Comparative Analysis of Apigenin-3 Acetate versus Apigenin and Methyl-Prednisolone in Inhibiting Proliferation and Gene Expression of Th1 Cells in Multiple Sclerosis.

OBJECTIVE: In spite of the advances in therapeutic modalities, morbidity, due to multiple sclerosis (MS), still remains high. Therefore, a large body of research is endeavouring to discover or develop novel therapies with improved efficacy for treating MS patients. In the present study, we examined the immunomodulatory effects of apigenin (Api) on peripheral blood mononuclear cells (PBMCs) isolated from MS patients. We also developed an acetylated form of Api (apigenin- 3-acetate) to improve In its blood-brain barrier (BBB) permeability. Additionally, we compared its anti-inflammatory properties to original Api and methyl-prednisolone-acetate (a standard therapy), as a potential option in treating MS patients. MATERIALS AND METHODS: The current study was an experimental-interventional research. The half maximal inhibitory concentration (IC50) values for apigenin-3-acetate, apigenin, and methyl-prednisolone-acetate were determined in healthy volunteers' PBMCs (n=3). Gene expressions of T-box transcription factor (TBX21 or T-bet) and IFN-γ, as well as proliferation of T cells isolated from MS patients' PBMCs (n=5), were examined in co-cultures of apigenin-3-acetate, Api and methyl-prednisolone-acetate after 48 hours of treatment, using quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Our findings showed that apigenin-3-acetate, apigenin, and methyl-prednisolone-acetate at concentrations of 80, 80, and 2.5 M could inhibit Th1 cell proliferation after 48 hours (P=0.001, P=0.036, and P=0.047, respectively); they also inhibited T-bet (P=0.015, P=0.019, and P=0.022) and interferon-γ (IFN-γ) gene expressions (P=0.0001). CONCLUSION: Our findings suggested that Api may have anti-inflammatory properties, possibly by inhibiting proliferation of IFN-producing Th1 cells. Moreover, comparative immunomodulatory effects were found for the acetylated version of apigenin-3-acetate versus Api and methyl-prednisolone-acetate.

The Immunomodulatory Aspect of Quercetin Penta Acetate on Th17 Cells Proliferation and Gene Expression in Multiple Sclerosis.

OBJECTIVE: The function of Th17 cells in the neuroinflammatory process in multiple sclerosis (MS) has been previously clarified. It has been suggested that Quercetin can influence MS due to a variety of anti-inflammatory effects. The present study aimed to examine in vitro immunomodulatory aspects of Quercetin Penta Acetate as a modified compound on Th17 cells of MS patients and also to compare its effects with Quercetin. MATERIALS AND METHODS: In this experimental study, peripheral blood mononuclear cell (PBMCs) were isolated and stained with CFSE then, half-maximal inhibitory concentration (IC50) values were determined using different doses and times for Quercetin Penta Acetate, and Methyl Prednisolone Acetate. Th17 cell proliferation was analyzed by flow cytometry and the expression levels of IL-17 and RORc genes were assessed by real-time polymerase chain reaction (PCR) method. RESULTS: The results showed that IL-17 gene expression was inhibited by Quercetin Penta Acetate (P=0.0081), but Quercetin Penta Acetate did not have a significant inhibitory effect on Th17 cells proliferation (P= 0.59) and RORc gene expression (P=0.1), compared to Quercetin. CONCLUSION: Taken together, our results showed some immunomodulatory aspects of Quercetin Penta Acetate on Th17 cells are more effective than Quercetin and it could be considered in the treatment of MS.

Modulation of Th17 Proliferation and IL-17A Gene Expression by Acetylated Form of Apigenin in Patients with Multiple Sclerosis.

The presence of Th17 cells in CNS lesion of MS patients due to their inflammatory cytokines secretion is in line with the deterioration of the disease. Currently, the use of natural compounds with anti-inflammatory properties such as flavonoids have been considered to reduce inflammation in these patients, but the remaining issue is how deliver these compounds to the site of inflammation. Acetylation is a way to better uptake compound by cells and cross through cellular layers with tight junctions. This study aimed to investigate the in vitro effects of the Apigenin 3-Acetate on Th17 cells of MS patients and compare its efficacy with Apigenin and Methyl Prednisolone Acetate. IC50 for Apigenin 3-Acetate, and Methyl Prednisolone Acetate were determined using three healthy volunteers. The peripheral blood mononuclear cells (PBMCs) of five MS patients were isolated and co-cultured with a selected dose of Apigenin, Apigenin 3-Acetate, and Methyl Prednisolone Acetate for 48 hr, and then theproliferation of Th17 cells in isolated PBMCs was assessed by flow cytometry. The levels of RAR-related orphan receptor (RORC) and IL-17A expression were also determined by quantitative real-time PCR. The results showed that Apigenin 3-Acetate inhibited Th17 cells proliferation (P value: 0.018) at 80 µM concentration after 48 hr. Additionally, IL-17A gene expression significantly (P value≤ 0.0001) inhibited by Apigenin, Apigenin 3-Acetate and Methyl Prednisolone Acetate in 80 µM, 80 µM and 2.5 µM (selected dose in IC50 determination) respectively These results demonstrate that Acetate increases anti-inflammatory effects of Apigenin on Th17 cells.

Therapeutic potential of quercetin on human breast cancer in different dimensions.

BACKGROUND: There has been an extensive range of incidence and mortality of breast cancer (BC), and the comprehensively available treatments for BC have not been completely successful in achieving satisfactory outcomes up to date. HYPOTHESIS: Recently, we are watching intense attention paid to the utilization of natural compounds as a novel therapeutic strategy for cancer treatment. Quercetin, a dietary flavonol in a large group of commonly consumed foods, is widely illustrated to apply inhibitory effects on cancer progression through several mechanisms including apoptosis enhancement, cell cycle arrest, metastasis and angiogenesis inhibition, antioxidant replication and estrogen receptor modulation. METHODS: We reviewed the most relevant papers published from 2009 to 2018 (except 15 articles), using "pub med" and "web of science" and the search terms "Quercetin"; "Breast cancer"; "Flavonoid"; "Apoptosis"; "Cell cycle"; "chemotherapy"; "Drug resistance"; "Metastasis; "Oxidative stress", "Breast cancer receptors" and "Quercetin derivatives". We selected studies on the association of quercetin with breast cancer in different dimensions. RESULTS: Despite the remarkable number of studies on quercetin's efficacy, multiple aspects of this herbal compound have not been clarified well and this review provides a summarized update of the recent evidence on biologically available efficacies of quercetin which would establish a further biological basis for the potential therapeutic acquisition of quercetin as an anticancer drug. CONCLUSION: Basic, epidemiological and genetic studies point to the potential role of quercetin in the treatment of breast cancer, but randomized and controlled trials are of great importance to establish the clinical efficacy of quercetin in ill or at-risk subjects.

The significant impact of apigenin on different aspects of autoimmune disease.

Autoimmune diseases are among the highest diseases to diagnose and treat. The current "gold standard" of care for these diseases is immunosuppressive drugs which interfere with overall immune responses; their long-term high-dose treatments would expose the patient to opportunistic, life-threatening and long-term malignant infections. Considering the side effects and toxicity of these drug and also the beneficial effects of herbal compounds among their consumers, the professional investigation on the exact mechanism of the plant's major element has grown much attention in the last years. Apigenin as an extracting compound of plants, such as parsley and celery, which has a variety of biological effects, such as anti-inflammatory, anti-cancer and antioxidant effects. This review is intended to summarize the various effects of Apigenin on several autoimmune diseases which have been worked on so far. The pluralization of the obtained results has revealed Apigenin's effects on pro-inflammatory cytokines such as IL-1ß, chemokines such as ICAM-1, immune cells proliferation such as T cells, apoptosis, and various signaling pathways. According to these preclinical findings, we recommend that further robust unbiased studies should be done to use Apigenin as a supplementary or therapeutic element in autoimmune disease.