five crocins. The engineered E57 strain produced crocins III and V with a total yield of 11.50 mg/L, and the E579 strain produced crocins I-V with a total output of 8.43 mg/L at shake-flask level. This study identified a marvelous genetic element (N212m) for crocin biosynthesis and achieved its de novo biosynthesis in E. coli using glucose. This study provides a reference for the large-scale production of five crocins using E. coli cell factories.

Folic acid-modified nanocrystalline cellulose for enhanced delivery and anti-cancer effects of crocin.

Crocin is a carotenoid compound in saffron with anti-cancer properties. However, its therapeutic application is limited by its low absorption, bioavailability, and stability, which can be overcome through nanocarrier delivery systems. This study used surface-modified Nano-crystalline cellulose (NCC) to deliver crocin to cancer cells. NCC modified with CTAB were loaded with crocin and then conjugated with folic acid (NCF-CR-NPs). The synthesized nanoparticles (NPs) were characterized using FTIR, XRD, DLS, and FESEM. The crystallinity index of NCC was 66.64%, higher than microcrystalline cellulose (61.4%). The crocin loading and encapsulation efficiency in NCF-CR-NPs were evaluated. Toxicity testing by MTT assay showed that NCF-CR-NPs had higher toxicity against various cancer cell lines, including colon cancer HT-29 cells (IC50 ~ 11.6 µg/ml), compared to free crocin. Fluorescent staining, flow cytometry, and molecular analysis confirmed that NCF-CR-NPs induced apoptosis in HT-29 cells by increasing p53 and caspase 8 expression. The antioxidant capacity of NCF-CR-NPs was also evaluated using ABTS and DPPH radical scavenging assays. NCF-CR-NPs exhibited high free radical scavenging ability, with an IC50 of ~ 46.5 µg/ml for ABTS. In conclusion, this study demonstrates the potential of NCF-CR-NPs to deliver crocin to cancer cells effectively. The NPs exhibited enhanced anti-cancer and antioxidant activities compared to free crocin, making them a promising nanocarrier system for crocin-based cancer therapy.

Insight into saffron associated microbiota from different origins and explore the endophytes for enhancement of bioactive compounds.

Crocus sativus L. is a perennial crop for its valuable active compounds. Plant-associated microbes impact on the quality and efficacy of medicinal herbs by promoting bioactive components accumulation. However, how microbes influence the accumulation of bioactive components in saffron have not been well studied. Here, the microbiome in C. sativus derived from 3 core production areas were deciphered by 16S rDNA sequencing and the relationship between endophytes and bioactive ingredients were further investigated. The main results are as follows: (1) Both Comamonadaceae and Burkholderiaceae were positively correlated with the content of bioactive components in the stigmas. (2) The synthesis of crocin was positively correlated with Xanthomonadaceae, negatively correlated with Lachnospiraceae and Prevotellaceae. Therefore, further investigation is required to determine whether Xanthomonadaceae plays an unknown function in the synthesis of crocin. These findings provide guidelines for disentangling the function of endophytes in the production of bioactive ingredients and thus for microbe-mediated breeding.

Crocin's role in modulating MMP2/TIMP1 and mitigating hypoxia-induced pulmonary hypertension in mice.

To explore the molecular pathogenesis of pulmonary arterial hypertension (PAH) and identify potential therapeutic targets, we performed transcriptome sequencing of lung tissue from mice with hypoxia-induced pulmonary hypertension. Our Gene Ontology analysis revealed that "extracellular matrix organization" ranked high in the biological process category, and matrix metallopeptidases (MMPs) and other proteases also played important roles in it. Moreover, compared with those in the normoxia group, we confirmed that MMPs expression was upregulated in the hypoxia group, while the hub gene Timp1 was downregulated. Crocin, a natural MMP inhibitor, was found to reduce inflammation, decrease MMPs levels, increase Timp1 expression levels, and attenuate hypoxia-induced pulmonary hypertension in mice. In addition, analysis of the cell distribution of MMPs and Timp1 in the human lung cell atlas using single-cell RNAseq datasets revealed that MMPs and Timp1 are mainly expressed in a population of fibroblasts. Moreover, in vitro experiments revealed that crocin significantly inhibited myofibroblast proliferation, migration, and extracellular matrix deposition. Furthermore, we demonstrated that crocin inhibited TGF-ß1-induced fibroblast activation and regulated the pulmonary arterial fibroblast MMP2/TIMP1 balance by inhibiting the TGF-ß1/Smad3 signaling pathway. In summary, our results indicate that crocin attenuates hypoxia-induced pulmonary hypertension in mice by inhibiting TGF-ß1-induced myofibroblast activation.

Crocin nano-chitosan-coated compound improves anxiety disorders, learning, and spatial memory in Alzheimer's model induced by beta-amyloid in rats.

Objectives: Alzheimer's disease (AD) is a neurodegenerative disease that results in the gradual breakdown of brain tissue, causing the deterioration of intellectual function and ability. Crocin is a saffron carotenoid compound proven to have excellent neuroprotective and anti-inflammation properties, although it has some limitations such as low stability and bioavailability. Therefore, in the current research, we tried to improve these limitations by using nanotechnology and chitosan as the carrier. Our study examined the therapeutic effects of crocin nano-chitosan-coated compound and compared it with intact crocin in lower dosages than other studies in AD rat models. Materials and Methods: Encapsulating crocin into chitosan nanoparticles was done through a modified technique to improve its limitations. The AD rat model was induced by bilaterally injecting beta-amyloid (Aß) peptide into the frontal lobe using a stereotaxic device. To evaluate memory, we conducted the Barnes maze test, and to evaluate anxiety, we used the elevated plus maze test. Also, histological tests were conducted to evaluate neuronal damage in each group. Results: Crocin nano-chitosan-coated administration significantly improved specific memory indicators compared to the Aß and other treated groups. A significant decrease in anxiety indicators was detected compared to the Aß and other treated groups. Finally, the results of hippocampus staining indicated a meaningful difference between the Aß group and other treated groups, compared to the crocin nano-chitosan-coated group. Conclusion: Treatment with low dosages of crocin in the nano-coated form exhibited great efficacy in reducing AD's adverse effects compared to the same dosage of intact crocin.