crocin and Inflammation

Chronic stress and high levels of glucocorticoids produce functional and structural changes in brain and especially in the hippocampus, an important limbic system structure that plays a key role in cognitive functions including learning and memory. Alzheimer's disease (AD) is a chronic neurodegenerative disease that usually starts slowly and worsens over time. Indeed, cognitive dysfunction, neuronal atrophy, and synaptic loss are associated with both AD and chronic stress. Recent preclinical and clinical studies have highlighted a possible link between chronic stress, cognitive decline and the development of AD. It is suggested that Tau protein is an essential mediator of the neurodegenerative effects of stress and glucocorticoids towards the development of AD pathology. Recent findings from animal and humans studies demonstrated that saffron and its main constitutive crocin are effective against chronic stress-induced cognitive dysfunction and oxidative stress and slowed cognitive decline in AD. The inhibitory actions on acetylcholinesterase activity, aggregation of beta-amyloid protein into amyloid plaques and tau protein into neurofibrillary tangles, and also the antioxidant, anti-inflammatory, and the promotion of synaptic plasticity effects are among the possible mechanisms to explain the neuroprotective effects of saffron. New evidences demonstrate that saffron and its main component crocin might be a promising target for cognition improvement in AD and stress-related disorders.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Antioxidants; Brain; Carotenoids; Cholinesterase Inhibitors; Chronic Disease; Cognition; Crocus; Humans; Inflammation; Nootropic Agents; Oxidative Stress; Phosphorylation; Risk Factors; Stress, Psychological; tau Proteins

Crocin, a water-soluble carotenoid, is known as a pharmacologically active compound, particularly for its potent anti-oxidant activity. The present work provides a comprehensive review of the available literature concerning the anti-inflammatory properties of crocin in various organs/systems as well as its anti-nociceptive effects. PubMed, Scopus, and Web of Science electronic databases were systematically searched up to 28 March 2020 to detect all relevant preclinical and human studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. In total, 104 studies were included for qualitative synthesis. This systematic search and review indicated that crocin not only combats reactive oxygen species production and suppresses pro-inflammatory cytokines secretion but also alleviates inflammation in various organs (e.g. the lung, heart, brain, and kidney), in a series of animal models and in vitro experiments, via regulating mainly NF-κB pathway and NF-κBp65 translocation to the cell nucleus. In this context, modulation of PI3K/Akt appears to be a favorable crocin target contributing to NF-κB pathway inhibition. Even though data is limited in humans with only one clinically relevant study retrieved, the results of preclinical studies regarding anti-inflammatory/anti-nociceptive effects of crocin are promising and warrant further testing in clinical settings.

Topics: Animals; Anti-Inflammatory Agents; Carotenoids; Cytokines; Gene Expression Regulation; Humans; Inflammation; Pain

Neurodegenerative disorders are characterized by mitochondrial dysfunction and subsequently oxidative stress, inflammation, and apoptosis that contribute to neuronal cytotoxicity and degeneration. Recent studies reported that crocin, a carotenoid chemical compound common in crocus and gardenia flowers, has protective effects in neurodegenerative disorders due to its anti-oxidative, anti-inflammatory, and anti-apoptotic properties in the nervous system. This article reviews the new experimental, clinical, and pharmacological studies on the neuroprotective properties of crocin and its potential mechanisms to modulate metabolic oxidative stress and inflammation in neurodegenerative disorders.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Carotenoids; Humans; Inflammation; Neurodegenerative Diseases; Neuroprotective Agents; Oxidative Stress

Polycystic ovary syndrome (PCOS) is a multifactorial reproductive condition common in women of reproductive age. Hyperlipidemia, insulin resistance, obesity, and chronic low-grade inflammation are associated with PCOS. In a clinical trial study, women with PCOS were divided into two groups (n = 25 each): the intervention group receiving crocin (15 mg, twice daily) and the control group receiving a placebo. The duration of intervention in both groups was 12 weeks. Pre- and postintervention, demographic information, lipid profile, fasting blood glucose (FBG), fasting insulin, and inflammatory markers (interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-α]) were measured. Intervention with crocin significantly increased the mean high-density lipoprotein cholesterol postintervention compared to the placebo group, while exerting a suppressive effect on the increase in mean low-density lipoprotein cholesterol, triglycerides, and cholesterol levels. Intervention with crocin also exerted inhibitory effects on changes in FBG and insulin, so that crocin improved insulin and cardioprotective indices. Finally, despite the increased inflammatory markers (IL-6 and TNF-α) in the placebo group, crocin treatment had protective effects on their increased changes. Thus, crocin supplementation could be considered in the therapeutic targets of women with PCOS.

Topics: Biomarkers; Blood Glucose; Carotenoids; Cholesterol, HDL; Dietary Supplements; Double-Blind Method; Female; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Polycystic Ovary Syndrome; Triglycerides; Tumor Necrosis Factor-alpha

Inflammation and oxidative stress is a risk factor for the development of long-term consequences in patients with type 2 diabetes mellitus (T2DM). This study was designed to investigate the effects of crocin consumption on oxidative stress and inflammatory markers in patients with T2DM. In this clinical trial with a parallel-group design, 50 patients with T2DM were randomly assigned to either the crocin or the placebo group. The crocin group received 15 mg crocin twice daily, whereas the placebo group received corresponding placebos. At baseline and the end of week 12, serum high sensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-ɑ (TNF-ɑ), nuclear factor-κB (NF-κB), and malondialdehyde (MDA) were measured. Compared with placebo group, crocin reduced hs-CRP (-1.03 vs. 1.42, p = .007), TNF-ɑ (-0.8 vs. 0.28, p = .009), and NF-κB (-0.39 vs. 0.01, p = .047) after 12 weeks intervention; these improvements were also significant in comparison with the baseline values. Plasma IL-6 decreased significantly in the crocin group at the end of week 12 compared to baseline (p = .037), whereas no significant change was observed in the placebo group. Plasma concentration of MDA did not change within and between groups after intervention. This study indicates that daily administration of 30 mg crocin supplement to patients with T2DM reduces the concentrations of hs-CRP, TNF-ɑ, and NF-κB which are involved in the pathogenesis of complications of T2DM.

Topics: Biomarkers; Carotenoids; Diabetes Mellitus, Type 2; Dietary Supplements; Humans; Inflammation; Oxidative Stress

Multiple sclerosis (MS) is an autoimmune disease in which the immune system attacks the nerve cells, resulting in neurological disorders. Oxidative stress, free radicals, and neuritis have important roles in MS pathogenesis. Here, we aim to evaluate the effect of crocin on inflammatory markers, oxidative damage, and deoxyribonucleic acid (DNA) damage in the blood of patients with MS. A total of 40 patients were divided into two groups, drug and placebo-treated groups, using random assignment. Participants of the intervention and control groups received two crocin capsules or placebo per day for 28 days, respectively. Findings revealed a significant decrease in the level of important pathogenic factors in MS, including lipid peroxidation, DNA damage, tumor necrosis factor-alpha, and interleukin 17 as well as a significant increase in the total antioxidant capacity in the serum of patients treated with crocin compared with the placebo group. Our results suggest the beneficial and therapeutic effects of crocin in MS.

Topics: Adult; Antioxidants; Biomarkers; Carotenoids; Crocus; DNA Damage; Double-Blind Method; Female; Humans; Inflammation; Interleukin-17; Lipid Peroxidation; Male; Multiple Sclerosis; Oxidative Stress; Plant Extracts; Tumor Necrosis Factor-alpha; Young Adult

Ulcerative colitis (UC) is an inflammatory bowel disease with characteristic inflammation to mucosal cells in rectum and colon leading to lesions in mucosa and submucosa. Moreover, crocin is a carotenoid compound among active constituents of saffron with many pharmacological effects as antioxidant, anti-inflammatory and anticancer activities. Therefore, we aimed to investigate therapeutic effects of crocin against UC through affecting the inflammatory and apoptotic pathways. For induction of UC in rats, intracolonic 2 ml of 4% acetic acid was used. After induction of UC, part of rats was treated with 20 mg/kg crocin. cAMP was measured using ELISA. Moreover, we measured gene and protein expression of B-cell lymphoma 2 (BCL2), BCL2-associated X (BAX), caspase-3/8/9, NF-κB, tumor necrosis factor (TNF)-α and IL-1β/4/6/10. Colon sections were stained with hematoxylin-eosin and Alcian blue or immune-stained with anti-TNF-α antibodies. Microscopic images of colon sections in UC group revealed destruction of intestinal glands associated with infiltration of inflammatory cell and severe hemorrhage. While images stained with Alcian blue showed damaged and almost absent intestinal glands. Crocin treatment ameliorated morphological changes. Finally, crocin significantly reduced expression levels of BAX, caspase-3/8/9, NF-κB, TNF-α, IL-1β and IL-6, associated with increased levels of cAMP and expression of BCL2, IL-4 and IL-10. In conclusion, protective of action of crocin in UC is proved by restoration of normal weight and length of colon as well as improvement of morphological structure of colon cells. The mechanism of action of crocin in UC is indicated by activation of anti-apoptotic and anti-inflammatory effects.

Topics: Alcian Blue; Animals; Anti-Inflammatory Agents; Apoptosis; bcl-2-Associated X Protein; Carotenoids; Caspase 3; Colitis, Ulcerative; Colon; Disease Models, Animal; Inflammation; NF-kappa B; Rats; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha

Chronic rhinosinusitis with nasal polyps (CRSwNP) is subdivided into type 1 and type 2 inflammatory responses according to the mucosal inflammatory patterns. Crocin can reduce the level of T-helper type 2 cell (Th2) cytokines, such as interleukin-4 (IL-4), and inhibit the nuclear factor kappa-B (NF-κB) signaling pathway.. This study aimed to investigate the role of group 2 innate lymphoid cells (ILC2s) in type 2 inflammation in eosinophilic nasal polyps and the inhibitory effect of crocin on this inflammation.. Immunohistochemistry and immunofluorescence were used to detect the expression of transcription factors and the infiltration of ILC2s in tissues. An ILC2 stimulation model. Significantly more GATA-binding protein-3 (GATA3)-positive cells and chemoattractant receptor-homologous molecule expressed on T-helper type 2 cell (CRTH2)-positive cells, but fewer T-box expressed in T cell (T-bet)-positive cells, were found in eosinophilic nasal polyps (NPwEos). The expression levels of GATA3 and CRTH2 were significantly higher in NPwEos. Recombinant IL-33 stimulation increased the expression of GATA3, CRTH2, and type 2 cytokines (IL-4, IL-5, and IL-13) in ILC2s. In an IL-33-stimulated. Crocin inhibited type 2 inflammation induced by ILC2 activation at low concentrations via inhibiting the activation of NF-κB.

Topics: Cytokines; Humans; Immunity, Innate; Inflammation; Interleukin-33; Interleukin-4; Lymphocytes; Nasal Polyps; NF-kappa B; Rhinitis

Endoplasmic reticulum (ER) stress plays a pivotal role in the pathogenesis of asthma. The present study aimed to investigate the reducing or suppressing effects of crocin in ovalbumin (OVA)-sensitized mice on ER stress markers. Mice were divided into six groups (n = 5 per group) including control, OVA-sensitized (OVA), OVA-treated crocin (OVA-Cr25, OVA-Cr50, and OVA-Cr100 mg/kg), and OVA-treated dexamethasone (1 mg/kg), (OVA-Dexa) groups. Animals 5 later groups were sensitized to OVA and the treatment groups received intraperitoneally crocin/dexamethasone in the last 5 days of the model. At the end of the study, lung tissue was evaluated for airway inflammation, caspase 12 and CHOP protein levels, and expression of ER stress markers using real-time-PCR. Sensitization with OVA significantly caused airway inflammation and induction of ER stress in mice compared to the control group based on the elevated inflammatory cells and ER stress markers in the lung tissue. Treatment with crocin and dexamethasone reduced airway inflammation and suppressed ER stress markers. Interestingly, in the OVA-Cr100 group, the suppressive effects on ER stress apoptotic markers were comparable to the OVA-Dexa group. The results suggest that crocin mediates maladaptive ER stress conditions possibly by creating adaptive ER stress status and driving protein folding correctly.

Topics: Animals; Carotenoids; Disease Models, Animal; Endoplasmic Reticulum Stress; Inflammation; Lung; Mice; Mice, Inbred BALB C; Ovalbumin

Breast cancer (BC) is the most commonly diagnosed cancer confronting women worldwide. Crocin, a glycosylated carotenoid extracted from Crocus sativus L., possesses anti-cancer and anti-inflammatory activities. This study tried to explore the influences of crocin on proliferation and inflammation of BC cells, and to investigate the possible mechanism. The protein levels of protein kinase C theta (PRKCQ) and nuclear factor kappa B (NF-κB) p-p65 and p65 were examined using western blot analysis. The potential targets of crocin were predicted using the PharmMapper database. Cell viability and proliferation were determined utilizing CCK-8 and EdU incorporation assays, respectively. Inflammation was assessed by detecting the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) using RT-qPCR and ELISA. Results showed that crocin inhibited NF-κB activation and suppressed cell viability and proliferation in BC cells. Crocin caused a significant reduction of levels of TNF-α and IL-1β, suggesting that crocin suppressed inflammation in BC cells. NF-κB inhibition decreased proliferation and inflammation in BC cells. Additionally, PRKCQ was identified as a potential target of crocin according to PharmMapper database. Crocin treatment inhibited the activation of NF-κB in BC cells by reducing PRKCQ expression. Mechanistically, PRKCQ-dependent activation of NF-κB pathway reversed the effects of crocin on the proliferation and inflammation in BC cells. In conclusion, crocin inhibited NF-κB-mediated inflammation and proliferation in BC cells through reducing PRKCQ expression.

Topics: Breast Neoplasms; Carotenoids; Cell Proliferation; Female; Humans; Inflammation; NF-kappa B; Protein Kinase C-theta; Tumor Necrosis Factor-alpha

Currently, drugs for the treatment of diabetic nephropathy (DN) are lacking. This study aimed to explore the protective effect of crocin on DN.. Diabetes was induced in rats by streptozotocin (STZ), and changes in metabolism and renal parameters after crocin treatment were measured. Dihydroethidium (DHE) fluorescence and superoxide generation were used to detect the levels of reactive oxygen species (ROS) in rat renal tissues. Enzyme-linked immunosorbent assay was used to measure changes inflammation-related factors with crocin treatment. In addition, the expression of Nod-like receptor family pyrin domain-containing 3 (NLRP3) signaling pathway components was detected by western blot analysis, qRT-PCR, and immunohistochemistry.. Crocin lowered blood sugar, increased serum insulin levels, and improved diabetes-related symptoms, including kidney dysfunction. Masson trichrome staining revealed that crocin could improve renal tissue fibrosis caused by hyperglycemia. Moreover, crocin inhibited ROS production in renal tissues and generally inhibited the production of the proinflammatory factors TNF-α, IL-1β, and IL-18. Crocin exerted these functions by inhibiting the expression of the NLRP3 inflammasome in DN rats.. Crocin alleviates DN related oxidative stress and inflammation by inhibiting NLRP3 inflammasomes. Our results provide a new target for the treatment of DN.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Carotenoids; Diabetic Nephropathies; Inflammasomes; Inflammation; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Rats, Sprague-Dawley

To explore the mechanisms of crocin against glycocalyx damage and inflammatory injury in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) mice and LPS-stimulated human umbilical vein endothelial cells (HUVECs).. Mice were randomly divided into control, LPS, and crocin + LPS (15, 30, and 60 mg/kg) groups. HUVECs were separated into eight groups: control, crocin, matrix metalloproteinase 9 inhibitor (MMP-9 inhib), cathepsin L inhibitor (CTL inhib), LPS, MMP-9 inhib + LPS, CTL inhib + LPS, and crocin + LPS. The potential cytotoxic effect of crocin on HUVECs was mainly evaluated through methylthiazolyldiphenyl-tetrazolium bromide assay. Histological changes were assessed via hemotoxylin and eosin staining. Lung capillary permeability was detected on the basis of wet-dry ratio and through fluorescein isothiocyanate-albumin assay. Then, protein levels were detected through Western blot analysis, immunohistochemical staining, and immunofluorescence.. This study showed that crocin can improve the pulmonary vascular permeability in mice with LPS-induced ARDS and inhibit the inflammatory signaling pathways of high mobility group box, nuclear factor κB, and mitogen-activated protein kinase in vivo and in vitro. Crocin also protected against the degradation of endothelial glycocalyx heparan sulfate and syndecan-4 by inhibiting the expressions of CTL, heparanase, and MMP-9 in vivo and in vitro. Overall, this study revealed the protective effects of crocin on LPS-induced ARDS and elaborated their underlying mechanism.. Crocin alleviated LPS-induced ARDS by protecting against glycocalyx damage and suppressing inflammatory signaling pathways.

Topics: Animals; Capillary Permeability; Carotenoids; Cathepsin L; Cell Survival; Glucuronidase; Glycocalyx; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Lipopolysaccharides; Lung; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Permeability; Random Allocation; Respiratory Distress Syndrome; Signal Transduction; Syndecan-4

Topics: Animals; Behavior Observation Techniques; Behavior, Animal; Bronchoalveolar Lavage Fluid; Carotenoids; Crocus; Depression; Disease Models, Animal; Forced Expiratory Volume; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Nicotiana; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Signal Transduction; Smoke; Treatment Outcome

Depression is the leading cause of mental health-related disease globally, and it affects an estimated 300 million people worldwide. However, its physiological causes are not fully understood. Since available antidepressants fail to achieve complete disease remission, treating diversification of depression may be a useful contribution. Crocin, one of the main glycosylated carotenoids of saffron, has been found to have numerous pharmacological activities and has been reported to be associated with neuroprotective effects. However, the biological action of crocin-I, a major member of the crocin family, on depression-like behavior, neuroinflammation and oxidative damage in depressed animals remains unclear. The present study showed that crocin-I exerts significant antidepressant effects in a model of chronic corticosterone (CORT)-induced depression, as evidenced by the attenuation of depression-like behaviors in the open field test, forced swimming test and tail suspension test. The antidepressant activity of crocin-I was probably achieved through the suppression of neuroinflammation (IL-1β) and oxidative stress in the mouse hippocampus. Additionally, the oral administration of crocin-I at a dose of 40 mg/kg reduced the CORT-induced accumulation of nicotinamide in the liver of the mice to improve the synthesis of NAD

Topics: Animals; Antidepressive Agents; Behavior, Animal; Carotenoids; Corticosterone; Depression; Hippocampus; Inflammation; Interleukin-1beta; Liver; Male; Malondialdehyde; Mice; Mitochondria; Niacinamide; Oxidative Stress; Reactive Oxygen Species; Sirtuin 3

Sepsis causes organ dysfunctions via elevation of oxidative stress and inflammation. Lipopolysaccharide (LPS) is the major surface molecule of most gram-negative bacteria and routinely used as a sepsis model in investigation studies. Crocin is an active compound of saffron which has different pharmacological properties such as anti-oxidant and anti-inflammatory. In this research, the protective effect of crocin was evaluated against LPS-induced toxicity in the embryonic cardiomyocyte cell line (H9c2).. The cells were pre-treated with different concentration of crocin (10, 20 and 40 μM) for 24 h, and then LPS was added (10 μg/ml) for another 24 h. Afterward, the percentage of cell viability and the levels of inflammatory cytokines (TNF-α, PGE. Our results showed that LPS reduced cell viability, increased the levels of cytokines, gene-expression, nitric oxide, and thiol. Crocin attenuated the LPS-induced toxicity in H9c2 cells via reducing the levels of inflammatory factors (TNF-α, PGE. The observed results revealed that crocin has preventive effects on the LPS induced sepsis and its cardiac toxicity in-vitro model. Probably, these findings are related to anti-inflammatory and anti-oxidant properties of crocin. However, performing further animal studies are necessary to support the therapeutic effects of crocin in septic shock cardiac dysfunction.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Carotenoids; Cell Line; Cell Survival; Cytokines; Inflammation; Inflammation Mediators; Lipopolysaccharides; Myocytes, Cardiac; Nitric Oxide; Protective Agents; Rats; Signal Transduction

The neurodegeneration and neurobehavioral consequences of alcohol are serious and offering therapeutic approaches for management of these types of neurodegeneration is one of the main concerns of researchers in this manner. Alcohol-stimulated oxidative stress, apoptosis and inflammation, with modulation of involved signaling pathway in neuroprotection, was reported previously. Neuroprotective strategy for management of alcohol induced neurodegeneration through a new generation neuroprotective agent and based on modulation of some neuroprotective signaling pathway such as CREB/BDNF and Akt/GSK has always been superior to any other therapeutic interventions. Therefore, the introduction and development of potential new neuroprotective properties and clarification of their effects on major cell signaling such as CREB/BDNF and Akt/GSK is necessitated. During recent years, using new neuroprotective compounds with therapeutic probability for treatment of alcohol induced neuro-biochemical and neuro-behavioral malicious effects have been amazingly increased. Many previous studies have reported the neuroprotective roles of crocin (major active component of saffron) in multiple neurodegenerative events and diseases in animal model. But the role of crocin neuroprotective effects against alcohol induced neurodegeneration and neurobehavioral sequels and also role of CREB/BDNF and Akt/GSK in this manner remain unclear. Hence we hypothesized that by using crocin in alcohol dependent subject it would provide neuroprotection against alcohol induced neurodegeneration and neurobehavioral and probably can manage sequels of alcohol abuses. Also we hypothesized that crocin, via intonation of CREB/BDNF and Akt/GSK signaling pathway, can inhibit alcohol induced neurodegeneration. In this article, we tried to discuss our hypothesis regarding the possible role of crocin, as a potent neuroprotective agent, and also role of Akt/GSK and CREB/BDNF signaling pathway in treatment of alcohol induced neurodegeneration and neurobehavioral through its anti-inflammatory,anti-apoptotic, anti-oxidative stress and cognitive enhancer.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Brain-Derived Neurotrophic Factor; Carotenoids; Cyclic AMP Response Element-Binding Protein; Ethanol; Glycogen Synthase Kinase 3 beta; Humans; Inflammation; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents; Oxidative Stress; Proto-Oncogene Proteins c-akt; Signal Transduction

Methotrexate (MTX) is used commonly in the treatment of various cancers and inflammatory diseases; nevertheless, the associated hepatotoxicity has limited its clinical application. Crocin (CRO) is described as a natural carotenoid with analgesic, antioxidant, and antiinflammatory properties. This study aimed to determine the effects of CRO on MTX-induced hepatotoxicity.. For pretreatment, CRO at doses of 25 and 50 mg/kg (po), as well as 20 mg/kg (ip) of MTX, was injected in rats.. MTX led to hepatotoxicity, as confirmed by the significant increase in liver markers, histopathological changes, decreased GSH content, and reduced antioxidant enzyme activity (i.e., CAT, SOD, and GPx). It increased TNF-α, IL-1β, lipid peroxidation, and nitric oxide levels. Nevertheless, by increasing antioxidant defense in hepatic tissues and reducing oxidative stress and proinflammatory mediators, pretreatment with CRO could alleviate hepatotoxicity.. CRO can inhibit MTX-induced hepatotoxicity through improving antioxidant defense and reducing oxidative stress and inflammation.

Topics: Animals; Anti-Inflammatory Agents; Antimetabolites, Antineoplastic; Biomarkers; Carotenoids; Chemical and Drug Induced Liver Injury, Chronic; Dose-Response Relationship, Drug; Inflammation; Male; Methotrexate; Oxidative Stress; Rats, Wistar

Nephropathy is a serious complication of metabolic syndrome (MS), a global epidemic disorder. This study was undertaken to investigate the actions of diosmin and crocin, two natural ingredients, on diabetic nephropathy in a rat model of MS and the underlying mechanism(s). Metabolic syndrome was induced by the addition of 10% fructose to drinking water and placing the rats on high-salt diet for 16 weeks. Diosmin and Crocin were orally administrated daily for 10 weeks starting at week 6. At the end of study, arterial blood pressure was non-invasively recorded. Urine, serum and kidneys were collected for renal function, oxidative stress, glycemic parameters, inflammatory markers and histological analysis. Both Diosmin and Crocin improved insulin resistance, decreased blood pressure, uric acid, lipoproteins and blocked diabetic nephropathy as indicated by reduction of albumin excretion rate and albumin/creatinine ratio. They alleviated the impaired filtration in MS as indicated by increased creatinine clearance. They also ameliorated oxidative stress and the low-grade 1inflammation as indicated by reduction of serum TNF-α and inflammatory cells. These observations suggest that both Diosmin and Crocin alleviate metabolic syndrome and the associated nephropathy in rats, possibly, through inhibiting oxidative stress and inflammation.

Topics: Animals; Blood Glucose; Blood Pressure; Carotenoids; Diosmin; Drug Therapy, Combination; Glycation End Products, Advanced; Inflammation; Insulin; Insulin Resistance; Kidney Diseases; Kidney Glomerulus; Lipids; Male; Malondialdehyde; Metabolic Syndrome; Oxidative Stress; Rats, Wistar; Tumor Necrosis Factor-alpha; Uric Acid

Depression is one of the foremost psychological illness which is closely leagued with inflammation. Crocin is a natural product that exhibits both anti-inflammatory and anti-oxidant activities. However, little is known about anti-inflammatory mechanisms of crocin on LPS-induced anxiety and depressive-like behaviors. The objective of this study is emphasized on neuroprotective role of crocin against LPS-induced anxiety and depressive-like behaviors in mice. It is observed that crocin inhibited LPS-induced production of NO, TNF-α, IL-1β and ROS in BV-2 microglial cells. Moreover, crocin significantly declined the expression of iNOS, NF-κB p65 and CD16/32 (M1 marker), as well as elevated the expression of CD206 (M2 marker) in BV-2 cell line with decreased LPS-induced anxiety and depressive-like behaviors by improved locomotor activity, reduced sucrose intake, and decreased immobility time in forced swim and tail suspension test in Kunming mice. Expression of NLRP3, ASC and caspase-1 by i.p administration of LPS found to be neutralized with reduction in level of IL-1β, IL-18 and TNF-α in mouse hippocampus. In conclusion, these results suggested that crocin as a potential therapeutic candidate for neuro-inflammation and depressive-like behaviors induced by LPS. The effect was found to be due to inhibition of NLRP3 inflammasome and NF-κB and its promoted M1 to M2 phenotypic conversion of microglia.

Topics: Animals; Animals, Outbred Strains; Anxiety Disorders; Carotenoids; Cell Line; Depressive Disorder; Inflammasomes; Inflammation; Lipopolysaccharides; Mice; Microglia; Neuroprotective Agents; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Psychotropic Drugs; Signal Transduction

This study is to determine the role and mechanism of crocin in rheumatoid arthritis (RA). Totally 60 Wistar SD rats were randomly divided into control group, RA model group, methotrexate group, crocin high dose, middle dose, and low dose groups. The paw swelling degree, arthritis score, thymus and spleen index, the mRNA and protein levels of iNOS, and the serum content of TNF-α, IL-1β, and IL-6 were evaluated. Crocin treatment significantly alleviated the paw swelling of RA rats. The arthritis score in crocin treatment groups was significantly lower than that in RA model group. Additionally, the thymus index, but not the spleen index, declined remarkably in crocin treatment groups than in RA model group. Besides, crocin administration significantly reduced the iNOS production and the serum content of TNF-α, IL-1β, and IL-6. Crocin may exert potent anti-RA effects through inhibiting cytokine.

Topics: Animals; Arthritis, Rheumatoid; Carotenoids; Cytokines; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Inflammation; Male; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; RNA, Messenger; Spleen; Thymus Gland

Hemorrhagic shock (HS) is associated with an excessive activation of inflammation, contributing to multiple organ failure in numerous medical or surgical conditions. To explore the therapeutic potential of crocin, a natural compound with anti-inflammatory properties, we administered crocin to rats during resuscitation following HS induced by withdrawing blood. Compared with control animals which were sham-treated, HS-operated rats showed organ damages as manifested by enhanced markers of multiple organ dysfunctions. Crocin treatment substantially reduced these parameters in rats subjected to HS, suggesting an alleviation of tissue injuries such as in the kidney, liver, pancreas, and muscle. The activation of NF-κB (nuclear factor κB) pathway in lung tissue by HS, as shown by increased nuclear translocation of p65 and IκBα phosphorylation, was diminished by crocin treatment. The crocin administration also significantly decreased the serum levels of proinflammatory cytokine TNF-α (tumor necrosis factor-α) and interleukin (IL)-6, whereas increased the level of anti-inflammatory cytokine IL-10 in HS-operated rats. These studies indicate that crocin administration may reduce inflammation-driven tissue damage in patients with HS.

Topics: Animals; Biomarkers; Blood Pressure; Carotenoids; Heart Rate; Inflammation; Male; Multiple Organ Failure; NF-kappa B; Rats, Wistar; Shock, Hemorrhagic; Signal Transduction

Allergic asthma is a chronic respiratory disease with a prevalent T helper (Th2)-mediated immune reaction. Crocin, the major bioactive constituent of saffron, has been reported in multiple studies to have numerous pharmacological activities, including prominent anti-oxidant activities. In the current study, the anti-asthmatic potential of crocin was evaluated. Adult male Swiss Albino mice were administered 10mg of ovalbumin (OVA) mixed with 1mg of aluminum hydroxide intraperitoneally on days 0 and 7 and were administered crocin (25mg/kg) orally daily for 16days. Asthma progression was associated with significant increase in the lung/body weight index, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), lung total protein content, and serious index of lung permeability, indicating pulmonary edema with accumulation of serous fluids within the lungs. Serum lactate dehydrogenase (LDH) activity and lung malondialdehyde (MDA) content were significantly increased, while lung superoxide dismutase (SOD) activity, reduced glutathione (GSH) levels, and serum and lung catalase activities were significantly decreased. These changes reflect significant pulmonary inflammation with concomitant disturbance of oxidant/antioxidant homeostasis. Moreover, tumor necrosis factor (TNF)-α, interleukin (IL)-4, and IL-13 contents in the lung were also significantly high after OVA sensitization. Crocin treatment significantly alleviated the OVA-induced allergic asthma-associated alterations in inflammatory and oxidative stress biomarkers. Crocin enhanced anti-oxidant defenses, reduced the incidence of oxidative stress, and restored pro-inflammatory cytokines to normal levels. Histopathological analysis showed significant lung improvement in crocin-treated mice. In conclusion, crocin showed a significant protective effect against allergic asthma progression, which was associated with down-regulation of inflammatory cytokine expression and restoration of oxidant/antioxidant homeostasis.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Carotenoids; Crocus; Cytokines; Disease Models, Animal; Humans; Hypersensitivity; Inflammation; Inflammation Mediators; Interleukin-13; Interleukin-4; Male; Mice; Oxidative Stress; Respiratory System; Signal Transduction

Osteoarthritis is the most prevalent form of arthritis, affecting a large part of population. It has been reported that muscle weakness and inflammation contribute to osteoarthritis development and progression. Oxidative stress plays important roles in muscle dysfunction and inflammation induction. Crocin, a component of saffron, has excellent antioxidative property. However, it is unclear if crocin can be a potential medicine for osteoarthritis therapy. Osteoarthritis in rats was induced by meniscectomy (MNX) surgery. Then, rats were given with 30 mg/kg of crocin daily for 10 days after osteoarthritis induction. The parameters were determined 7 days after crocin administration. MNX surgery induced osteoarthritis in rats. Crocin treatment significantly decreased osteoarthritis-associated joint pain, decreased muscular interleukin-6 (IL-6) level, and increased citrate synthase (CS) activity, as well as myosin heavy chain (MHC) IIα expression. In addition, crocin reduced muscular lipid peroxidation (LPO) and Nrf2 expression and increased glutathione production and glutathione peroxidase activity. Finally, crocin inhibited the activity of JNK, but not ERK, to repress NF-κB activation and inflammation induction. Crocin attenuates osteoarthritis symptoms through alleviating oxidative stress and inflammation, suggesting that crocin is a potential medicine for osteoarthritis therapy.

Topics: Animals; Arthralgia; Carotenoids; Inflammation; Muscle Weakness; Muscles; Osteoarthritis; Oxidative Stress; Rats

The clinical application of the chemotherapeutic agent; Doxorubicin (DOX) is limited by its toxic effects on several body organs. The current study was conducted to evaluate the cardiao-protective effects of crocin, a predominant bioactive constituent of Saffron against DOX-induced myocardial toxicity.. Adult male Sprague Dawley rats received DOX (3.5 mg/kg twice weekly) for 3 weeks with and without daily crocin (10 and 20 mg/kg, orally) for 3 weeks.. DOX injection significantly elevated serum levels of aspartate aminotransferase (AST), cardiac specific-creatine kinase (CK-MB), cardiac Troponin T and lactate dehydrogenase (LDH) with impaired electrocardiogram (ECG) profile, indicating DOX-induced myocardial toxicity. Moreover, cardiac specimen examination revealed myocardial inflammatory infiltration with multifocal areas of myocardial degeneration/necrosis. DOX injection significantly increased numbers of active anti-Cd 68 positivity stained cells and significantly-induced myocardial apoptosis. Finally, there was a significant increase in cardiac TNF-α, IL-1β and caspase-3 expression associated with significant decrease in IL-10. Crocin treatment resulted in a significant dose dependent attenuation of DOX-induced myocardial toxicity. It improved ECG profile and restored normal cardiac architecture. Furthermore, crocin reduced oxidative stress, enhanced host anti-oxidant defenses and decreased apoptosis as well. Additionally, crocin restored the balance between pro-and anti-inflammatory cytokines. The improvement in biochemical parameters was accompanied by significant myocardial improvement as seen in histopathological specimen.. Crocin has a cardioprotective effect against DOX-induced cardiomayopathy. Anti-inflammatory, antioxidant and antiapoptic properties of crocin are thought to be involved in the observed cardioprotective effect.

Topics: Animals; Apoptosis; Calcium; Carotenoids; Down-Regulation; Doxorubicin; Electrocardiography; Heart; Inflammation; Male; Rats; Rats, Sprague-Dawley; Troponin T

This study evaluated whether crocin, a bioactive component of saffron, has a protective effect on kidney through reducing the oxidative stress and inflammatory response in aged rats. In this study the changes in activities of antioxidant enzymes, lipid peroxidation, glutathione (GSH) levels and the expression of pro-inflammatory cytokines in the serum and renal tissue were evaluated by ELISA and RT-PCR, respectively. The middle and aged rats were given intraperitoneal injections of crocin (10, 20, 30 mg/kg/day) for 4 weeks. After 4 weeks, animals were anesthetized with diethyl ether. The kidney samples were taken for biochemical analysis. The results revealed the aging was associated with a significant decrease in the activities of antioxidant enzymes, and GSH content with increase in lipid peroxidation level in kidney of the aged rats (p < 0.001). The increased levels of serum renal functional parameter, oxidative parameters (p < 0.01) and also pro-inflammatory cytokine levels were significantly reduced by crocin administration (p < 0.05). The aged rats exhibited a dysregulation of the oxidative stress, and inflammation in the kidneys, but crocin treatment significantly reduced the expression of the inflammatory genes. These results provide pivotal documentation that crocin has a renoprotective effects against the development of oxidative stress and inflammation in the kidney of old rats. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Aging; Animals; Carotenoids; Crocus; Inflammation; Kidney; Male; Oxidative Stress; Rats; Rats, Wistar

This study investigated the protective effects and mechanisms of crocin, an extract of saffron, on brain damage after traumatic brain injury (TBI) in mice. C57BL/6 mice were subjected to controlled cortical impact (CCI)-induced TBI. Pretreatment with crocin (20mg/kg) had protective effects against TBI, demonstrated by improved neurological severity score (NSS) and brain edema, decreased microglial activation and release of several pro-inflammatory cytokines, and decreased cell apoptosis. TBI activated Notch signaling, as shown by upregulated levels of Notch intracellular domain (NICD) and Hes1 mRNA, and pretreatment with crocin further increased Notch activation. However, pretreatment with DAPT (100mg/kg), a gamma-secretase inhibitor, significantly suppressed crocin-induced activation of Notch signaling and attenuated the ability of crocin to protect mice against TBI-induced inflammation and apoptosis. Therefore, these results suggest that crocin has neuroprotective effects against TBI in mice, and these effects are at least partially dependent on activation of Notch signaling.

Topics: Animals; Apoptosis; Brain Edema; Brain Injuries; Carotenoids; Inflammation; Male; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Receptors, Notch; Signal Transduction

As intervertebral disc (IVD) degeneration has been proven to contribute to low back pain (LBP), drug treatment aiming at attenuating IVD degeneration may prove to be benefiical. Crocin, a bioactive component of saffron, has been found to exert anti-inflammatory effects on cartilage. In the present study, the anti-inflammatory and anti-catabolic effects of crocin on rat IVDs were analyzed in vitro and ex vivo. Nucleus pulposus (NP) cells were isolated from the lumbar IVDs of Sprague-Dawley rats. The NP cells were first treated with various concentrations of crocin, and then stimulated with lipopolysaccharide (LPS) to induce inflammation. Subsequently, RT-qPCR and enzyme-linked immunosorbent assay were carried out to measure the expression levels of catabolic enzymes, pro-inflammatory factors and the components of the extracellular matrix (ECM). In addition, western blot analysis was also used to investigate the related signaling pathways. The whole spinal motion segment (vertebra-IVD-vertebra section) of the rats was isolated and cultured in the presence or absence of LPS and crocin for 7 days. The ex vivo effects of crocin on the ECM of the IVD structures were determined by histological and biochemical analysis. In vitro, crocin significantly inhibited the LPS-induced overexpression of catabolic enzymes [matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif (ADAMTS)-4 and ADAMTS‑5], pro-inflammatory factors [interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6 and inducible nitric oxide synthase (iNOS)] and Toll-like receptor (TLR)‑2 in a concentration-dependent manner. Notably, crocin partly prevented the downregulation of aggrecan and type II collagen (collagen‑II). Moreover, crocin suppressed the LPS-induced activation of the mitogen-activated protein kinase (MAPK) pathway by inhibiting the phosphorylation of c-Jun N-terminal kinase (JNK). Ex vivo experiments demonstrated that crocin protected the rat IVDs from the LPS-induced depletion of the ECM components, including proteoglycan and collagen-II. In conclusion, crocin effectively suppressed the degeneration-related inflammation and catabolism in rat IVDs in vitro and ex vivo, suggesting that crocin has potential for use as a therapuetic strategy in the treatment of LBP.

Topics: Animals; Anti-Inflammatory Agents; Carotenoids; Extracellular Matrix; Inflammation; Intervertebral Disc; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinases; Metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction

Crocin and safranal are the active substances of saffron and have many biological properties. In the present study, we compared the effects of crocin, safranal and diclofenac on local inflammation and its induced pain in rats.. Local inflammation was induced by intraplantar (ipl) injection of carrageenan (100 μl, 2%). Paw thickness was measured before and after carrageenan injection. Inflammatory pain responses including cold allodynia, mechanical allodynia and hyperalgesia were assessed using acetone spray and von Frey filament tests, respectively. The number of neutrophils in inflammatory zone was counted 6.5 h after injection of carrageenan.. Carrageenan produced edema, cold allodynia, mechanical allodynia and hyperalgesia and caused neutrophil infiltration in paw tissues. Crocin at doses of 25, 50 and 100 mg/kg, safranal at doses of 0.5, 1 and 2 mg/kg and diclofenac (as a reference drug) at a dose of 10 mg/kg attenuated edema, suppressed inflammatory pain responses and decreased the number of neutrophils.. The present study showed anti-inflammatory and antinociceptive activities for crocin, safranal and diclofenac in carrageenan model of local inflammation and inflammatory pain.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Carotenoids; Carrageenan; Cyclohexenes; Diclofenac; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Hyperalgesia; Inflammation; Male; Neutrophil Infiltration; Pain; Pain Threshold; Rats; Rats, Wistar; Terpenes; Time Factors

Articular cartilage degeneration and inflammation are the hallmark of progressive arthritis and is the leading cause of disability in 10-15% of middle aged individuals across the world. Cartilage and synovium are mainly degraded by either enzymatic or non-enzymatic ways. Matrix metalloproteinases (MMPs), hyaluronidases (HAases) and aggrecanases are the enzymatic mediators and inflammatory cytokines and reactive oxygen species being non-enzymatic mediators. In addition, MMPs and HAases generated end-products act as inflammation inducers via CD44 and TLR-4 receptors involved NF-κB pathway. Although several drugs have been used to treat arthritis, numerous reports describe the side effects of these drugs that may turn fatal. On this account several medicinal plants and their isolated molecules have been involved in modern medicine strategies to fight against arthritis. In view of this, the present study investigated the antiarthritic potentiality of Crocin, a dietary colorant carotenoid isolated from stigma of Crocus sativus. Crocin effectively neutralized the augmented serum levels of enzymatic (MMP-13, MMP-3 and MMP-9 and HAases) and non-enzymatic (TNF-α, IL-1β, NF-κB, IL-6, COX-2, PGE(2) and ROS) inflammatory mediators. Further, Crocin re-established the arthritis altered antioxidant status of the system (GSH, SOD, CAT and GST). It also protected the bone resorption by inhibiting the elevated levels of bone joint exoglycosidases, cathepsin-D and tartrate resistant acid phosphatases. Taken together, Crocin revitalized the arthritis induced cartilage and bone deterioration along with inflammation and oxidative damage that could be accredited to its antioxidant nature. Thus, Crocin could be an effective antiarthritic agent which can equally nullify the arthritis associated secondary complication.

Topics: Acid Phosphatase; Animals; Antioxidants; Arthritis, Experimental; Blotting, Western; Bone Resorption; Carotenoids; Cartilage, Articular; Cathepsin D; Cytokines; Dietary Supplements; Glutathione; Hyaluronoglucosaminidase; Inflammation; Inflammation Mediators; Isoenzymes; Liver; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Rats; Rats, Wistar; Superoxide Dismutase; Tartrate-Resistant Acid Phosphatase