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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., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Plants, including pumpkins ( Cucurbita spp.), are an interesting source of nutrients and bioactives with various health benefits. In this research, carotenoid extracts obtained from the pulp of eight pumpkin varieties, belonging to the C. moschata and C. maxima species, were tested for cytotoxicity on SH-SY5Y neuroblastoma cells. The results showed that pumpkin bioactives exert a cytotoxic action against the tested cells, in particular Butternut extract at a 100 μM (53.69 μg/mL) concentration after 24 h of treatment and Mantovana extract at 50 μM (26.84 μg/mL) after 48 h. Moreover, the carotenoid extracts also showed interesting in vitro antioxidant activity, evaluated by ABTS and ORAC assays. To fully characterize the qualitative and quantitative profile of carotenoids in the tested extracts, a high-performance chromatographic technique was performed, revealing that pumpkin pulp carotenoids were mainly represented by β-carotene, mono- and di-esterified hydroxy- and epoxy-carotenoids. Moreover, the carotenoid dataset was also useful for discriminating samples from two different species. In conclusion, the results of the present study highlight the potential anti-cancer activity of pumpkin carotenoid extracts and the possibility of using them as chemotherapeutic adjuvants.

Manihot esculenta (cassava) roots is a major food crop for its energy content. Leaves contain nutrients and demonstrate biological properties but remain undervalorized. In order to develop a bioguided optimization of cassava nutrition-health properties, we compared the phytochemistry and bioactive potential of cassava root flour extract (CF) with cassava flour extract enriched with 30% leaves powder (CFL). Cassava flour supplementation impact was explored on flour composition (starch, fiber, carotenoids, phenolic compounds), in vivo glycemic index, and bioactivity potential using macrophage cells. We assessed the impact of cassava flour supplementation on free radicals scavenging and cellular production of pro-inflammatory mediators. CFL showed higher levels of fiber, carotenoids, phenolic compounds, and lower glycemic index. Significantly higher bioactive properties (anti-inflammatory and antioxidant) were recorded, and inhibition of cytokines production has been demonstrated as a function of extract concentration. Overall, our results indicate that enrichment of cassava flour with leaves significantly enhances its nutrition-health and bioactive potential. This bioguided matrix recombination approach may be of interest to provide prophylactic and therapeutic dietary strategy to manage malnutrition and associated chronic non-communicable diseases characterized by low-grade inflammation and unbalanced redox status. It would also promote a more efficient use of available food resources.

Chronic kidney disease (CKD) affects more than 850 million people worldwide, contributing to morbidity and mortality, particularly through cardiovascular disease (CVD). The altered composition in CKD patients leads to increased production and absorption of uremic toxins such as trimethylamine (TMA) and its oxidized form, trimethylamine N-oxide (TMAO), which are associated with cardiovascular risks. This study investigated the potential of supplementary interventions with high-carotenoid-content gac fruit extract and probiotics to mitigate serum TMAO by modulating the gut microbiota. We conducted an animal study involving 48 male Wistar rats, divided into six groups: the control, CKD control, and four treatment groups receiving gac fruit extract, carotenoid extract, or combinations with Ligilactobacillus salivarius and Lactobacillus crispatus and Lactobacillus casei as a standard probiotic. CKD was induced in rats using cisplatin and they were supplemented with choline to enhance TMA production. The measures included serum creatinine, TMAO levels, gut microbiota composition, and the expression of fecal TMA lyase and intestinal zonula occluden-1 (ZO-1). CKD rats showed increased TMA production and elevated serum levels of TMAO. Treatment with gac fruit extract and selective probiotics significantly altered the composition of the gut microbiota by decreasing Actinobacteriota abundance and increasing the abundance of Bacteroides . This combination effectively promoted ZO-1 expression, reduced fecal TMA lyase, and subsequently lowered serum TMAO levels, demonstrating the therapeutic potential of these interventions. Our results highlight the benefits of gac fruit extract combined with probiotics for the effective reduction in serum TMAO levels in rats with CKD, supporting the further exploration of dietary and microbial interventions to improve outcomes in patients with CKD.

Carotenoids are natural pigments utilized as colourants and antioxidants across food, pharmaceutical and cosmetic industries. They exist in carbon chain lengths of C 30 , C 40 , C 45 and C 50 , with C 40 variants being the most common. Bacterioruberin (BR) and its derivatives are part of the less common C 50 carotenoid group, synthesized primarily by halophilic archaea. This study analysed the compositional characteristics of BR extract (BRE) isolated from 'Haloferax marinum' MBLA0078, a halophilic archaeon isolated from seawater near Yeoungheungdo Island in the Republic of Korea, and investigated its antioxidant activity and protective effect on lipopolysaccharide (LPS)-induced C2C12 myotube atrophy. The main components of BRE included all-trans-BR, monoanhydrobacterioruberin, 2-isopentenyl-3,4-dehydrorhodopin and all-trans-bisanhydrobacterioruberin. BRE exhibited higher antioxidant activity and DNA nicking protection activity than other well-known C 40 carotenoids, such as β-carotene, lycopene and astaxanthin. In C2C12 myotubes, LPS treatment led to a reduction in myotube diameter and number, as well as the hypertranscription of the muscle-specific ubiquitin ligase MAFbx and MuRF1. BRE mitigated these changes by activating the Akt/mTOR pathway. Furthermore, BRE abolished the elevated cellular reactive oxygen species levels and the inflammation response induced by LPS. This study demonstrated that 'Hfx. marinum' is an excellent source of natural microbial C 50 carotenoids with strong antioxidant capacity and may offer potential protective effects against muscle atrophy., (© 2024 The Author(s). Microbial Biotechnology published by John Wiley & Sons Ltd.)

Emerging evidence suggests that crocin rescues stress-induced depressive symptoms in mice via stimulation of hippocampal neurogenesis. Glutamate modulators mainly involving N-methyl- d -aspartate (NMDA) receptors (NMDARs) have highlighted a role in neural development, synaptic plasticity, and depression. The research presented here was designed to appraise the interaction between NMDAR agents and crocin on depressive-related behaviors in the NMRI male mice exposed to acute restraint stress (ARS) for a period of 4 h. The mice were submitted to the splash test, forced swimming test, and tail suspension test to evaluate depressive-like behavior. The ARS decreased the grooming duration in the splash test and increased immobility time in the forced swimming test and tail suspension test, suggesting a depressive-like phenotype. NMDA (0.25 and 0.5 μg/mouse, intracerebroventricular) did not alter depression-related profiles in both non-acute restraint stress (NARS) and ARS mice, while the same doses of NMDAR antagonist D-AP5 potentiated the antidepressive-like activities in the ARS mice compared with the NARS mice. Moreover, a low dose of NMDA did not change depression-related parameters in the crocin-treated NARS or ARS mice, while D-AP5 enhanced the crocin response in the NARS and ARS mice. Isobologram analysis noted a synergism between crocin and D-AP5 on antidepressive-like behavior in the NARS and ARS mice. Collectively, the combination of crocin and D-AP5 was shown to mitigate depression symptoms and can be potentially used for the treatment of depression disorders., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: White matter lesions (WMLs) are increasingly linked to the pathological process of chronic vascular dementia (VaD). An effective crocins fraction extracted from Gardenia Fructus, GJ-4, has been shown to improve cognitive function in several Alzheimer's disease models and VaD models., Objectives: To explore the potential mechanisms of GJ-4 on WMLs in a chronic VaD mouse model., Methods: The chronic VaD mouse model was established, and WMLs were characterized by cerebral blood flow (CBF), behavioral tests, LFB staining, and immunohistochemistry. The anti-oxidative effect of GJ-4 was validated by examining biochemical parameters (SOD, MDA, and GSH) and the Keap1-Nrf2/HO-1 pathway. The impact of GJ-4 on lipid metabolism in WM was further investigated through lipidomic analysis., Results: GJ-4 significantly attenuated cognitive impairments and improved the CBF of BCAS (bilateral common carotid artery stenosis)-induced mice. Mechanism research showed that GJ-4 could enhance cognition by promoting the repair of WMLs by inhibiting oxidative stress. Furthermore, GJ-4 treatment significantly reduced chronic cerebral hypoperfusion (CCH)-induced WMLs via improving lipid metabolism disorder in the WM., Conclusion: This research has provided valuable insights into the significance of WMLs in CCH-induced VaD and underscored the potential of GJ-4 as a therapeutic agent for improving cognitive function by targeting WMLs. These findings suggest that GJ-4 is a promising candidate for the treatment of VaD., Competing Interests: Declaration of competing interest The authors declare that they have no known conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is characterized by, among other things, dementia and a decline in cognitive performance. In AD, dementia has neurodegenerative features and starts with mild cognitive impairment (MCI). Research indicates that apoptosis and neuronal loss occur in AD, in which oxidative stress plays an important role. Therefore, reducing oxidative stress with antioxidants is a natural strategy to prevent and slow down the progression of AD. Carotenoids are natural pigments commonly found in fruits and vegetables. They include lipophilic carotenes, such as lycopene, α- and β-carotenes, and more polar xanthophylls, for example, lutein, zeaxanthin, canthaxanthin, and β-cryptoxanthin. Carotenoids can cross the blood-brain barrier (BBB) and scavenge free radicals, especially singlet oxygen, which helps prevent the peroxidation of lipids abundant in the brain. As a result, carotenoids have neuroprotective potential. Numerous in vivo and in vitro studies, as well as randomized controlled trials, have mostly confirmed that carotenoids can help prevent neurodegeneration and alleviate cognitive impairment in AD. While carotenoids have not been officially approved as an AD therapy, they are indicated in the diet recommended for AD, including the consumption of products rich in carotenoids. This review summarizes the latest research findings supporting the potential use of carotenoids in preventing and alleviating AD symptoms. A literature review suggests that a diet rich in carotenoids should be promoted to avoid cognitive decline in AD. One of the goals of the food industry should be to encourage the enrichment of food products with functional substances, such as carotenoids, which may reduce the risk of neurodegenerative diseases.

Enhalus acoroides , a tropical seagrass, is known for its significant contribution to marine ecosystems and its potential health benefits due to bioactive compounds. This study aims to compare the carotenoid levels in E. acoroides using green extraction via ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE) and to evaluate the biological properties of these extracts against oxidative stress, diabetes, and obesity through in silico and in vitro analyses. E. acoroides samples were collected from Manado City, Indonesia, and subjected to UAE and MAE. The extracts were analyzed using UHPLC-ESI-MS/MS to identify carotenoids, including β-carotene, lutein, lycopene, β-cryptoxanthin, and zeaxanthin. In silico analysis was conducted to predict the compounds' bioactivity, toxicity, and drug-likeness using WAY2DRUG PASS and molecular docking with CB-Dock2. The compounds C3, C4, and C7 demonstrated notable interactions, with key metabolic proteins and microRNAs, further validating their potential therapeutic benefits. In vitro assays evaluated antioxidant activities using DPPH and FRAP assays, antidiabetic properties through α-glucosidase and α-amylase inhibition, and antiobesity effects via lipase inhibition and MTT assay with 3T3-L1 cells. Results indicated that both UAE and MAE extracts exhibited significant antioxidant, antidiabetic, and antiobesity activities. MAE extracts showed higher carotenoid content and greater biological activity compared to UAE extracts. These findings suggest that E. acoroides , mainly when extracted using MAE, has promising potential as a source of natural bioactive compounds for developing marine-based antioxidant, antidiabetic, and antiobesity agents. This study supplements existing literature by providing insights into the efficient extraction methods and the therapeutic potential of E. acoroides carotenoids.

This in vivo study performed in rat adjuvant arthritis aims to advance the understanding of astaxanthin's therapeutic properties for the possible treatment of rheumatoid arthritis (RA) in monotherapy and along with the standard RA treatment, methotrexate (MTX), in combination therapy. The main goal was to elucidate astaxanthin's full therapeutic potential, evaluate its dose dependency, and compare its effects in monotherapy with other carotenoids such as β-carotene and β-cryptoxanthin (KXAN). Moreover, potential differences in therapeutic activity caused by using different sources of astaxanthin, synthetic (ASYN) versus isolated from Blakeslea trispora (ASTAP), were evaluated using one-way ANOVA (Tukey-Kramer post hoc test). KXAN was the most effective in reducing plasma MMP-9 levels in monotherapy, significantly better than MTX, and in reducing hind paw swelling. The differences in the action of ASTAP and ASYN have been observed across various biometric, anti-inflammatory, and antioxidative parameters. In combined therapy with MTX, the ASYN + MTX combination proved to be better. These findings, especially the significant anti-arthritic effect of KXAN and ASYN + MTX, could be the basis for further preclinical studies.

Antioxidants are endogenous and exogenous substances with the ability to inhibit oxidation processes by interacting with reactive oxygen species (ROS). ROS, in turn, are small, highly reactive substances capable of oxidizing a wide range of molecules in the human body, including nucleic acids, proteins, lipids, carbohydrates, and even small inorganic compounds. The overproduction of ROS leads to oxidative stress, which constitutes a significant factor contributing to the development of disease, not only markedly diminishing the quality of life but also representing the most common cause of death in developed countries, namely, cardiovascular disease (CVD). The aim of this review is to demonstrate the effect of selected antioxidants, such as coenzyme Q10 (CoQ10), flavonoids, carotenoids, and resveratrol, as well as to introduce new antioxidant therapies utilizing miRNA and nanoparticles, in reducing the incidence and progression of CVD. In addition, new antioxidant therapies in the context of the aforementioned diseases will be considered. This review emphasizes the pleiotropic effects and benefits stemming from the presence of the mentioned substances in the organism, leading to an overall reduction in cardiovascular risk, including coronary heart disease, dyslipidaemia, hypertension, atherosclerosis, and myocardial hypertrophy.

Experimental evidence indicates that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists ketamine and MK-801 induce schizophrenia-like symptoms in rodents, including cognitive deficits. Crocins are among the active components of the plant Crocus sativus L. and were found to be effective in different models of psychiatric disorders comprising schizophrenia. The present study was designed to evaluate the efficacy of the joint administration of sub-effective doses of crocins with those of the atypical antipsychotics clozapine and risperidone in alleviating nonspatial recognition and emotional memory deficits induced either by ketamine (3 mg/kg) or MK-801 (0.1 mg/kg) in the rat. To this end, the object recognition and the step-through passive avoidance tests were used. Co-administration of sub-effective doses of crocins (5 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted nonspatial recognition and emotional memory deficits induced by NMDA receptor antagonists. The current findings suggest that this combinatorial treatment was efficacious in attenuating cognitive impairments related to the blockade of the NMDA receptor. In addition, the present results support the potential of crocins as an adjunctive drug for the therapy of schizophrenia., (© 2024 The Author(s). Phytotherapy Research published by John Wiley & Sons Ltd.)

Smoking is one of the main causes of death in the world. Cigarette use is related with various components of metabolic syndrome (e.g., insulin resistance, raised blood pressure, dyslipidemia, oxidative stress, inflammation state) and psychiatric disorders. This study was conducted to determine the effect of crocin (Cro) supplementation on nicotine dependence, anxiety, depression, and metabolic indices in smokers. A total of 50 smokers were selected and randomly categorized into two groups (crocin and placebo). The intervention group received crocin (30 mg per day; n = 25) and placebo (containing Avicel; n = 25) once a day. The primary (nicotine dependence, depression, and anxiety inventory) and secondary (metabolic indices) outcomes were assessed at the start of the intervention and after the 3 months. Multiple linear regression models were used to assess the treatment effects on the outcomes adjusting for confounding variables. The primary outcome results such as nicotine dependence, depression, and anxiety inventory did not have a significant difference among the intervention groups (P > 0.05). Also in the secondary outcomes, fasting plasma glucose (FPG), insulin, and homeostasis model of assessment-insulin resistance (HOMA-IR) levels did indicate a significant difference by Cro intervention (β - 3.27 mg/dL; 95% CI, - 5.23, - 1.31; P = 0.002; β - 0.76 μIU/mL; 95% CI, - 1.38, - 0.15; P = 0.01; β - 0.18; 95% CI, - 0.29, - 0.07; P = 0.002), respectively. There were also significant reductions in serum levels of high-sensitivity C-reactive protein (hs-CRP) (β - 0.72 mg/L; 95% CI, - 1.37, - 0.07; P = 0.03), compared with the placebo. Cro intake may have favorable effects on the level of FPG, insulin, HOMA-IR, and hs-CRP in smokers. However, due to the small sample size and limited scientific reports on smokers, further studies are necessary. ClinicalTrial.gov Identifier: IRCT20170420033551N11., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rheumatoid arthritis (RA), an immune-mediated inflammatory disease, is characterized by a large number of infiltrated immune cells and abnormally elevated reactive oxygen species (ROS) in the joint. Various proinflammatory factors secreted by macrophages and the elevated ROS by inflammatory cells are deeply intertwined and together contribute to joint damage. Targeted and sustained anti-inflammation and antioxidation strategies are needed for RA treatment. To alleviate the oxidative stress and target the source of inflammatory cytokines, we developed a thermosensitive injectable hydrogel, Dex-DSLip/Cro@Gel, to coordinate the targeted anti-inflammatory and antioxidation effects. Within the injectable gel, dexamethasone (Dex)-loaded liposomes (Dex-DSLip), modified with dextran sulfate (DS), target macrophages via interaction with scavenger receptor A (SR-A). Simultaneously, crocin I (Cro) is loaded in the gel with a high loading capacity. The porous structure of Dex-DSLip/Cro@Gel successfully prolongs the retention time of both drugs and sustains the release of Dex and Cro. After intra-articular injection of Dex-DSLip/Cro@Gel in RA rats, the expression of inflammatory factors in the ankle joints was significantly reduced. Joint erythema and bone erosion were markedly alleviated. Through the synergistic effects of Dex and Cro, Dex-DSLip/Cro@Gel demonstrates targeted anti-inflammatory and antioxidation effects as well as mitigated bone erosion and long-term therapeutic effects for RA. This thermosensitive injectable nanocomposite hydrogel synergizes anti-inflammatory and antioxidation effects and targets the microenvironment in the joint, offering a new approach for RA treatment.

Mesenchymal stem cells (MSCs) have high priority in clinical applications for treatment of immune disorders because of their immunomodulatory function. A lot of researches have currently been undertaken to enhance the stemness capacities of the cells and pick an excellent type of MSCs for clinical approaches. This study aims to assess the immunomodulatory related MicroRNAs (miRNAs) expression as well as their target genes in both adipose derived stem cells (Ad-SCs) and dental pulp derived stem cell (DP-SCs) in the presence or lack of Crocin (saffron plant's bioactive compound). For this purpose, first MSCs were extracted from adipose and dental pulp tissues, and then their mesenchymal nature was confirmed using flow cytometry and differentiation tests. Following the cell treatment with an optimal-non-toxic dose of Crocin (Obtained by MTT test), the expression of 4 selected immunomodulatory-related micro-RNAs (Mir-126, -21, -23, and-155) and their target genes (PI3K/ Akt 1 and 2/ NFKB and RELA) were assessed by RT-PCR. Our findings revealed that miRNA-23 and miRNA-126 were up-regulated in both types of cells treated with Crocin, while in the other side, miRNA-21 and miRNA-155 were down-regulated in DP-SCs and were up-regulated in Ad-SCs under treatment. Moreover, the real-time PCR results indicated that Crocin could significantly down regulate the expression of PI3K/ Akt1/ Akt2/ NFKB/ RELA genes in DP-SCs and PI3K/Akt2 genes in Ad-SCs and up regulate the expression of Akt1/ NFKB/ RELA genes in recent cells. Based on the analysis of the obtained data, the immunoregulatory effects of Crocin were higher in DP-SCs than in Ad-SCs. In conclusion, Crocin could control essential signaling pathways related to the inflammation by regulating the expression of related- miRNAs genes that play a key function in the immune regulation pathways in MSCs. Our findings can give an understanding of the mechanisms by which Crocin enhances the immunomodulatory feature of MSCs. According to the research findings, DP-SCs are probably a better immunomodulator in Crocin treatment than Ad-SCs and it may be helpful for MSCs selection in clinical applications for modulation or treatment of autoimmune disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, we tried to explore the influence of various tricarboxylic acid (TCA) cycle intermediates on carotenoid production and with a focus on enhancing pigment biosynthesis, we conducted two statistical analysis. In case of TCA intermediates influence on pigment production by Paracoccus marcusii RSPO1; fumaric acid, and malic acid were observed as potent enhancers of pigment biosynthesis. Further, to optimize key media components for enhanced carotenoid production, the Plackett-Burman design was employed encompassing carbon, nitrogen sources, TCA cycle intermediates, and metal salts. The selected factors after Plackett Burman were fine-tuned through Response Surface Methodology and the optimal concentrations that have remarkably elevated carotenoid production were starch-2.24 g/l, MgSO 4 -0.416 g/l, ZnSO 4 -0.0157 g/l, and fumaric Acid-16 mM. Further, evaluation of pigment cytotoxicity against normal (Vero) and Non-Small Cell Carcinoma (A549) cells was performed. The resultant IC 50 values were quantified as 161.3 µg/ml and 7.623 µg/ml for Vero and A549 cells, respectively. Moreover, a reactive oxygen species (ROS) determination study in A549 cells was done which have shown a noteworthy threefold ROS production in A549 cells through fluorescence spectroscopic observation. This implies that the bacterial carotenoids can act as potent pro-oxidants against cancerous cells while being nontoxic toward normal cells.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Crocetin (CCT), a natural bioactive compound extracted and purified from the traditional Chinese medicinal herb saffron, has been shown to play a role in neurodegenerative diseases, particularly depression. However, due to challenges with solubility, targeting, and bioavailability, formulation development and clinical use of CCT are severely limited. In this study, we used the emulsification-reverse volatilization method to prepare CCT-loaded nanoliposomes (CN). We further developed a borneol (Bor) and lactoferrin (Lf) dual-modified CCT-loaded nanoliposome (BLCN) for brain-targeted delivery of CCT. The results of transmission electron microscope (TEM) and particle size analysis indicated that the size of BLCN (∼140 nm) was suitable for transcellular transport across olfactory axons (∼200 nm), potentially paving a direct path to the brain. Studies on lipid solubility, micropolarity, and hydrophobicity showed that BLCN had a relatively high Lf grafting rate (81.11 ± 1.33 %) and CCT entrapment efficiency (83.60 ± 1.04 %) compared to other liposomes, likely due to Bor improving the lipid solubility of Lf, and the combination promoting the orderly arrangement of liposome membrane molecules. Microplate reader and fluorescence microscopy analysis showed that BLCN efficiently promoted the endocytosis of fluorescent coumarin 6 into HT22 cells with a maximal fluorescence intensity of (13.48 ± 0.80 %), which was significantly higher than that of CCT (5.73 ± 1.17 %) and CN (12.13 ± 1.01 %). BLCN also exhibited sustained function, remaining effective for more than 12 h after reaching a peak at 1 h in cells, while CN showed a significant decrease after 4 h. The uptake mechanisms of BLCN in HT22 cells mainly involve energy-dependent, caveolae-mediated, and microtubule-mediated endocytosis, as well as micropinocytosis. Furthermore, BLCN displayed a significant neuroprotective effect on HT22 cells in glutamate-, corticosterone-, and H 2 O 2 -induced models. Tissue fluorescence image analysis of mice showed that BLCN exhibited substantial retention of fluorescent DiR in the brain after nasal administration for 12 h. These findings suggest that CCT has the potential for cellular uptake, neuroprotection, and targeted delivery to the brain following intranasal administration when encapsulated in Bor and Lf dual-modified nanoliposomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Apocarotenoids have short carbon chain structures cleaved at a polyene-conjugated double bond. They can be biosynthesized in plants and microorganisms. Animals ingest carotenoids through food and then metabolize them into apocarotenoids. Although several apocarotenoids have been identified in the body, their precise health functions are still poorly understood. This study investigated the anti-inflammatory activities of apo-12'-capsorubinal in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. It was confirmed that apo-12'-capsorubinal was not cytotoxic to the macrophages at the concentrations tested. Apo-12'-capsorubinal treatment led to a marked downregulation of interleukin (IL)-6 protein and Il6 mRNA levels. This apocarotenoid exhibited more potent inhibitory effects than its parent carotenoids, capsanthin and capsorubin. Furthermore, apo-12'-capsorubinal, but not its parent carotenoids, promoted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of Nrf2-target genes, such as heme oxygenase 1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1), in a dose-dependent manner. Furthermore, a comparison using apo-12'-zeaxanthinal and 7,8-dihydro-8-oxo-apo-12'-zeaxanthinal revealed that the α, β-unsaturated carbonyl group on the polyene linear chain mediated the enhanced nuclear Nrf2 translocation, HO-1 expression, and inhibition of IL-6 production. In contrast, apo-12'-mytiloxanthinal, which harbored a hydroxyl group at C-8 of apo-12'-capsorubinal, did not exhibit any of these activities. These results indicated that the β carbon of the α, β-unsaturated carbonyl group in the linear part of the polyene chain is crucial to the Nrf2-activating and anti-inflammatory effects of apo-12'-capsorubinal. This study will advance our knowledge of the physiological significance of xanthophyll-derived apocarotenoids and their potential use as nutraceuticals and pharmaceuticals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tomatoes are well known for their impressive nutritional value among vegetables. However, the industrial processing of tomatoes generates a significant amount of waste. Specifically, 10% to 18% of the raw materials used in tomato processing become waste. This waste can seriously affect ecosystems, such as freshwater bodies, wetlands, rivers, and other natural environments, if not properly managed. Interestingly, tomato waste, specifically the skin, contains lycopene, a potent antioxidant and antimutagenic that offers a range of health benefits. This makes it a valuable ingredient in industries such as food and cosmetics. In addition, researchers are exploring the potential of lycopene in the treatment of various types of cancer. This systematic review, guided by the PRISMA 2020 methodology, examined studies exploring the possibility of tomato peel as a source of lycopene and carotenoids for cancer treatment. The findings suggest that tomato peel extracts exhibit promising anticancer properties, underscoring the need for further investigation of possible therapeutic applications. The compiled literature reveals significant potential for using tomato peel to create new cancer treatments, which could potentially revolutionize the field of oncology. This underscores the importance of continued research and exploration, emphasizing the urgency and importance of the scientific community's contribution to this promising area of study.

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., (© 2024. The Author(s).)

Nutraceuticals, that include food ingredients and bioactives from natural products, confer physiological health benefits and protection against chronic diseases. Annatto is a tropical shrub grown in Central and South America and parts of India. Its seeds are rich in the edible carotenoid-derived apocarotenoid pigment, bixin, which is used as a natural colorant in food, textiles, and cosmetics, and is now gaining attention for its potential health-promoting attributes. Here, we compared a green solvent (ethyl lactate) based extraction of bixin and associated metabolites in annatto seeds (crushed and seed coat) with two other conventional solvents (acetone and acid-base). Bixin was characterized in the extracts using UV-visible- and FTIR-spectroscopy and thin-layer chromatography. The bixin-containing solvent extracts were then profiled for other co-existing metabolites using GC-MS analysis, which were found to be sesquiterpenes, terpenes, terpenoids, phytosterols, and tocotrienols. Their bioactivity was evaluated based on antioxidant and wound-healing efficacies and compared with pure bixin, using NIH-3T3 fibroblast cells in-vitro. Pure bixin, as well as the annatto solvent extracts, showed strong antioxidant and wound healing properties, wherein pure bixin and green solvent extract (ethyl lactate coat) exhibited higher levels of antioxidant activity, achieving 46.00% and 44.60% reduction in MDA levels, respectively, as well as enhanced wound-healing activity, with 54.09% and 53.60% wound closure within 24 h. The green solvent extracts of annatto seeds revealed: (a) differential bioactive profiles in annatto seeds (crushed and seed coat) in comparison with other solvents, and (b) strong antioxidant and wound healing properties. Thus, ethyl lactate extraction shows strong potential for sustainable environmental friendly production of functional foods/nutraceuticals from annatto seeds.

Background: Autophagy is recognized as a promising therapeutic target for traumatic brain injury (TBI). Crocetin is an aglycone of crocin naturally occurring in saffron and has been found to alleviate brain injury diseases. However, whether crocetin affects autophagy after TBI remains unknown. Therefore, we explore crocetin roles in autophagy after TBI., Methods: We used a weight-dropped model to induce TBI in C57BL/6J mice. Neurological severity scoring (NSS) and grip tests were used to evaluate the neurological level of injury. Brain edema, neuronal apoptosis, neuroinflammation and autophagy were detected by measurements of brain water content, TUNEL staining, ELISA kits and western blotting., Results: Crocetin ameliorated neurological dysfunctions and brain edema after TBI. Crocetin reduced neuronal apoptosis and neuroinflammation and enhanced autophagy after TBI., Conclusion: Crocetin alleviates TBI by inhibiting neuronal apoptosis and neuroinflammation and activating autophagy.

Crocins are bioactive glucosylated apocarotenoids that confer a yellow pigmentation. In addition to their coloring ability, crocins offer potential health benefits because of their antioxidant and anti-inflammatory properties. These compounds are present in the flowers and fruits of a few plant species, including saffron, gardenia, Buddleja and Verbascum species. Saffron extracts have been used for the formulation of functional foods. However, there is no evidence of the use of the other plants producing crocins in the food industry. This study evaluated the effect of the addition of ground dry flowers of two Verbascum species, with antioxidant activity, as well as dry fruit powder, from a recently engineered tomato plant producing fruits that accumulate high levels of crocins, as functional ingredients during the processing of rice, wheat cous-cous and maize noodles, providing a yellow pigmentation. Correlation analyses revealed that the increased antioxidant activity in the three food matrices was due to the presence of crocins, which showed no toxicity. Furthermore, in vitro digestion showed that crocins were more bioaccessible from rice than from cous-cous or maize noodles, inferring the importance of the food matrix in bio accessibility. The obtained results showed the commercial potential of Verbascum 's flowers, as a source of crocins, natural pigments with antioxidant activities.

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-β1-induced fibroblast activation and regulated the pulmonary arterial fibroblast MMP2/TIMP1 balance by inhibiting the TGF-β1/Smad3 signaling pathway. In summary, our results indicate that crocin attenuates hypoxia-induced pulmonary hypertension in mice by inhibiting TGF-β1-induced myofibroblast activation., (© 2024. The Author(s).)

Introduction: Since the drug resistance in Candida species is becoming a serious clinical challenge, novel alternative therapeutic options, particularly herbal medicine, have attracted increasing interest. This study aimed to pinpoint the potential antifungal activity of crocin (Cro), the efficacy of the niosomal formulation of Cro (NCro), and the synergistic activity of both formulations in combination with fluconazole (FLC) against susceptible and resistant C. albicans isolates., Material and Methods: NCro was formulated using the heating method. The in vitro antimycotic activity of Cro, NCro, and FLC was evaluated. Checkerboard and isobologram assays evaluated the interaction between both formulations of Cro and FLC. Necrotic and apoptotic effects of different agents were analyzed using the flow cytometry method. In silico study was performed to examine the interactions between Lanosterol 14 alpha-demethylase and Cro as a part of our screening compounds with antifungal properties., Results: NCro exhibited high entrapment efficiency up to 99.73 ± 0.54, and the mean size at 5.224 ± 0.618 µm (mean ± SD, n = 3). Both formulations of Cro were shown to display good anticandidal activity against isolates. The synergistic effect of the NCro in combination with FLC is comparable to Cro (P-value =0.03). Apoptotic indicators confirmed that tested compounds caused cell death in isolates. The docking study indicated that Cro has interactivity with the protein residue of 14α-demethylase., Conclusion: The results showed a remarkable antifungal effect by NCro combined with FLC. Natural compounds, particularly nano-sized carrier systems, can act as an effective therapeutic option for further optimizing fungal infection treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 SFMM. Published by Elsevier Masson SAS. All rights reserved.)

The antioxidant properties of crocin are attracting interest, yet the underlying mechanisms by which crocin mitigates oxidative stress-induced intestinal damage have not been determined. This study aimed to elucidate the effects of crocin on oxidative stress, apoptosis, and intestinal epithelial injury in intestinal epithelial cells (IPEC-J2). Using an H 2 O 2 -induced oxidative stress model in IPEC-J2 cells, crocin was added to assess its effects. Cell viability and apoptosis were evaluated using methyl thiazolyl tetrazolium assays and flow cytometry. Additionally, oxidative stress markers, such as superoxide dismutase (SOD), catalase (CAT), reactive oxygen species (ROS), and malondialdehyde (MDA), were quantified. We investigated, in which cell oxidation and apoptosis were measured at the gene and protein levels and employed transcriptome analysis to probe the mechanism of action and validate relevant pathways. The results showed that crocin ameliorates H 2 O 2 -induced oxidative stress by reducing ROS and MDA levels and by countering the reductions in CAT, total antioxidant capacity, and SOD. Crocin also attenuates the upregulation of key targets in the Nrf2 pathway. Furthermore, it effectively mitigated IPEC-J2 cell apoptosis caused by oxidative stress, as evidenced by changes in cell cycle factor expression, apoptosis rate, mitochondrial membrane potential, and apoptosis pathway activity. In addition, crocin preserves the integrity of the intestinal barrier by protecting tight junction proteins against oxidative stress. Transcriptome sequencing analysis suggested that the mitochondrial pathway may be a crucial mechanism through which crocin exerts its protective effects. In summary, crocin decreases oxidative stress molecule formation, inhibits Nrf2 pathway activity, prevents apoptosis-induced damage, enhances oxidative stress resistance in IPEC-J2 cells, and maintains redox balance in the pig intestine., (© 2024 Wiley Periodicals LLC.)

Rapid-eye movement (REM) sleep deprivation (SD) can induce manic-like behaviors including hyperlocomotion. On the other hand, crocin (one of the main compounds of Crocus sativus L. or Saffron) may be beneficial in the improvement of mental and cognitive dysfunctions. Also, crocin can restore the deleterious effects of SD on mental and cognitive processes. In this study, we investigated the effect of REM SD on female rats' behaviors including depression- and anxiety-like behaviors, locomotion, pain perception, and obsessive-compulsive-like behavior, and also, the potential effect of crocin on REM SD effects. We used female rats because evidence on the role of REM SD in modulating psychological and behavioral functions of female (but not male) rats is limited. REM SD was induced for 14 days (6h/day), and crocin (25, 50, and 75 mg/kg) was injected intraperitoneally. Open field test, forced swim test, hot plate test, and marble burying test were used to assess rats' behaviors. The results showed REM SD-induced manic-like behavior (hyperlocomotion). Also, REM SD rats showed decreased anxiety- and depression-like behavior, pain subthreshold (the duration it takes for the rat to feel pain), and showed obsessive compulsive-like behavior. However, crocin at all doses partially or fully reversed REM SD-induced behavioral changes. In conclusion, our results suggested the possible comorbidity of OCD and REM SD-induced manic-like behavior in female rats or the potential role of REM SD in the etiology of OCD, although more studies are needed. In contrast, crocin can be a possible therapeutic choice for decreasing manic-like behaviors., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Lycopene as a natural antioxidant that have been studied for ultraviolet radiation (UVR) photo protection and is one of the most effective carotenoids to scavenge reactive oxygen species (ROS). This review aims to summarize the protective effect of tomato and lycopene on skin photo damage and skin photoaging in healthy subjects by reviewing the existing population intervention experiments. A total of five electronic databases including PubMed, Scopus, EBSCO, Web of Science and Cochrane Library were searched from inceptions to January 2021 without any restriction. Out of 19336 publications identified, 21 fulfilled the inclusion criteria and were meta-analysis. Overall, interventions supplementing tomato and lycopene were associated with significant reductions in Δa*, MMP-1, ICAM-1 and skin pigmentation; while tomato and lycopene supplementation were associated with significant increase in MED, skin thickness and skin density. Based on the results of this systematic review and meta-analysis, supplementation with tomato and lycopene could reduce skin erythema formation and improve the appearance and pigmentation of the skin, thereby preventing light-induced skin photodamage and skin photoaging. Lycopene-rich products could be used as endogenous sun protection and may be a potential nutraceutical for sun protection.

Background: Ischemia reperfusion (I/R) injury is a frequent occurrence during liver transplantation surgery, resulting from the temporary cessation of blood flow and subsequent restoration of blood flow. Serious I/R injury is a significant factor causing transplant failure. Hepatic I/R process is characterized by excessive inflammation, oxidation, and apoptosis. Crocetin (Crt) is a natural compound exhibiting beneficial roles in various I/R-induced organ damages. However, Crt's potential role in hepatic I/R remains unexplored., Objective and Methods: In order to reveal the impact of Crt on hepatic I/R and the associated signaling pathway, we utilized a syngeneic orthotopic liver transplantation rat model to induce hepatic I/R injury., Results: Pretreatment with Crt significantly mitigated hepatic I/R injury. This was evident by decreased activities of serum ALT, AST and LDH, indicating improved liver function. Crt treatment also alleviated oxidative stress, as demonstrated by decreased serum MDA content and elevated serum SOD and GSH-Px activities. Furthermore, Crt suppressed inflammatory responses by downregulating both the serum and liver IL-1β, IL-6 and TNF-α while upregulating IL-10 expression. Additionally, Crt reduced apoptosis by decreasing pro-apoptotic Bax, cleaved caspase-3 and cleaved caspase-9, while increasing anti-apoptotic Bcl2 expression. Notably, these protective effects of Crt were dose-dependent. Moreover, our data indicates that Crt plays protective functions during hepatic I/R via disrupting Keap1/Nrf2 interaction and activating Nrf2/HO-1 signaling. This was further supported by observations of alleviated hepatic histopathological changes in I/R rats treated with Crt., Conclusions: Crt shows potential as a therapeutic agent for preventing hepatic I/R injury during clinical liver transplantation., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Social isolation is a reliable method used for the induction of depression and psychiatric disorders in rodents. It has been suggested that social isolation can lead to hyperlocomotion, as a schizophrenic-like symptom in rodents. On the other hand, crocin (the major constituent of Crocus sativus) induces a wide-range of neuroprotective and mood enhancer effects. In the present study, we aimed to investigate the effect of acute crocin on social isolation-induced behavioral changes and BDNF expression in the hippocampus. Novelty-suppressed feeding test, open field test, marble burying test, hot plate, forced swim test, and the shuttle box were used to assess anxiety-like behavior, locomotor activity, obsessive-compulsive-like (OCD-like) behavior, pain threshold, depressive-like behavior, and passive avoidance memory, respectively. Real-time PCR was used to assess BDNF hippocampal expression level. The results showed that social isolation decreased anxiety- and depressive-like behavior, pain threshold, and BDNF expression, and induced OCD-like behavior and hyperlocomotion. Crocin dose-dependently restored the effect of social isolation on pain threshold, locomotor activity, depressive-like behavior, OCD-like behavior, and BDNF expression. Passive avoidance memory performance was also unaffected. In conclusion, we showed a hyperlocomotion profile and OCD-like behaviors, and a robust decrease in pain threshold in socially isolated rats. It can be suggested that social isolation from adolescence induces a "hyperlocomotion state" that affects all the behavioral functions of rats. Also, the function of BDNF can be related to a hyperlocomotion state and OCD-like symptom. It seems that BDNF expression level can be related to the therapeutic effect of crocin., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The effect of Crocus sativus on several disorders has been discussed or even confirmed, but the efficacy of this herb on the female reproductive system has not been well presented. In this regard, this systematic review comprehensively discussed the efficacy of C. sativus and its main phytochemical compounds on the female reproductive system and its disorders for the first time. In this systematic review, scientific databases, including PubMed, Web of Sciences, Google Scholar, Scopus, and Scientific Information Database, were explored profoundly. In vivo, in vitro, and human studies published until the end of July 2023, which had investigated the pharmacological properties of C. sativus, crocin, crocetin, safranal, or picrocrocin on the female reproductive system, were selected. A total of 50 studies conducted on the effect of C. sativus on the female reproductive system were acquired. These studies confirmed the efficacy of C. sativus or its main phytochemical ingredients in several aspects of the female reproductive system, including regulation of sex hormones, folliculogenesis, ovulation, and protection of the ovary and uterus against several oxidative stress. Several retrieved studies indicated that this herb also can alleviate the symptoms of patients suffering from dysmenorrhea, premenstrual syndrome, menopause, polycystic ovary disease (PCOD), and sexual dysfunction. Furthermore, it is a promising candidate for future studies or even trials regarding ovarian and cervical cancers. This review concluded that C. sativus can improve the symptoms of several female reproductive system disorders, which is particularly due to the presence of phytochemical ingredients, such as crocin, crocetin, and safranal., (© 2024 John Wiley & Sons Ltd.)

Multiple sclerosis (MS) is an autoimmune disorder characterized by the degeneration of myelin and inflammation in the central nervous system. Trans sodium crocetinate (TSC), a novel synthetic carotenoid compound, possesses antioxidant, anti-inflammatory and neuroprotective effects. This study aimed to evaluate the protective effects of TSC against the development of experimental autoimmune encephalomyelitis (EAE), a well-established model for MS. Female BALB/C57 mice were divided into different groups, including control, EAE, vehicle, TSC-treated (25, 50, and 100 mg/kg, administered via gavage) + EAE, methyl prednisone acetate + EAE, and TSC-treated (100 mg/kg, administered via gavage for 28 days) groups. EAE was induced using MOG35-55, complete Freund's adjuvant, and pertussis toxin. In the mice spinal cord tissues, the oxidative markers (GSH and MDA) were measured using spectrophotometry and histological evaluation was performed. Mitophagic pathway proteins (PINK1and PARKIN) and inflammatory factors (IL-1β and TNF-α) were evaluated by western blot. Following 21 days post-induction, EAE mice exhibited weight loss, and the paralysis scores increased on day 13 but recovered after TSC (100 mg/kg) administration on day 16. Furthermore, TSC (50 and 100 mg/kg) reversed the altered levels of MDA and GSH in the spinal cord tissue of EAE mice. TSC (100 mg/kg) also decreased microgliosis, demyelination, and the levels of inflammatory markers IL-1β and TNF-α. Notably, TSC (100 mg/kg) modulated the mitophagy pathway by reducing PINK1 and Parkin protein levels. These findings demonstrate that TSC protects spinal cord tissue against EAE-induced MS through anti-inflammatory, antioxidant, and anti-mitophagy mechanisms., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Biochemical and physical changes during the cryopreservation process adversely affect sperm function required for fertilization. Recently, many studies have been conducted to find effective pre-freezing treatments to limit these damages. The present study aimed to investigate the effects of pre-freezing treatment with quercetin and crocin, individually or in combination, on sperm parameters after thawing procedure. For this, semen samples from 20 normozoospermic men were collected and then each sample was divided into five equal parts: 1. fresh group 2. frozen-thawed group without addition of antioxidants 3. frozen-thawed group containing 1 mM crocin, 4. frozen-thawed group containing 50 μM quercetin, and 5. frozen-thawed group containing a combination of 1 mM crocin and 50 μM quercetin. Pre-cryopreservation and post-thaw sperm motility, morphology, viability, DNA fragmentation, reactive oxygen species [1] (ROS) levels, and mitochondrial membrane potential [2] (MMP) were investigated. Cryopreservation significantly reduced sperm quality. Both crocin and quercetin individually improved sperm progressive motility, decreased ROS levels, reduced DNA fragmentation, and marginally increased MMP, though crocin seems to be more successful in protecting sperm quality. More interestingly, the combined addition of crocin and quercetin to the sperm-freezing medium did not show positive effects on sperm quality. Crocin and quercetin may play a role in mitigating the cryopreservation-induced injury to sperm., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

The ideal and highly anticipated dressing for skin wounds should provide a moist environment, possess antibacterial properties, and ensure sustained drug release. In the present work, a hyaluronic acid-based hydrogel was formed by cross-linking crocetin and CaCO 3 @polyelectrolyte materials (CaCO 3 @PEM) microspheres with HA hydrogels via hydrogen bond and amido bonding (CaCO 3 @PEM@Cro@HA hydrogel, CPC@HA hydrogel). Moreover, the CPC@HA hydrogel had the capability of sustained, controlled release of calcium ions and crocetin via pH-sensitive and accelerated skin wound healing. The experiment results showed that the CPC@HA hydrogel exhibited porous network structures, stable physical properties, and had antibacterial properties and biocompatibility in vitro. In addition, the CPC@HA hydrogel covering on the skin wound could reduce inflammation and promote wound healing. The high expression of angiogenic cytokines (CD31) and epidermal terminal differentiation markers (Loricrin) of wound healing tissue suggested the CPC@HA hydrogel also had the function of promoting the remodeling of regenerated skin. Overall, CPC@HA hydrogel has promising potential for clinical applications in accelerating skin wound repair., (© 2024 Wiley-VCH GmbH.)

Staphylococcus aureus and Staphylococcus epidermidis stand as notorious threats to human beings owing to the myriad of infections they cause. The bacteria readily form biofilms that help in withstanding the effects of antibiotics and the immune system. Intending to combat the biofilm formation and reduce the virulence of the pathogens, we investigated the effects of carotenoids, crocetin, and crocin, on four Staphylococcal strains. Crocetin was found to be the most effective as it diminished the biofilm formation of S. aureus ATCC 6538 significantly at 50 µg/mL without exhibiting bactericidal effect (MIC >800 µg/mL) and also inhibited the formation of biofilm by MSSA 25923 and S. epidermidis at a concentration as low as 2 µg/mL, and that by methicillin-resistant S. aureus MW2 at 100 µg/mL. It displayed minimal to no antibiofilm efficacy on the Gram-negative strains Escherichia coli O157:H7 and Pseudomonas aeruginosa as well as a fungal strain of Candida albicans . It could also curb the formation of fibrils, which partly contributes to the biofilm formation in S. epidermidis . Additionally, the ADME analysis of crocetin proclaims how relatively non-toxic the chemical is. Also, crocetin displayed synergistic antibiofilm characteristics in combination with tobramycin. The presence of a polyene chain with carboxylic acid groups at its ends is hypothesized to contribute to the strong antibiofilm characteristics of crocetin. These findings suggest that using apocarotenoids, particularly crocetin might help curb the biofilm formation by S. aureus and S. epidermidis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Paramanya, Lee and Lee.)

Background: Crocin has a good prospect in the treatment of Alzheimer's disease (AD), but the mechanisms underlying its neuroprotective effects remain elusive. This study aimed to investigate the neuroprotective effects of Crocin and its underlying mechanisms in AD., Methods: AD mice were set up by injecting Aβ 25-35 solution into the hippocampus. Then, the AD mice were injected intraperitoneally with 40 mg/kg/day of Crocin for 14 days. Following the completion of Crocin treatment, an open-field test, Y-maze test and Morris water maze test were conducted to evaluate the impact of Crocin on spatial learning and memory deficiency in mice. The effects of Crocin on hippocampal neuron injury, proinflammatory cytokine expressions (IL-1β, IL-6, and TNF-α), and PI3K/AKT signaling-related protein expressions were measured using hematoxylin and eosin staining, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) experiments, respectively., Results: Crocin attenuated Aβ 25-35 -induced spatial learning and memory deficiency and hippocampal neuron injury. Furthermore, the Western blot and qRT-PCR results showed that Crocin effectively suppressed inflammation and activated the PI3K/AKT pathway in Aβ 25-35 -induced mice., Conclusion: Crocin restrained neuroinflammation via the activation of the PI3K/AKT pathway, thereby ameliorating the cognitive dysfunction of AD mice., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Saffron is a spice derived from the flower of Crocus sativus L., which has been used for centuries as a coloring and flavoring agent, as well as a source of medicinal compounds. Saffron contains various bioactive constituents, such as crocin, crocetin, safranal, picrocrocin, and kaempferol, that have shown potential benefits for human health. Among them, crocin is the most abundant and characteristic constituent of saffron, responsible for its bright red color and antioxidant properties. One of the most promising applications of saffron and its constituents is in the prevention and treatment of neurological disorders, such as depression, anxiety, Alzheimer's disease, Parkinson's disease, and other brain disorders. Saffron and its constituents have been reported to exert neuroprotective effects through various mechanisms, such as modulating neurotransmitters, enhancing neurogenesis, reducing neuroinflammation, regulating oxidative stress, activating the Nrf2 signaling pathway, and modulating epigenetic factors. Several clinical and preclinical studies have demonstrated the efficacy and safety of saffron and its constituents in improving cognitive function, mood, and other neurological outcomes. In this review, we summarize the current evidence on the therapeutic potential of saffron and its constituents in neurological disorders, from bench to bedside. We also discuss the challenges and future directions for the development of saffron-based therapies for brain health., (© 2024 John Wiley & Sons Ltd.)

Halophilic archaea, also termed haloarchaea, are a group of moderate and extreme halophilic microorganisms that constitute the major microbial populations in hypersaline environments. In these ecosystems, mainly aquatic, haloarchaea are constantly exposed to ionic and oxidative stress due to saturated salt concentrations and high incidences of UV radiation (mainly in summer). To survive under these harsh conditions, haloarchaea have developed molecular adaptations including hyperpigmentation. Regarding pigmentation, haloarchaeal species mainly synthesise the rare C 50 carotenoid called bacterioruberin (BR) and its derivatives, monoanhydrobacterioruberin and bisanhydrobacterioruberin. Due to their colours and extraordinary antioxidant properties, BR and its derivatives have been the aim of research in several research groups all over the world during the last decade. This review aims to summarise the most relevant characteristics of BR and its derivatives as well as describe their reported antitumoral, immunomodulatory, and antioxidant biological activities. Based on their biological activities, these carotenoids can be considered promising natural biomolecules that could be used as tools to design new strategies and/or pharmaceutical formulas to fight against cancer, promote immunomodulation, or preserve skin health, among other potential uses.

Until non-hormonal therapeutic targets for endometriosis are suggested, we focused on mitochondrial function and autophagy regulation in the disease. Transcrocetin is a carotenoid and retinoic acid with high antioxidant potency and antiproliferative effects in several diseases. In this study, we demonstrated the therapeutic mechanisms of transcrocetin in endometriosis using the End1/E6E7 and VK2/E6E7 cell lines. Transcrocetin suppressed the viability and proliferation of these cell lines and did not affect the proliferation of normal uterine stromal cells. p21 Waf1/Cip1 as a cell cycle regulator and target of p53, were increased by transcrocetin and caused the G1 arrest via inhibition of cyclin-dependent kinase activity, which might further cause cell death. Furthermore, we confirmed endoplasmic reticulum stress and calcium ion dysregulation in the cytosol and mitochondrial matrix, disrupting the mitochondrial membrane potential. Mitochondrial bioenergetics were suppressed by transcrocetin, and oxidative phosphorylation-related gene expression was downregulated. Moreover, the proliferation of End1/E6E7 and VK2/E6E7 cells was regulated by transcrocetin-induced oxidative stress. Finally, we verified the impairment of autophagic flux following pre-treatment with chloroquine. Therefore, transcrocetin may be a potent therapeutic alternative for endometriosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chemical-based carotenoids have large implications to health as they may cause adverse side effects. Naturally occurring carotenoids mainly from microalgal sources are emerging as excellent substitute to combat cancer diseases. Astaxanthin is the most powerful antioxidant that derived from selected established microalgae with limited yield. Microalgal bioprospecting may provide the high-yielding sources for astaxanthin production. Hence, in the present research, freshwater microalgae Monoraphidium sp. (NCM no. 5585) and Scenedesmus obliquus (NCM no. 5586) were chosen to explore the unique potential of producing astaxanthin. Identification of bioactive metabolites in extracted carotenoid was analyzed through HPLC. Astaxanthin is identified as a major bioactive metabolite in both carotenoid fraction and β carotene only in Scenedesmus obliquus. Antioxidant potential of microalgal carotenoids was obtained by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) and Ferric-reducing antioxidant power (FRAP) assay. The anti-proliferation activity of the extracted carotenoid from Monoraphidium sp. and Scenedesmus obliquus was evaluated against hepatocellular liver carcinoma cell line HUH7 by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) colorimetric assay. Higher astaxanthin in Monoraphidium sp. leads to boosted antioxidant and anti-proliferation activity contrary to Scenedesmus obliquus that possess both astaxanthin and β carotene. Though freshwater microalgae have a huge potential to create beneficial metabolites like carotenoids, they are rarely studied in the pharmaceutical industry. This work was the first to investigate the anti-proliferative activity of Monoraphidium sp. and Scenedesmus obliquus carotenoid fraction on the HUH7 hepatocarcinoma cell line., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Bisphenol A (BPA) engenders testicular toxicity via hydroxyl free radical genesis in rat striatum and depletion of the endogenous antioxidants in the epididymal sperms. The multi-drug resistance efflux carrier; P-glycoprotein (P-gp) expel the BPA from the testis and is responsible for the testicular protection through the deactivation of numerous xenobiotics. In our study, we investigated whether the BPA-induced testicular toxicity could be circumvented through administration of an antioxidant; crocin (Cr). Implication of P-gp expression was also investigated. Rats administered BPA (10 mg/kg b.w. orally for 14 days), dropped the body weight, testes/body weight ratio, total protein content, testosterone, follicle stimulating hormone, luteinizing hormone, and sperm motility & count, total antioxidant status, glutathione content and antioxidant enzymes (superoxide dismutase and catalase), concomitant with the elevation of the percentage abnormal sperm morphology, as well as testicular lipid peroxides and nitrite/nitrate levels. Histopathological examination showed spermatogenesis disorders after the BPA rats exposure. The immunohistochemical study showed up-regulation of the P-gp as evident by increasing immunoreactivity in interstitial cells, with positive localization in some spermatogonia cells. The BPA-treated rats showed positive immunoreactivity against caspase-3. The co-intake of Cr (200 mg/kg b.w./day, i.p. 14 days) along with the BPA, significantly ameliorated all the mentioned parameters, boosted histopathological image, fell the caspase-3 up-regulation, and perched the P-gp expression. We showed that, Cr promotes P-gp as an approach to nurture the testicles against the BPA toxicity. In conclusion; Cr lessens the oxidative stress conditions to safeguard rats from the BPA-induced testicular toxicity and sex hormones abnormalities, reducing apoptosis and up-regulating P-gp., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Crocin is a major class of medicinal components in saffron. This study aimed to determine whether crocin directly promotes the proliferation and osteogenic differentiation of human periodontal ligament stem cells (PDLSCs) in vitro and in vivo., Materials and Methods: CCK8 cell proliferation assay, reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot analysis and Alizarin Red staining were performed in PDLSCs using crocin as a stimulant. DKK1 was used to selectively inhibit Wnt/β-catenin signaling, and Western blotting was performed to investigate the underlying mechanism. The PDLSCs were mixed with calcium phosphate cement and implanted into nude mice subcutaneously to study the effect of crocin on PDLSC osteogenic differentiation in vivo., Results: The CCK-8 assay showed that crocin did not promote the proliferation of PDLSCs. Treatment with 400 μM crocin significantly promoted PDLSC mRNA levels of ALP, COL1 and OCN; RUNX2 and BMP2 protein expression; mineralized nodule formation in vitro and in vivo; and ALP activity in tissues in vivo. In addition, crocin significantly promoted the phosphorylation of β-catenin and cyclin D1. DKK1 inhibits Wnt/β-catenin activation and partially reverses crocin-mediated promotion of PDLSC osteogenic differentiation., Conclusion: Crocin may contribute to the regeneration of periodontal bone tissue., (© 2023 Wiley Periodicals LLC.)

Mauritia flexuosa, known as buriti in Brazil, is a widespread palm tree in Amazonia. It has many ethnobotanical uses, including food, oil, and medicine. The oil obtained from buriti's fruit pulp has high levels of monounsaturated fatty acids, carotenoids, and tocopherols, and is used in the food, cosmetic, and pharmaceutical industries for its antioxidant properties. Many biological activities have been reported for buriti oil, such as antioxidant, antimicrobial, chemopreventive, and immunomodulatory. Due to its high content of bioactive compounds, buriti oil is considered a functional ingredient with possible benefits in preventing oxidative stress and chronic diseases, particularly in the gastrointestinal tract. Peptic ulcer disease is a multifactorial disorder, involving lesions in the stomach and duodenum mucosa, which has a complex healing process. In this context, some nutrients and bioactive compounds help the maintenance of gastrointestinal mucosal integrity and function, such as carotenoids, tocopherols, and unsaturated fatty acids, which makes buriti oil an interesting candidate to be used in the prevention and management of gastrointestinal diseases. This study aimed to evaluate the gastroprotective and antiulcer effects of buriti oil and its possible mechanisms of action. Buriti oil reduced the ulcerative area and lipid peroxidation induced by ethanol. The gastroprotective activity of buriti oil partially depends on nitric oxide and sulfhydryl compounds. In acetic acid-induced gastric ulcers, buriti oil accelerated healing and stimulated the formation of new gastric glands. These results demonstrated the potential of buriti oil as a functional ingredient to promote health benefits in the gastrointestinal tract., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Shrimp processing generates substantial waste, which is rich in valuable components such as polysaccharides, proteins, carotenoids, and fatty acids. This review provides a comprehensive overview of the valorization of shrimp waste, mainly shrimp shells, focusing on extraction methods, bioactivities, and potential applications of these bioactive compounds. Various extraction techniques, including chemical extraction, microbial fermentation, enzyme-assisted extraction, microwave-assisted extraction, ultrasound-assisted extraction, and pressurized techniques are discussed, highlighting their efficacy in isolating polysaccharides, proteins, carotenoids, and fatty acids from shrimp waste. Additionally, the bioactivities associated with these compounds, such as antioxidant, antimicrobial, anti-inflammatory, and antitumor properties, among others, are elucidated, underscoring their potential in pharmaceutical, nutraceutical, and cosmeceutical applications. Furthermore, the review explores current and potential utilization avenues for these bioactive compounds, emphasizing the importance of sustainable resource management and circular economy principles in maximizing the value of shrimp waste. Overall, this review paper aims to provide insights into the multifaceted aspects of shrimp waste valorization, offering valuable information for researchers, industries, and policymakers interested in sustainable resource utilization and waste-management strategies.

Nicotine is a psychostimulant that induces neurochemical and behavioral changes upon chronic administration, leading to neurodegenerative conditions associated with smoking. As of now, no preventive or therapeutic strategies are known to counteract nicotine‑induced neurodegeneration. In this study, we explore the neuroprotective effects of crocin, a bioactive agent commonly found in saffron - a spice derived from the flower of Crocus sativus - using a rat model. The dose‑dependent effects of crocin were evaluated in nicotine‑induced neurodegeneration and compared with a control group. Neurobehavioral changes, assessed through the elevated plus maze, the open field test, the forced swim test, and the Morris water maze, as well as oxidative stress in the hippocampus, were evaluated. Interestingly, nicotine administration resulted in depression, anxiety, and abnormal motor and cognitive functions, while crocin treatment protected the rat brain from these abnormalities. The beneficial effects of crocin were associated with reduced oxidative stress biomarkers such as malondialdehyde, along with increases in superoxide dismutase, glutathione peroxidase, and glutathione reductase activities. These results demonstrate that crocin can mitigate nicotine‑induced neurodegeneration by reducing oxidative stress, potentially offering a protective measure against neurodegenerative effects in smokers.

Sericin derived from the white cocoon of Bombyx mori has been attracting more attention for its utilization in food, cosmetics, and biomedicine. The potential health benefits of natural carotenoids for humans have also been well-established. Some rare strains of Bombyx mori ( B. mori ) produce yellow-red cocoons, which endow a potential of natural carotenoid-containing sericin. We hypothesized that natural carotenoid-containing sericin from yellow-red cocoons would exhibit better properties compared with white cocoon sericin. To investigate the physicochemical attributes of natural carotenoid-containing sericin, we bred two silkworm strains from one common ancestor, namely XS7 and XS8, which exhibited different cocoon colors as a result of the inconsistent distribution of lutein and β-carotene. Compared with white cocoon sericin, the interaction between carotenoids and sericin molecules in carotenoid-containing sericin resulted in a unique fluorescence emission at 530, 564 nm. The incorporation of carotenoids enhanced the antibacterial effect, anti-cancer ability, cytocompatibility, and antioxidant of sericin, suggesting potential wide-ranging applications of natural carotenoid-containing sericin as a biomass material. We also found differences in fluorescence characteristics, antimicrobial effects, anti-cancer ability, and antioxidants between XS7 and XS8 sericin. Our work for the first time suggested a better application potential of natural carotenoid-containing sericin as a biomass material than frequently used white cocoon sericin.

Pigmented corn is a gramineae food of great biological, cultural and nutritional importance for many Latin American countries, with more than 250 breeds on the American continent. It confers a large number of health benefits due to its diverse and abundant bioactive compounds. In this narrative review we decided to organize the information on the nutrients, bioactive compounds and phytochemicals present in pigmented corn, as well as their effects on human health. Phenolic compounds and anthocyanins are some of the most studied and representative compounds in these grasses, with a wide range of health properties, mainly the reduction of pro-oxidant molecules. Carotenoids are a group of molecules belonging to the terpenic compounds, present in a large number of pigmented corn breeds, mainly the yellow ones, whose biological activity incorporates a wide spectrum. Bioactive peptides can be found in abundance in corn, having very diverse biological effects that include analgesic, opioid and antihypertensive activities. Other compounds with biological activity found in pigmented corn are resistant starches, some fatty acids, phytosterols, policosanols, phospholipids, ferulic acid and phlobaphenes, as well as a great variety of vitamins, elements and fibers. This review aims to disseminate and integrate the existing knowledge on compounds with biological activity in pigmented corn in order to promote their research, interest and use by scientists, nutrition professionals, physicians, industries and the general population.