Challenges in Mesenchymal Stromal Cell-based Therapies.

Over 50 years have passed since discovering mesenchymal stromal cells (MSCs). Initially, despite gaps in the knowledge of the identity of these cells, their therapeutic aspects were recognized. Consequently, MSCs became candidates for treating a wide range of diseases. However, the therapeutic effects of MSCs are not stable in the long term, and there are inconsistent data on their clinical efficacy. Even though more than 1000 MSC-based clinical trials have been registered, and the safety of MSCbased cell therapies has been proven, data on the clinical efficacy of MSCs have not been enough to warrant FDA approval for clinical treatment and marketing purposes. The available information on MSCs still contains some controversies, perhaps owing to little progress in understanding their in vivo identity. MSCs have been used for therapeutic purposes despite poor knowledge of their in vivo origin or functions. Hence, perhaps we need to go back to the basics of MSCs and spend more time understanding the biology of these cells. An improved understanding of MSCs' location and function within tissues may improve their therapeutic efficacy and, consequently, their establishment as a cell therapy product.

Mesenchymal Stem Cells Regenerate Diabetic Foot Ulcers: A Review Article.

Background: Diabetes is one of the metabolic diseases characterized by hyperglycemia, with many complications. Diabetic foot ulcer (DFU) is a significant complication of diabetes. Various therapy procedures have been recently described for DFU improvement. Methods: Using PubMed, Scopus, Science Direct, and Google Scholar to discover the therapeutic effects of bee products, this review study was conducted in 2018-2019 by searching PubMed, Scopus, Science Direct, and Google Scholar databases. Results: Cell therapies with various cell candidates such as mesenchymal stem cells (MSCs) are increasingly introduced into routine medical care to manage skin wounds. The applying of these cells for tissue regeneration was initially based on the capability of MSCs to differentiate into specialized cells within the injured tissue. Paracrine signaling and differentiation mechanisms have both been contributed to improving tissue repair by MCSs. However, the role of MSCs differentiation is less due to the poor survival of these cells at the site of injury. Conclusion: At the same time, paracrine signaling or their secretome is the primary mechanism of MSCs that stimulate neovascularization and re-epithelialization and mobilization of inhabitant stem cells. In this review study, we discuss the role of MSCs and their secretome that can improve the use of this new approach in treating ulcers and DFU.

Flow Cytometric Measurement of Reactive Oxygen Species to Assess the Effects of Preconditioning Total Body Irradiation on NOG Mice.

BACKGROUND: Preclinical development of new drugs for cancer immunotherapy requires preconditioning total body irradiation (TBI) of mice to be humanized via hematopoietic stem cell transplantation. To assess the effect of preconditioning TBI, we detected the reactive oxygen species (ROS), Annexin V, propidium iodide (PI) level in bone marrow samples by flow cytometer. METHODS: We divided all NOG mice between irradiated (n = 20) and control groups (n = 10) for two time points. Irradiated mice were exposed to 3.5 Gy of radiation. After sacrificing BM samples were collected, the flow cytometric percentage of ROS, Annexin V, and PI markers were investigated on days 2 and 14 after exposure. RESULTS: At the first time point, the level of ROS was higher in the irradiated group than in the control group, and this difference was statistically significant (P < 0.05). Also, at the second time point, the mean differences of all markers in the irradiated group were significantly compared to the control group (P < 0.05). CONCLUSION: Thus, in NOG mice, the measurement of ROS level is helpful to the assessment of preconditioning TBI.

Application of Wharton jelly-derived mesenchymal stem cells in patients with pulmonary fibrosis.

Pulmonary fibrosis is a devastating disease that eventually leads to death and respiratory failure. Despite the wide range of drugs, including corticosteroids, endothelin antagonist, and pirfenidone, there is no effective treatment, and the only main goal of treatment is to alleviate the symptoms as much as possible to slow down the progression of the disease and improve the quality of life. Lung transplantation may be a treatment option for a few people if pulmonary fibrosis develops and there is no established treatment. Pulmonary fibrosis caused by the COVID19 virus is another problem that we face in most patients despite the efforts of the international medical communities. Therefore, achieving alternative treatment for patients is a great success. Today, basic research using stem cells on pulmonary fibrosis has published promising results. New stem cell-based therapies can be helpful in patients with pulmonary fibrosis. Wharton jelly-derived mesenchymal stem cells are easily isolated in large quantities and made available for clinical trials without causing ethical problems. These cells have higher flexibility and proliferation potential than other cells isolated from different sources and differentiated into various cells in laboratory environments. More clinical trials are needed to determine the safety and efficacy of these cells. This study will investigate the cellular and molecular mechanisms and possible effects of Wharton jelly-derived mesenchymal stem cells in pulmonary fibrosis.

Probiotic effects on sperm parameters, oxidative stress index, inflammatory factors and sex hormones in infertile men.

Decreased sperm motility is one of the main causes of male infertility. The aim of this study was to evaluate the effects of probiotic supplementation on semen quality, seminal oxidative stress biomarkers, inflammatory factors and reproductive hormones. In this randomised, double-blind controlled clinical trial, 52 men with idiopathic oligoasthenoteratozoospermia attending a urology clinic, were randomly assigned to either an intervention or placebo (n = 26) group. This investigation was registered by the identification code of IRCT20141025019669N7 in the clinical trials registry of Iran. The Intervention group took 500 mg of Probiotics daily and the placebo group took a daily placebo for 10 weeks. Semen parameters, total antioxidant capacity, malondialdehyde, inflammatory factors and reproductive hormones were measured at baseline and at the end of the study. After the intervention, ejaculate volume, number, concentration and the percentage of motile sperm, total antioxidant capacity of plasma significantly increased and the concentration of plasma malondialdehyde and inflammatory markers significantly decreased in the intervention group. Probiotic supplementation in infertile men lead to a significant increase in sperm concentration and motility and a significant reduction in oxidative stress and inflammatory markers. Therefore, oral intake of probiotics has the potential to be one of the ways to deal with oxidative damage of sperm.

Development and Clinical Application of Tumor-derived Exosomes in Patients with Cancer.

A tumor is an abnormal growth of cells within a tissue that can lead to death due to late diagnosis, poor prognosis, drug resistance, and finally enhanced metastasis formation. Exosomes are nanovesicles that have been derived from all the different cell types. These vesicles can transfer various molecules, including the distinct form of nucleic acids (mRNA, miRNA, and circRNA) and proteins. Tumor-derived exosomes (TEXs) have exceptionally important roles through multiple molecular and cellular pathways like progression, tumorigenesis, drug resistance, and as well as metastasis. TEXs are detectable in all body fluids such as serum and urine, a convenient and non-invasive way to access these nano-sized vesicles. TEXs lead to the symptom expression of genetic aberrations in the tumor cell population, making them an accurate and sensitive biomarker for the diagnosis and prognosis of tumors. On the other hand, TEXs contain major histocompatibility complexes (MHCs) and play important dual roles in regulating tumor immune responses: they can mediate both immune activation and suppression through tumor-associated immunity. Despite numerous scientific studies, there are still many technical barriers to distinguish TEXs from non-tumor-derived exosomes. Even so, removing exosomes leading to a wide difference in outcomes inside a patient's body. Hence, controversial pieces of evidence have demonstrated the vital role of TEXs as hopeful biomarkers for the early detection of cancers, evaluation of therapeutic effects, and monitoring of the patient.

Improving Effect of Ellagic Acid on Sleep Quality and Gastrointestinal Symptoms in Patient With Irritable Bowel Syndrome: Randomized Double-Blind Clinical Trial.

BACKGROUND: The quality of sleep in people with irritable bowel syndrome (IBS) is reduced by increased oxidative stress and clinical problems. Assessing the effects of ellagic acid (EA) on sleep quality and gastrointestinal symptoms in patients with IBS was the aim of this study. METHODS: In this research that was conducted as a randomized, double-blind, placebo-controlled clinical trial, 44 patients with IBS were enlisted. Individuals approved by the project clinical counselor were divided into two intervention groups to receive 180 mg of EA per day (n = 22) and a placebo group (n = 22) for 2 months. Petersburg's Sleep Quality (PSQI) questionnaire and IBS severity score system (IBSSS) were assessed at the beginning and end of the study. Statistical analysis was performed using SPSS software. RESULTS: At the end of the study, changes in mean PSQI and scores related to sleep subgroups were significant between the two groups (P < .05). Also, the significant changes were not seen in sleep and sleep subgroups scores in the placebo group at the end of the study (P > .05). EA consumption reduced IBSSS score and IBS symptoms in the intervention group after 2 months (P < .05). DISCUSSION: The results arisen from this study indicated that receiving EA had a beneficial effect on sleep quality and gastrointestinal symptoms in IBS patients. The antioxidant and anti-inflammatory properties of EA may be responsible for these beneficial effects.

The Hippo signaling pathway in leukemia: function, interaction, and carcinogenesis.

Cancer can be considered as a communication disease between and within cells; nevertheless, there is no effective therapy for the condition, and this disease is typically identified at its late stage. Chemotherapy, radiation, and molecular-targeted treatment are typically ineffective against cancer cells. A better grasp of the processes of carcinogenesis, aggressiveness, metastasis, treatment resistance, detection of the illness at an earlier stage, and obtaining a better therapeutic response will be made possible. Researchers have discovered that cancerous mutations mainly affect signaling pathways. The Hippo pathway, as one of the main signaling pathways of a cell, has a unique ability to cause cancer. In order to treat cancer, a complete understanding of the Hippo signaling system will be required. On the other hand, interaction with other pathways like Wnt, TGF-ß, AMPK, Notch, JNK, mTOR, and Ras/MAP kinase pathways can contribute to carcinogenesis. Phosphorylation of oncogene YAP and TAZ could lead to leukemogenesis, which this process could be regulated via other signaling pathways. This review article aimed to shed light on how the Hippo pathway interacts with other cellular signaling networks and its functions in leukemia.

Randomized double blind clinical trial evaluating the Ellagic acid effects on insulin resistance, oxidative stress and sex hormones levels in women with polycystic ovarian syndrome.

OBJECTIVE: The design of this study was due to the report of the antioxidant properties of Ellagic acid (EA) for its evaluation on the Insulin resistance (IR), oxidative stress and sex hormones levels in women with polycystic ovarian syndrome (PCOS). METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 60 patients were recruited. Patients were randomly allocated consumed a capsule containing 200 mg of EA per day (n = 30) or placebo (n = 30) for 8 weeks. The fasting blood sugar (FBS), insulin, IR, total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), total antioxidant capacity (TAC), Malondialdehyde (MDA), C-reactive protein (CRP), Tumor necrosis factor-alpha (TNF-α), sex hormones and anti-mullerian hormone (AMH) were measured at the beginning and end of the study. RESULT: At the end of the study, the mean of FBS, insulin, IR, TC, TG, LDL, MDA, CRP, TNF-α, total testosterone, prolactin and AMH were significantly decreased in the intervention group compared to the placebo group (P < 0.05). Also, there was a significant increase in the mean of TAC after supplementation with EA (P < 0.05). At the end of the study, no significant changes were observed in the mean of anthropometric factors, physical activity and food intake (P > 0.05). CONCLUSION: EA supplementation can be helpful as a diet supplement in women with PCOS through improvement in insulin resistance. This supplement may be used to reduce metabolic disorders in women. TRIAL REGISTRATION: This study was retrospectively (07-07-2019) registered in the Iranian website ( www.irct.ir ) for registration of clinical trials ( IRCT20141025019669N12 ).

Decreased insulin resistance in diabetic patients by influencing Sirtuin1 and Fetuin-A following supplementation with ellagic acid: a randomized controlled trial.

BACKGROUND: The beneficial effects of polyphenols have been reported. This study aimed to investigate the effect of oral Ellagic acid (EA) supplement on insulin resistance (IR) and Fetuin-A and serum sirtuin1 (SIRT1) in type 2 diabetics. METHODS: In this double-blind, randomized clinical trial, 44 diabetic patients were selected. Patients were assigned to the intervention group (22 subjects) and placebo (22 subjects) and received a capsule containing 180 mg of EA per day or placebo for eight weeks, respectively. At the beginning and end of the study, anthropometric indices, fasting plasma glucose (FPG), plasma insulin level, IR, Fetuin-A, and SIRT1 were measured. Statistical analysis was performed using SPSS software. RESULTS: At the beginning and end of the study, there was no significant difference between the two groups regarding anthropometric indices (P > 0.05). At the end of the survey, EA supplementation significantly reduced FPG, insulin, IR, and Fetuin-A and increased SIRT1 levels compared with the placebo group (P < 0.05). However, these changes were not significant in the placebo group (P > 0.05). CONCLUSION: EA with antioxidant properties plays an essential role in reducing the macrovascular and microvascular complications of diabetes by reducing inflammation and insulin resistance. Trial registration The protocol of this clinical trial is registered with the Iranian Registry of Clinical Trials ( http://www.IRCT.IR , identifier: IRCT20141025019669N13).

Curcumin Nanomicelle Improves Lipid Profile, Stress Oxidative Factors and Inflammatory Markers in Patients Undergoing Coronary Elective Angioplasty; A Randomized Clinical Trial.

BACKGROUND: Curcumin has demonstrated many pharmacological effects including antioxidants, anti-inflammation, eliminating free radicals, anti-tumor, lipid regulation, and anti-coagulation. OBJECTIVE: This study aimed to assess and compare the effects of curcumin and nano-curcumin on lipid profile, oxidative stress, and inflammatory factors related to patient's heart. METHODS: This randomized, double-blind, placebo-controlled clinical trial was conducted on 90 patients undergoing coronary elective angioplasty who were randomly divided into 3 groups. The doses administered for 8 weeks were a 500 mg capsule of curcumin daily for the first group and an 80 mg capsule of nano-curcumin for the second group. However, the placebo group received capsules like curcumin. Lipid profile, oxidative stress factors, and inflammatory markers were measured at the baseline and end of the experiment. RESULTS: Statistically significant changes were observed in the total cholesterol (TC), triacylglycerol (TG) and low-density lipoprotein cholesterol (LDL-C) in the intervention groups to the control group (p<0.05). Curcumin and nano-curcumin supplementation also exhibited significant changes in plasma levels of total antioxidant capacity (TAC), malondialdehyde (MDA), Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), high-sensitivity C-reactive protein (hs- CRP), Interleukin 1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) in comparison to the placebo (p<0.05). Furthermore, the nano-curcumin group compared to the curcumin group demonstrated significant changes (p<0.05) in TC, TG, SOD, MDA and TNF-α levels. CONCLUSION: The effects of curcumin on nano formula may be better for cardiac patients due to its high bioavailability.

Effect of lipoic acid supplementation on gene expression and activity of glutathione S-transferase enzyme in infertile men.

Oxidative stress has become the focus of interest as a potential cause of male infertility. We evaluate effects of lipoic acid (LA) supplementation on glutathione S-transferase (GST) expression. This randomized, triple-blind, placebo-controlled clinical trial was conducted on 44 infertile males with idiopathic asthenozoospermia. Men were randomized to receive 600 mg LA or placebo once daily for 12 weeks and semen samples and venous blood samples were obtained. GST expression, reactive oxygen species (ROS) levels, GST activity and reproductive hormone profiles were also measured. GST expression in the intervention group were significantly higher than the control group. Also, at the end of the study, GST activity increased, and ROS levels decreased significantly compared to the baseline. Additionally, the intervention group showed an increase in testosterone and decrease in serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin after 12 weeks, but this difference was not significant. We conclude a 12-week treatment with LA leads to improvements in reproductive hormones in serum, and significantly reduces the generation of ROS and increases the gene expression and activity of GST in seminal fluid.

Randomized, double-blind, placebo-controlled clinical trial studying the effects of Turmeric in combination with mefenamic acid in patients with primary dysmenorrhoea.

Primary dysmenorrhea (PDM) is one of the common complaints in women. This study aimed to assess the effects of turmeric and mefenamic acid and a combination compared with placebo on PDM. This clinical trial was conducted on dormitory students with PDM. Subjects completed the visual analog scale (VAS) before randomization. One hundred twenty-eight patients, randomly assigned to one of following groups: Turmeric group (n=32), mefenamic acid group (n=32), turmeric and mefenamic acid group (n=32), and placebo group (n=32). Turmeric and mefenamic acid were administrated in 500mg and 250mg, respectively. Pain severity was assessed in the baseline and the end line by VAS. Statistical analysis was performed using SPSS software. The combination of turmeric and mefenamic acid, dramatically, alleviated pain in comparison to other groups. Our results illustrated that combination of turmeric and mefenamic acid would be better in pain alleviation in PDM.

The Role of the Curcumin for Inducing Apoptosis in Acute Lymphoblastic Leukemia Cells: A Systematic Review.

Acute lymphoblastic leukemia (ALL) is a hematological malignancy of lymphoid progenitor cells associated with excessive proliferation of lymphocytes. Curcumin, a polyphenolic compound, is known to possess anticancer activity. However, the mechanism of apoptosis induction differs in cancers. In this study, we discuss the potential apoptosis and anticancer effect of curcumin on the ALL. After choosing Medical Subject Headings (MeSH) keywords, including "Curcumin", "acute lymphoblastic leukemia", "apoptosis", as well as searching Medline/PubMed, Scopus, Sciencedirect. hand searching in key journals, list of references of selected articles and gray literature, without time and language limitation, articles up to December 2017 were entered into this review. In this review, 244 articles were acquired at the primary search. Study selection and quality assessment processes were done based on Cochrane library guidelines. According to six articles that were selected, curcumin could enhance the antitumor activity of chemotherapy drugs such as L-asparaginase. Curcumin induces apoptosis in Pre B- ALL and T- ALL cells by decreased NF-kB levels, increased p53 levels, PARP-1 cleavage. Also, the induction of growth-arrest and apoptosis in association with the blockade of constitutively active JAK-STAT pathway suggests this be a mechanism by curcumin. Curcumin could be used for the treatment of cancer like ALL.

The role of mesenchymal stromal cells in immune modulation of COVID-19: focus on cytokine storm.

The outbreak of coronavirus disease 2019 (COVID-19) pandemic is quickly spreading all over the world. This virus, which is called SARS-CoV-2, has infected tens of thousands of people. Based on symptoms, the pathogenesis of acute respiratory illness is responsible for highly homogenous coronaviruses as well as other pathogens. Evidence suggests that high inflammation rates, oxidation, and overwhelming immune response probably contribute to pathology of COVID-19. COVID-19 causes cytokine storm, which subsequently leads to acute respiratory distress syndrome (ARDS), often ending up in the death of patients. Mesenchymal stem cells (MSCs) are multipotential stem cells that are recognized via self-renewal capacity, generation of clonal populations, and multilineage differentiation. MSCs are present in nearly all tissues of the body, playing an essential role in repair and generation of tissues. Furthermore, MSCs have broad immunoregulatory properties through the interaction of immune cells in both innate and adaptive immune systems, leading to immunosuppression of many effector activities. MSCs can reduce the cytokine storm produced by coronavirus infection. In a number of studies, the administration of these cells has been beneficial for COVID-19 patients. Also, MSCs may be able to improve pulmonary fibrosis and lung function. In this review, we will review the newest research findings regarding MSC-based immunomodulation in patients with COVID-19.

Perspective of placenta derived mesenchymal stem cells in acute liver failure.

Acute Liver failure (ALF) is a life-threatening disease and is determined by coagulopathy (with INR ≥ 1.5) and hepatic encephalopathy as a result of severe liver injury in patients without preexisting liver disease. Since there are problems with liver transplantation including lack of donors, use of immunosuppressive drugs, and high costs of this process, new therapeutic approaches alongside current treatments are needed. The placenta is a tissue that is normally discarded after childbirth. On the other hand, human placenta is a rich source of mesenchymal stem cells (MSCs), which is easily available, without moral problems, and its derived cells are less affected by age and environmental factors. Therefore, placenta-derived mesenchymal stem cells (PD-MSCs) can be considered as an allogeneic source for liver disease. Considering the studies on MSCs and their effects on various diseases, it can be stated that MSCs are among the most important agents to be used for novel future therapies of liver diseases. In this paper, we will investigate the effects of mesenchymal stem cells through migration and immigration to the site of injury, cell-to-cell contact, immunomodulatory effects, and secretory factors in ALF.

Mesenchymal stromal cells induce inhibitory effects on hepatocellular carcinoma through various signaling pathways.

Hepatocellular carcinoma (HCC) is the most prevalent type of malignant liver disease worldwide. Molecular changes in HCC collectively contribute to Wnt/ß-catenin, as a tumor proliferative signaling pathway, toll-like receptors (TLRs), nuclear factor-kappa B (NF-κB), as well as the c-Jun NH2-terminal kinase (JNK), predominant signaling pathways linked to the release of tumor-promoting cytokines. It should also be noted that the Hippo signaling pathway plays an important role in organ size control, particularly in promoting tumorigenesis and HCC development. Nowadays, mesenchymal stromal cells (MSCs)-based therapies have been the subject of in vitro, in vivo, and clinical studies for liver such as cirrhosis, liver failure, and HCC. At present, despite the importance of basic molecular pathways of malignancies, limited information has been obtained on this background. Therefore, it can be difficult to determine the true concept of interactions between MSCs and tumor cells. What is known, these cells could migrate toward tumor sites so apply effects via paracrine interaction on HCC cells. For example, one of the inhibitory effects of MSCs is the overexpression of dickkopf-related protein 1 (DKK-1) as an important antagonist of the Wnt signaling pathway. A growing body of research challenging the therapeutic roles of MSCs through the secretion of various trophic factors in HCC. This review illustrates the complex behavior of MSCs and precisely how their inhibitory signals interface with HCC tumor cells.

Effect of alpha-lipoic acid at the combination with mefenamic acid in girls with primary dysmenorrhea: randomized, double-blind, placebo-controlled clinical trial.

Primary dysmenorrhea is a common gynecologic disorder and is one of the main causes for referral to the gynecology clinic. This study aimed to determine the effects of alpha-lipoic acid (ALA) and mefenamic acid and a combination compared with placebo on the girls with primary dysmenorrhea. This double-blind, placebo-controlled clinical trial done on population consisted of female students living in dormitories of Qazvin University of Medical Sciences who had moderate to severe dysmenorrhea using the Visual Analog Scale (VAS) questionnaire. Participants were randomly divided into four groups (n = 100): ALA, mefenamic acid, ALA + mefenamic acid and placebo groups. ALA and mefenamic acid were administrated in 600 mg and 250 mg, respectively. The severity of the pain was measured in the beginning and the end of the study. Statistical analysis was performed using SPSS software (SPSS Inc., Chicago, IL). Our final results suggested that, although mefenamic acid significantly decreased the menstrual pain, ALA supplementation, 600 mg, would be more efficient than mefenamic acid in 250 mg. Also, the combination of ALA and mefenamic acid significantly has been far. Considering the ALA supplementation effect on pain relief in patients with primary dysmenorrhea, this antioxidant can be recommended for the healing of symptoms of these patients.

Mutations and Common Polymorphisms in ADAMTS13 and vWF Genes Responsible for Increasing Risk of Thrombosis.

BACKGROUND AND OBJECTIVE: ADAMTS13 (A Disintegrin-like and Metalloproteases with Thrombospondin type-1 repeats, member-13) plays an important role in vascular hemostasis by cleaving the von Willebrand Factor (vWF). ADAMTS13 and vWF are involved in the development of ischemic heart disease. In this review paper, we examine the effects of Single Nucleotide Polymorphisms (SNPs) and mutations in the vWF and ADAMTS13 genes and their contribution to the development of thrombosis. METHODS: Relevant English-language literature was searched and retrieved from PubMed search engine (2001-2017). The following keywords were used: "ADAMTS13", "vWF", "Polymorphism", and Thrombosis". RESULTS: SNPs in the ADAMTS13 and vWF genes cause genetic variability and affect the plasma levels of these genes. Moreover, environmental (such as age, smoking, hypertension) and genetic factors (like ABO blood groups) play a role in the development of different polymorphisms in ADAMTS13 and vWF genes. CONCLUSION: The increased or decreased activity of these two genes as a result of genetic changes and the development of thrombosis are a challenging and contradictory matter, and the study of genetic variability in ADAMTS13 and vWF genes may be helpful in the diagnosis of thrombotic disorders.

Vitamin E and fish oil, separately or in combination, on treatment of primary dysmenorrhea: a double-blind, randomized clinical trial.

Primary dysmenorrhea is one of the most common complaints of women. The aim of this study was to investigate the adjuvant effect of vitamin E and omega-3 fatty acids, separately or in combination, supplements on pain in the treatment of primary dysmenorrhea. This clinical trial conducted on students of university. Qualified girls completed the VAS before randomization. Arrangement was determined according to the severity of the pain (mild 0-3; moderate 3.1-6; severe 6.1-10). One hundred patients were randomly assigned to four groups receiving omega-3 (n = 25), vitamin E (n = 25), vitamin E- omega-3 (n = 25), or placebo (n = 25). Three hundred milligrams of omega-3 capsules (180 mg EPA and 120 mg DHA) and 200 international units (IU) vitamin E were administered daily. Severity of the pain measured in the beginning and the end of the study. Omega-3 and vitamin E supplements effectively relieved menstrual pain compared with the placebo. But in group with combination of vitamin E + omega-3 has a considerable effect on menstrual pain when compared with other groups (p < .05). Using of Nonsteroidal anti-inflammatory drug has high complication; however, Fish oil and vitamin E are helpful in reducing of dysmenorrhea pain and can be replaced with them.