trans-sodium-crocetinate and Inflammation

Uterine ischemia/reperfusion (I/R) injury often occurs during many complex surgical procedures, such as uterus transplantation, cesarean, and myomectomy, which may lead to the loss of uterine function and failure of the operation. Crocetin (CRO), as one of the major active constituents from saffron extract, shows protective effects against reactive oxygen species, inflammation, and apoptosis. However, the role of CRO in protecting the uterus against I/R-induced injury has never been investigated. This study aims to clarify the protective role of CRO against I/R injury and the underlying mechanisms.. Sprague-Dawley rats were randomly divided into five groups: the control group, I/R group, 20 mg/kg CRO-treated I/R group, 40 mg/kg CRO-treated I/R group, and 80 mg/kg CRO-treated I/R group. Rats were given daily gavages with different doses of CRO or vehicle for five consecutive days. The rat uterine I/R model was created by routine method with 1h ischemia and 3h reperfusion. The serum and uterine tissues were collected, the changes in malondialdehyde (MDA) level and superoxide dismutase (SOD) activity, the mRNA and protein levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and IL-10, the protein levels of B-cell chronic lymphocytic leukemia/lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), caspase-3, nuclear factor erythroid 2-related factor (Nrf)-2, and heme oxygenase (HO)-1, were measured. The histological changes were examined by HE staining. The number of apoptotic cells was analyzed by flow cytometry.. Uterine I/R significantly induced MDA level, suppressed SOD activity, upregulated levels of pro-inflammatory cytokines, down-regulated level of the antiinflammatory cytokine, induced caspase-3-dependent apoptosis, activated the protein expression of Nrf-2 and HO-1, and caused uterine damage. However, pre-administration of CRO effectively reversed I/R-induced above changes and further enhanced Nrf-2/HO- 1 activation in a dose-dependent manner.. Pre-administration of CRO effectively alleviates I/R-induced oxidative stress, inflammation, apoptosis, and tissue injury probably through activating the Nrf- 2/HO-1 pathway, suggesting a protective role of CRO in I/R-induced uterus injury.

Topics: Animals; Apoptosis; Caspase 3; Cytokines; Female; Inflammation; Ischemia; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reperfusion; Reperfusion Injury; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Glycation, oxidative stress, and inflammation due to the elevation of transforming growth factor-β1 (TGF-β1) participate in diabetic nephropathy (DN). Thus, we investigated for the first time the effect of crocetin (Crt) on the renal histopathological parameters, TGF-β1 and glycation, oxidative stress, as well as inflammatory markers in the DN rat model.. Forty male Wistar rats were randomly divided into 4 equal groups: normal (N), N + Crt, DN, and DN + Crt. DN was induced in rats with a combination of nephrectomy and streptozotocin. Treated groups received 100 mg/kg of Crt via intraperitoneal injection monthly for 3 months. Different glycation (glycated albumin, glycated LDL, Methylglyoxal, and pentosidine), oxidative stress (advanced oxidation protein products, malondialdehyde, glutathione, and paraoxonase-I (PON-1)), and inflammatory markers (tumor necrosis factor-α, myeloperoxidase, and TGF-β1), blood glucose, insulin, lipid profile, creatinine in the serum, and proteinuria, as well as the glyoxalase-1 (GLO-1) activity, was determined.. Crt decreased renal biochemical (Cre and PU) and histopathological (glomerulosclerosis) renal dysfunction parameters, diverse glycation, oxidative stress, and inflammatory markers in the DN rats. Furthermore, the treatment corrected glycemia, insulin resistance, and dyslipidemia as well as induced the activities of GLO-1 and PON-1. Over and above, the treatment decreased TGF-β1 in their serum (p > 0.001).. Crocetin improved DN owing to an advantageous effect on metabolic profile. Further, the treatment with a reducing effect on TGF-β1, oxidative stress, glycation, and inflammation markers along with an increase in Glo-1 activity showed multiple protective effects on kidney tissue.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Inflammation; Male; Rats; Rats, Wistar; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factors

The anti-inflammatory and anti-apoptotic properties of crocetin have been widely demonstrated in numerous diseases. However, the exact role and mechanism of crocetin in acute pancreatitis have not been elucidated. Thus, this paper aims at exploring whether crocetin could be used to alleviate acute pancreatitis and further demonstrating the underlying mechanisms. Cell viability of caerulein-induced pancreatic exocrine cell line AR42J treated with crocetin was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT). Apoptosis and inflammation of these treated cells were detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), western blot and enzyme linked immunosorbent assay (ELISA). The expression of sirtuin-1 (SIRT1) was quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. After knockdown of SIRT1, cell viability, apoptosis and inflammation were measured again by corresponding kits. Finally, the NF-κB nuclear translocation and proteins in the NF-κB signaling were examined. Crocetin remarkably suppressed the apoptosis and inflammation of caerulein-induced AR42J cells. The decreased expression of SIRT1 was increased in caerulein-induced AR42J cells after exposure to crocetin. After knockdown of SIRT1, the alleviative effects of crocetin were found to be canceled in these cells. Furthermore, SIRT1 knockdown promoted the NF-κB signal transduction. On the whole, we presented the first evidence for the importance of SIRT1-NF-κB axis in acute pancreatitis and proposed that crocetin alleviates the caerulein-induced apoptosis and inflammation in AR42J cells by activating SIRT1 via NF-κB.

Topics: Acute Disease; Apoptosis; Carotenoids; Ceruletide; Humans; Inflammation; NF-kappa B; Pancreatitis; Sirtuin 1; Vitamin A

Depression is a serious mood disorder, and crocetin has a variety of pharmacological activities, including antidepressant effect. The alterations of intestinal flora have a significant correlation with depression, and crocetin can alter the composition of intestinal flora in mice with depression-like behaviors.. This study investigated the underlying antidepressant mechanisms of crocetin through multi-omics coupled with biochemical technique validation.. Chronic unpredictable stress (CUMS) was used to induce mice model of depression to evaluate the antidepressant effect of crocetin through behavioral tests, and the metagenomic and metabolomic were used to explore the potential mechanisms involved. In order to verify its underlying mechanism, western blot (WB), Elisa, immune histological and HPLC techniques were used to detect the level of inflammatory cytokines and the level of metabolites/proteins related to tryptophan metabolism in crocetin-treated mice.. Crocetin ameliorated depression-like behaviors and increased mobility in depressive mice induced by CUMS. Metagenomic results showed that crocetin regulated the structure of intestinal flora, as well as significantly regulated the function gene related to derangements in energy metabolism and amino acid metabolism in mice with depression-like behaviors. Metabolomic results showed that the tryptophan metabolism, arginine metabolism and arachidonic acid metabolism played an essential role in exerting antidepressant-like effect of crocetin. According to multi-omics approaches and validation results, tryptophan metabolism and inflammation were identified and validated as valuable biological processes involved in the antidepressant effects of crocetin. Crocetin regulated the tryptophan metabolism in mice with depression-like behaviors, including increased aryl hydrocarbon receptor (AhR) expression, reduced indoleamine 2,3-dioxygenase 1 (IDO1) and serotonin transporter (SERT) expression in the hippocampus, elevated the content of 5-HT, kynurenic acid in serum and 5-HT, tryptophan in hippocampus. In addition, crocetin also attenuated inflammation in mice with depression-like behaviors, which presented with reducing the production of inflammatory cytokines in serum and colon. Meanwhile, crocetin up-regulated the expression of zonula occludens 1 (ZO-1) and occludin in ileum and colon to repair the intestinal barrier for preventing inflammation transfer.. Our findings clarify that crocetin exerted antidepressant effects through its anti-inflammation, repairment of intestinal barrier, modulatory on the intestinal flora and metabolic disorders, which further regulated tryptophan metabolism and impacted mitogen-activated protein kinase (MAPK) signaling pathway to enhance neural plasticity, thereby protect neural.

Topics: Animals; Antidepressive Agents; Arachidonic Acid; Arginine; Cytokines; Depression; Gastrointestinal Microbiome; Hippocampus; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation; Kynurenic Acid; Mice; Mitogen-Activated Protein Kinases; Occludin; Receptors, Aryl Hydrocarbon; Serotonin; Serotonin Plasma Membrane Transport Proteins; Stress, Psychological; Tryptophan

Crocetin, a natural compound, has been demonstrated to exhibit beneficial effects in cardiovascular diseases. Previous studies demonstrated that crocetin reduced ischemia/reperfusion (I/R) injury by attenuating cytotoxicity and cellular apoptosis. However, the previous mechanistic studies did not fully elucidate its pharmacological effects on cardiac damage, especially I/R injury. The present study verified its cardioprotective effects in a Langendorff perfusion system, an ex vivo model of I/R. It was demonstrated that crocetin significantly attenuated the activities of pro‑inflammatory cytokines and nuclear factor erythroid‑2 related factor 2 (Nrf2)/heme oxygenase‑1 signaling. The present study provided novel insight that crocetin regulated the unfolded protein response (UPR) and decreased associated protein levels to protect the heart. Furthermore, it was identified that Nrf2 played a key role in the cardioprotective effect of crocetin by attenuating inflammation and the UPR.

Topics: Animals; Cardiotonic Agents; Carotenoids; Cell Line; Inflammation; Male; Myocardial Reperfusion Injury; Myocardium; NF-E2-Related Factor 2; Perfusion; Rats, Sprague-Dawley; Signal Transduction; Unfolded Protein Response; Vitamin A

Arsenic trioxide (ATO) has been shown to induce hepatic injury. Crocetin is a primary constituent of saffron, which has been verified to have antioxidant and anti-inflammatory effects. In the current experiment, we evaluated the efficacy of crocetin against ATO-induced hepatic injury and explored the potential molecular mechanisms in rats.. Rats were pretreated with 25 or 50 mg/kg crocetin 6 h prior to treating with 5 mg/kg ATO to induce hepatic injury daily for 7 days.. Treatment with crocetin attenuated ATO-induced body weight loss, decreases in food and water consumption, and improved ATO-induced hepatic pathological damage. Crocetin significantly inhibited ATO-induced alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) increases. Crocetin prevented ATO-induced liver malondialdehyde (MDA) and reactive oxygen species (ROS) levels. Crocetin abrogated the ATO-induced decrease of catalase (CAT) and superoxide dismutase (SOD) activity. Crocetin was found to significantly restore the protein levels of interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor-alpha (TNF-α). Furthermore, crocetin promoted the expression of nuclear factor erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADP(H): quinone oxidoreductase 1 (NQO1).. These findings suggest that crocetin ameliorates ATO-induced hepatic injury in rats. In addition, the effect of crocetin might be related to its role in antioxidant stress, as an anti-inflammatory agent, and in regulating the Nrf2 signaling pathway.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arsenic Trioxide; Carotenoids; Chemical and Drug Induced Liver Injury; Inflammation; Injections, Intraperitoneal; Male; Molecular Structure; NF-E2-Related Factor 2; Oxidative Stress; Protective Agents; Rats; Rats, Sprague-Dawley; Signal Transduction; Vitamin A

Arsenic trioxide (ATO) is commonly used to treat patients with acute promyelocytic leukemia since it was authorized by the U.S. Food and Drug Administration in the 1970s, but its applicability has been limited by its cardiotoxic effects. Therefore, the aim of the present study was to investigate the cardioprotective effects and underlying mechanism of crocetin (CRT), the critical ingredient of saffron. Sprague‑Dawley rats were then randomly divided into four groups (n=10/group): i) Control group; ii) ATO group, iii) CRT‑low (20 mg/kg) group; and iv) CRT‑high (40 mg/kg) group. Rats in the Control and ATO groups were intraperitoneally injected with equal volumes of 0.9% sodium chloride solution, and CRT groups were administered with either 20 and 40 mg/kg CRT. Following 6 h, all groups except the Control group were intraperitoneally injected with 5 mg/kg ATO over 10 days. Cardiotoxicity was indicated by changes in electrocardiographic (ECG) patterns, morphology and marker enzymes. Histomorphological changes in the heart tissue were observed by pathological staining. The levels of superoxide dismutase, glutathione peroxidase, malondialdehyde and catalase in the serum were analyzed using colometric commercial assay kits, and the levels of reactive oxygen species in the heart tissue were detected using the fluorescent probe dihydroethidium. The expression levels of inflammatory factors and activities of apoptosis‑related proteins were analyzed using immunohistochemistry. The protein expression levels of silent information regulator of transcription 1 were measured using western blotting. Cardiotoxicity was induced in male Sprague‑Dawley rats with ATO (5 mg/kg). CRT (20 and 40 mg/kg) and ATO were co‑administered to evaluate possible cardioprotective effects. CRT significantly reduced the heart rate and J‑point elevation induced by ATO in rats. Histological changes were evaluated via hematoxylin and eosin staining. CRT decreased the levels of creatine kinase and lactate dehydrogenase, increased the activities of superoxide dismutase, glutathione‑peroxidase and catalase, and decreased the levels of malondialdehyde and reactive oxygen species. Moreover, CRT downregulated the expression levels of the pro‑inflammatory factors IL‑1, TNF‑α, IL‑6, Bax and p65, as well as increased the expression of Bcl‑2. It was also identified that CRT enhanced silent information regulator of transcription 1 protein expression. Thus, the present study demonstrated that CRT treatment e

Topics: Animals; Antioxidants; Apoptosis; Arsenic Poisoning; Arsenic Trioxide; Cardiotonic Agents; Cardiotoxicity; Carotenoids; China; Heart; Inflammation; Male; Myocardium; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Vitamin A

Crocetin is a natural product possessing extraordinary therapeutic effects for various diseases. However, its extremely low solubility limits its application greatly. Conjugation of organic compounds containing heteroatoms such as N to poor soluble molecules can help the synthesized derivative to form stable hydrogen bonds by lowering the salvation energy, which will improve the solubility of the synthesized compounds. Herein, crocetin was modified by conjugating with piperidyl, diethylin and benzylamine to improve their solubility and bioactivities. In the present study, the conjugation of crocetin with piperidyl, diethylin and benzylamine and their influence on the solubility and the pharmacological effects of crocetin were investigated. With the described strategy, crocetin derivatives were synthesized and their structures were elucidated by

Topics: A549 Cells; Animals; Anticarcinogenic Agents; Apoptosis; Carotenoids; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Gardenia; Humans; Inflammation; MCF-7 Cells; Melanoma, Experimental; Mice; Plant Extracts; RAW 264.7 Cells; Vitamin A

Crocetin is an ingredient of traditional Chinese medicine and has therapeutic potential in various diseases due to its pharmacological properties, such as neuroprotection, anti-oxidative stress, and anti-inflammation. These properties might benefit the treatment of spinal cord injury. In the present study, we tested the effect of crocetin on neurite growth and sensorimotor dysfunction in a rat model of spinal cord injury. We evaluated the viability of cultured hippocampal neurons with tetrazolium dye and lactate dehydrogenase assays, visualized neurites and axons with antibody staining, and monitored motor and sensorimotor functions in rats with spinal cord injury using the Basso, Beattie, and Bresnahan assay and the contact plantar placement test, respectively, and measured cytokine expression using enzyme-linked immuno-absorbent assays. We found that crocetin (1) did not alter the viability of cultured hippocampal neurons; (2) accelerated neurite growth with preference for the longest process in individual hippocampal neurons; (3) reversed the inhibition of neurite growth by chondroitin sulfate proteoglycan and NogoA; (4) facilitated the recovery of motor and sensorimotor functions after spinal cord injury; and (5) did not inhibit pro-inflammatory responses, but restored the innervation of the descending 5-HT system in injured spinal cord. Crocetin promotes neurite growth and facilitates the recovery of motor and sensorimotor functions after spinal cord injury, likely through repairing neuronal connections.

Topics: Animals; Antioxidants; Behavior, Animal; Carotenoids; Disease Models, Animal; Hippocampus; Inflammation; Motor Activity; Neurites; Neurons; Rats; Recovery of Function; Spinal Cord Injuries; Vitamin A

Crocetin is a readily bioavailable and bioactive compound extracted from Saffron. Previous studies indicated its various biomedical properties including antioxidant and anti-coagulation potencies. However, its effect on inflammation, notably within the cardiovascular system, has not been investigated yet. In the present study, we utilized human umbilical vein endothelial cell (HUVEC) to elucidate the effect of Crocetin on vascular inflammation.. Cell viability and toxicity were evaluated by MTT and Lactate dehydrogenase (LDH) assay, respectively. Pro-inflammatory chemokine Monocyte Chemoattractant Protein-1 (MCP-1) and Interleukin-8 (IL-8) expressions were determined by RT-PCR and ELISA. With fluorescence labeled U937 cells, we examined immune cell adhesion to the inflamed HUVEC in vitro, which was further confirmed by the H&E staining in the murine subcutaneous endothelium in vivo.. Upon Lipopolysaccharide (LPS)-induced inflammatory response in HUVECs, Crocetin ameliorated cell cytotoxicity, suppressed MCP-1 and IL-8 expressions through blocking NF-κB p65 signaling transduction. Moreover, Crocetin inhibited immune cells adhesion and infiltration to inflamed endothelium, which is a key step in inflammatory vascular injury.. These findings suggest that Crocetin, a natural herb extract, is a potent suppressor of vascular endothelial inflammation.

Topics: Carotenoids; Cell Adhesion; Cell Death; Chemokine CCL2; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Interleukin-8; Lipopolysaccharides; RNA, Messenger; Signal Transduction; Transcription Factor RelA; U937 Cells; Vitamin A

Epidemiologic and experimental studies have pointed to an etiologic role of elevated plasma free fatty acids in insulin resistance, which is frequently associated with a state of low-grade inflammation. In this study, we investigated the effects of Crocetin, a unique carotenoid, on insulin resistance induced by palmitate in 3T3-L1 adipocytes. Exposure of palmitate led to an increase in insulin receptor substrate-1 (IRS-1) serine(307) phosphorylation as well as activation of c-Jun NH(2)-terminal kinase (JNK) and inhibitor kappaB kinase beta (IKKbeta), concomitantly with reductions of IRS-1 function and glucose metabolism. Interestingly, pretreatment with Crocetin almost reversed all of these abnormalities in a dose-dependent manner. IRS-1 serine(307) phosphorylation was significantly reduced by JNK or IKKbeta inhibitor, especially by combination of these two inhibitors. Moreover, palmitate treatment induced activation of protein kinase Ctheta (PKCtheta) while blocking PKCtheta significantly inhibited JNK and IKKbeta activation induced by palmitate or phorbol 12-myristate 13-acetate (PKC activator, PMA), and attenuated the palmitate-induced defects in insulin action. Crocetin demonstrated an impressive suppression in the activation of PKCtheta induced not only by palmitate but also by PMA in a dose-dependent manner. Taken together, Crocetin inhibited JNK and IKKbeta activation via suppression of PKCtheta phosphorylation, attenuating insulin insensitivity induced by palmitate in 3T3-L1 adipocytes.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Biological Transport; Carotenoids; Deoxyglucose; Enzyme Activation; Glucose; I-kappa B Kinase; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Isoenzymes; JNK Mitogen-Activated Protein Kinases; Mice; Palmitates; Phosphorylation; Protein Kinase C; Protein Kinase C-theta; Protein Kinase Inhibitors; Serine; Signal Transduction; Vitamin A