Significant Effect of Crocin on the Gene Expression of MicroRNA-21 and MicroRNA-155 in Patients with Osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis associated with gradual joint destruction. The current treatment aims to alleviate pain and inflammation and improve the quality of life. Crocin is an active ingredient in saffron, with anti-inflammatory properties. MicroRNAs are small, non-coding RNAs that regulate gene expression. We aimed to evaluate the effect of crocin on the gene expression of microRNA-146a, microRNA-155, microRNA-223, and microRNA-21 in OA patients and compare it with a placebo. This study was approved and registered in the Iranian Registry of Clinical Trials (2015021910507N2) and ClinicalTrials.gov identifier: NCT03375814. Forty OA patients were randomly divided into two equal groups, receiving either crocin or placebo. Peripheral blood samples were collected before and four months after the intervention. The pain was assessed using the visual analog scale, and laboratory tests included C-reactive protein and erythrocyte sedimentation rate. The expression levels of microRNA-146a, microRNA-155, microRNA-223, and microRNA-21 genes were evaluated by SYBR Green real-time PCR. The results showed that the gene expression levels of microRNA-21 and microRNA-155 in patients receiving crocin were significantly decreased and increased, respectively. No significant changes were observed in microRNA-146a and microRNA-223 gene expression levels. In conclusion, crocin's anti-inflammatory role might be partly attributed to its effects on the gene expression of microRNA-21 and microRNA-155.

A Significant Reduction in the Plasma Levels and Gene Expression of CCL2 in Patients with Osteoarthritis following Intervention with Krocina™.

Background: inflammatory chemokines such as CCL2 and CCL5 are involved in the progress of osteoarthritis. Crocin with antioxidant and anti-inflammatory properties can reduce the symptoms of osteoarthritis (OA). This study was performed investigate the effect of Krocina™, on the gene expressions and plasma levels of CCL2 and CCL5 in OA patients. Methods: The study included 35 patients that were randomized in the Krocina™ and placebo groups. The intervention was Krocina™ 15mg daily for four months. Clinical and paraclinical parameters were measured. CCL2 and CCL5 genes expression and plasma levels were determined using the SYBR Green Real-Time RT-PCR and Enzyme-linked Immunosorbent Assay (ELISA) techniques. Results: The C-reactive protein (CRP) value in the Krocina™ group and the visual analogue scale (VAS) value in the Krocina™ and placebo groups decreased significantly after the intervention. The gene expression of CCL2 in the Krocina™ and placebo groups decreased significantly. On the contrary, the gene expression of CCL5 in the Krocina™ and placebo groups increased significantly. Moreover, the plasma levels of CCL2 in the Krocina™ and placebo groups decreased meaningfully. There was no difference regarding the plasma levels of CCL5 within the Krocina™ and placebo groups before and after the intervention in either of the groups. Conclusion: Administration of Krocina™ reduced the clinical signs of inflammation and CRP and VAS value. Also, Krocina™ significantly decreased the plasma levels and gene expression of CCL2 in osteoarthritis patients.

A Significant Increase in the Gene Expression of GATA-3 Following the Treatment of Osteoarthritis Patients with Crocin.

Osteoarthritis (OA) is known to be the most prevalent form of joint disease. We conducted this clinical trial to investigate the effects of KrocinaTM, a natural product containing crocin, on the gene expression of unique transcription factors of various T cell subsets in patients with OA. We collected 40 peripheral blood samples of OA patients receiving Krocina™ and equal number of those who took a placebo (IRCT2015021910507N2, NCT03375814). RNA extraction was performed from the cultured peripheral blood mononuclear cells of the OA patients who received Krocina™ and placebo and SYBR Green Real-time PCR technique was applied to assess the relative gene expression of T-bet, GATA3, ROR-γt, and FOXP3 as the unique transcription factors of various T cell subsets. The relative gene expression of T-bet and ROR-γt insignificantly decreased in the Krocina™ receiving group as compared to the placebo group. In addition, the relative gene expressions of GATA-3 and FOXP3 after the treatment with KrocinaTM showed a significant and insignificant increase, respectively. Moreover, an insignificant decrease was observed in the gene expression of GATA-3 and FOXP3 in the placebo group. A significant and insignificant decrease in the gene expression of T-bet and ROR- γt was detected in the OA patients who received a placebo. GATA-3 is known as a unique transcription factor for the differentiation of T-cells to the Th2 subset. The significant increase in the gene expression of GATA-3 in the patients with OA treated with crocin may suggest the beneficial effect of crocin on shifting towards the Th2 subset and enhancing an anti-inflammatory condition.

Immunoregulatory Effects of Krocina™, a Herbal Medicine Made of Crocin, on Osteoarthritis Patients: A Successful Clinical Trial in Iran.

Osteoarthritis (OA) is the major cause of joint pain and disability. This research was planned to examine the effects of Krocina™, aherbal medicine made of crocin, an ingredient of saffron, in patients with OA. Forty patients suffering from OA were enrolled in our study and randomly divided into two groups, receiving Krocina™ and placebo, and the clinical trial continued for four months.Peripheral blood was taken from all patients and the percentage ofvarious subsets of T cells in addition to the levels of forkhead box protein P3 (FOXP3) and interleukin (IL)-17 were measured by flow cytometry technique. The visualan alog scale (VAS) index analysis decreased significantly in both groups (krocinaTM and placebo) (p<0.05). Assessment of the C-reactive protein (CRP) level in serum showed a significant decrease in the krocinaTM group (p<0.05). Moreover, we found a meaningful increase in the percentage of regulatory T cells (Tregs)cellin samples gathered from Krocina™ group (P=0.02) patients. The mean percentages of T helper (Th) 17 cellsinthe Krocina™ group and CD8+ T cellsin the placebo group patients were also meaningfully reduced (p<0.05). The geometric mean fluorescence intensity (GMFI) for IL-17 showed a significant decrease and increase in Krocina™ and placebo groups, respectively (p<0.05). No noticeable difference was observed in the percentages of Th cells and GMFI-FOXP3 in either group. Treg/Th17 ratio was shifted towards Tregscell in Krocina™ group at the end of the intervention. It is concluded that Krocina™ has immunoregulatory effects on patients with OA, ameliorating the disease.

Crocus Sativus (Saffron): An Immunoregulatory Factor in the Autoimmune and Non-autoimmune Diseases.

It has been reported that patients with arthritis, osteoarthritis, atherosclerosis, coronary artery disease, brain ischemia, diabetes, and inflammatory bowel disease (IBD) suffer from pro-inflammatory and oxidant related responses. Therefore, anti-inflammatory and anti-oxidant therapies are used to improve the quality of life of the patients. Saffron is a herbal drug that has immunomodulatory and antioxidant properties. Hence, Saffron and its components have been proposed as therapeutic agents for the treatment of the diseases. Therefore, this review article was designed to collect recent information regarding the effects of saffron and its components on the amelioration of the inflammatory symptoms in the autoimmune and non-autoimmune diseases and anti-cancerous effects from 1999 up to now via searching the Pubmed, Google Scholar, and Scopus databases. Due to fact that several investigations have reviewed the roles played by Saffron on autoimmune and non-autoimmune diseases such as multiple sclerosis, mood disorders, and Alzheimer's disease, this review article focuses on other diseases to keep the novelty of the present review for readers.

Amelioration of clinical symptoms of patients with refractory rheumatoid arthritis following treatment with autologous bone marrow-derived mesenchymal stem cells: A successful clinical trial in Iran.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune arthropathy characterized by synovial hyperplasia leading to functional impairment. Although the exact cause of RA is unknown, there is evidence suggesting the role of T cell subtypes in the pathogenesis of RA. Conventional therapy in some RA patients is associated with mild or severe side effects, and resistance of some patients has been reported to these types of therapy. The therapeutic potential of mesenchymal stem cells (MSCs) introduced them as a novel therapeutic choice for the treatment of rheumatic diseases. The aim of our study was to evaluate the effects of intravenous administration of autologous bone marrow-derived MSCs on the immunological, clinical and para-clinical factors such as regulatory T cells, Th17 cells, CD8+ T cells, CD4+ T cells, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR), visual analogue scale (VAS), ESR, C-reactive protein (CRP), rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP) antibodies in patients with refractory RA. Nine refractory RA patients with no other rheumatologic disorders were included in this study. All patients received a single intravenous dose of 1 × 106 autologous bone marrow-derived MSCs/kg, and were followed up at 1, 6 and 12 months after injection of MSCs. We found a significant decreasing trend in Th17 percentage and geometric mean fluorescence intensity for IL-17A following injection of MSCs at 12 months compared to the time point zero. Furthermore, a significant increase in regulatory T cells percentage was observed at the end of the first month after the intervention. DAS28-ESR decreased significantly at 1 and 12 months after MSC therapy. VAS score showed a significant decreasing trend during the follow-up periods. No significant difference was found for serum CRP and anti-CCP levels after the intervention. In conclusion, our data indicated that clinical symptoms were significantly ameliorated following the intravenous injection of autologous bone marrow-derived MSCs to the patients with refractory RA.