The role of bone marrow microenvironment (BMM) cells in acute myeloid leukemia (AML) progression: immune checkpoints, metabolic checkpoints, and signaling pathways.

Acute myeloid leukemia (AML) comprises a multifarious and heterogeneous array of illnesses characterized by the anomalous proliferation of myeloid cells in the bone marrow microenvironment (BMM). The BMM plays a pivotal role in promoting AML progression, angiogenesis, and metastasis. The immune checkpoints (ICs) and metabolic processes are the key players in this process. In this review, we delineate the metabolic and immune checkpoint characteristics of the AML BMM, with a focus on the roles of BMM cells e.g. tumor-associated macrophages, natural killer cells, dendritic cells, metabolic profiles and related signaling pathways. We also discuss the signaling pathways stimulated in AML cells by BMM factors that lead to AML progression. We then delve into the roles of immune checkpoints in AML angiogenesis, metastasis, and cell proliferation, including co-stimulatory and inhibitory ICs. Lastly, we discuss the potential therapeutic approaches and future directions for AML treatment, emphasizing the potential of targeting metabolic and immune checkpoints in AML BMM as prognostic and therapeutic targets. In conclusion, the modulation of these processes through the use of directed drugs opens up new promising avenues in combating AML. Thereby, a comprehensive elucidation of the significance of these AML BMM cells' metabolic and immune checkpoints and signaling pathways on leukemic cells can be undertaken in the future investigations. Additionally, these checkpoints and cells should be considered plausible multi-targeted therapies for AML in combination with other conventional treatments in AML. Video Abstract.

Resveratrol plus low-dose hydroxyurea compared to high-dose hydroxyurea alone is more effective in γ-globin gene expression and ROS reduction in K562 cells.

Hydroxyurea (HU) is an anti-cancer drug that is used for the treatment of hemoglobinopathies as a γ-globin inducer. However, its dose-dependent effects have hampered its clinical reliability. Resveratrol (RSV) is an antioxidant and γ-globin inducer. The present study aimed to assess their combined effects on the γ-globin gene expression and reactive oxygen species (ROS) level of K562 cells. The results indicated that the γ-globin gene expression was approximately two folds higher in the group treated with RSV 50 µM + HU 25 µM in comparison to HU 100 µM alone (***p < 0.001). However, there was an inverse relationship between the expression of γ-globin gene and HU concentration in the combined groups. Furthermore, the combinations of RSV and HU significantly reduced ROS levels compared to single drugs. Overall, the combination of these compounds was an appropriate strategy for increasing γ-globin expression, reducing oxidant levels, and alleviating the adverse effects of HU.

Immunomodulatory and clinical responses to zinc gluconate supplementation in patients with Behçet's disease: A double-blind, randomized placebo-controlled clinical trial.

BACKGROUND & AIMS: Toll-like receptor (TLR) 2 and 4 are involved in the pathogenesis of Behçet's disease (BD). The current study aimed to investigate the effect of zinc supplementation on TLR-2/4 expression and the clinical manifestations of BD. METHODS: In this double-blind placebo-controlled randomized clinical trial, 50 BD patients were randomly allocated into either zinc gluconate (30 mg/day) or placebo groups for 12 weeks. Before and after the intervention, the surface and mRNA expression level of TLR-2 and TLR-4 in the leukocytes, serum level of zinc and tumor necrosis factor-α (TNF-α), quality of life, anthropometric measures, and blood pressure of patients were collected. BD activity was studied using the nonocular Iranian Behçet's disease dynamic activity measure (IBDDAM), Behçet's disease current activity form (BDCAF), and total inflammatory activity index (TIAI) at the pre-and post-intervention phases. The effect sizes were compared between two groups using analysis of covariance. RESULTS: There were significant decrease in TLR-2 mRNA (P = 0.038) and protein expression (P = 0.034) and nonocular IBDDAM score (P = 0.046) in the zinc group compared to placebo at the endpoint. The serum level of zinc was increased in the zinc group (P < 0.001). Zinc supplementation significantly decreased the TLR-4 surface (P = 0.012) and mRNA expression (P = 0.028) within the group. However, this decrease was not significant compared to the placebo group. There was no significant difference between the two groups regarding the serum level of TNF-α, BDCAF, TIAI, quality of life, anthropometric measures, and blood pressure (P > 0.05). CONCLUSIONS: The present study revealed that zinc supplementation significantly improved nonocular IBDDAM score and TLR-2 expression in BD patients. GOV REGISTRATION NUMBER: NCT05098678.

Exosome as a target for cancer treatment.

Exosomes are small vesicles covered by a lipid bilayer, ranging in size from 50 nm to 90 nm, secreted by different cell types in the body under normal and pathological conditions. They are surrounded by cell-segregated membrane complexes and play a role in the pathological and physiological environments of target cells by transfer of different molecules such as microRNA (miRNA). Exosomes have been detected in many body fluids, such as in the amniotic fluid, urine, breast milk, blood, saliva, ascites, semen, and bile. They include proteins, lipids, and nucleic acids such as DNA, RNA, and miRNA, which have many functions in target cells under pathological and physiological conditions. They participate in pathological processes such as tumor growth and survival, autoimmunity, neurodegenerative disorders, infectious diseases, inflammation conditions, and others. Biomarkers in exosomes isolated from body fluids have allowed for a more precise and consistent diagnostic method than previous approaches. Exosomes can be used in a variety of intracellular functions, and with advances in molecular techniques they can be used in the treatment and diagnosis of many diseases, including cancer. These vesicles play a significant role in various stages of cancer. Tumor-derived exosomes have an important role in tumor growth, survival, and metastasis. In contrast, the use of stem cells in cancer treatment is a relatively new scientific area. We hope to address targeted use of miRNA-carrying exosomes in cancer therapy in this review paper.

Identification of intrinsically disordered regions in hub genes of acute myeloid leukemia: A bioinformatics approach.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Over the past decades, there has been a great challenge in the treatment of AML. A combination of gene expression profiling with computational approaches can lead to the identification of hub genes in AML. However, it is important to study the structure of these hub genes considering their importance in the protein-protein interaction (PPI) network of specific cancer. In this study, we designed an integrated method to analyze the presence of intrinsically disordered regions (IDRs) in selected hub genes of AML. A gene expression profile of AML was obtained from Gene Expression Omnibus (GEO) database. Further analysis identified differentially expressed genes (DEGs) in AML. Additionally, the top 15 hub genes following construction and analysis of the PPI network of DEGs were selected. Validation of hub genes revealed that there is a reverse relationship between overexpression of FLT3, PPBP, and PF4 genes and the survival of AML patients. Based on IDRs investigation, FLT3 and PF4 are partially disordered, while PPBP is mostly disordered. Through clustering the network into structural modules, we identified two important modules in the PPI network of DEGs that showed the important position of PPBP in module 1. Based on further analysis of protein flexibility and its important role in biological processes, we suggest that PPBP can be considered as a potential drug target in AML.

The Effect of ω3 Fatty Acids Supplementation on Levels of PPARγ and UCP2 Genes Expression, Serum Level of UCP2 Protein, Metabolic Status, and Appetite in Elite male Athletes: Protocol for a Randomized Control Trial.

Some genetic factors may influence body composition, such as PPARγ and UCP2. PPARγ plays an important role in body fat distribution. The objective of the present study is to determine the effects of omega3 fatty acids on the gene expression of PPARγ and UCP2, levels of blood lipid profile, fat mass, and fat-free mass, and appetite. Elite male athlete volunteers of up to 36 subjects were invited to participate in this RCT. Following a public announcement, volunteers were recruited from gyms, teams, and sports medicine boards in Tabriz, Iran. Gene's expression of PPARγ and UCP2, serum levels of blood lipid profile, fat mass, and fat-free mass was collected. Data collection time points include baseline in addition to 3 weeks follow up. The study was approved by the Ethics Committee of the Tabriz University Medical of Sciences (IR.TBZMED.REC.1398.782) in October 2019 and was registered with the Iranian Registry of Clinical Trials: 20190625044008N1 on December 19, 2019. Recruitment began in July and concluded in December 2019. As of August 19, 2019, we have screened 373 volunteers. 36 were enrolled. Baseline measurements of participants were collected. After three-week of intervention, end study measurements of participants were collected. The results are expected to be released in 2021. Participants have a median age of 21.86 (±3.15). The finding of this study showed Results showed PPARγ mRNA levels, and UCP2 mRNA and protein levels increased in the omega3 group (p < 0.05), as did REE (p < 0.05). Also, differences in the sensation of hunger or satiety were significant (p < 0.05). This study could result in the effects of omega-3 fatty acids on PPARγ, and UCP2 expressions, blood lipid profiles and body composition. In addition, the results of this trial can be used as baseline information for conducting further clinical and sport nutrition studies. TRIAL REGISTRATION: The trial was registered at the Iranian registry of the clinical trial website (www.irct.ir) as IRCT20190625044008N1 (https://en.irct.ir/trial/43332), registered at (19/12/2019). HIGHLIGHTS: Omega3 fatty acids as a ligand of metabolic-related genes, have a role in energy expenditure.Omega3 supplements effect on PPARγ and UCP2 mRNA expression as regulators of energy metabolismOmega3 supplements increased REE.Omega-3 supplementation could change the changes in body composition.For athletes, omega-3 simultaneously decreased fat mass and increased fat-mass.HDL-C increased after short-term supplementation with omega-3.Increased intake of omega-3, caused increased intake of energy and protein.

The effect of omega3 fatty acid supplementation on PPARγ and UCP2 expressions, resting energy expenditure, and appetite in athletes.

BACKGROUND: Omega3 fatty acids as a ligand of energy-related genes, have a role in metabolism, and energy expenditure. These effects are due to changes in the expression of peroxisome proliferator-activated receptor-gamma (PPARγ) and uncoupling protein2 (UCP2). This study evaluated the effect of omega3 supplements on PPARγ mRNA expression and UCP2 mRNA expression and protein levels, as regulators of energy metabolism, resting energy expenditure (REE), and appetite in athletes. METHODS: In a 3-week double-blind RCT in Tabriz, Iran, in 2019, 36 male athletes, age 21.86 (±3.15) y with 16.17 (±5.96)% body fat were randomized to either an intervention (2000 mg/day omega3; EPA: 360, DHA: 240) or placebo (2000 mg/day edible paraffin) groups. Appetite and REE were assessed before and after the intervention. PPARγ and UCP2 mRNA expression and UCP2 protein levels in blood were evaluated by standard methods. RESULTS: Results showed PPARγ mRNA levels, and UCP2 mRNA and protein levels increased in omega3 group (p < 0.05), as did REE (p < 0.05). Also, differences in the sensation of hunger or satiety were significant (p < 0.05). CONCLUSIONS: Our findings showed that omega3 supplementation leads to the up-regulation of PPARγ and UCP2 expressions as the indicators of metabolism in healthy athletes.

Profiling inflammatory cytokines following zinc supplementation: a systematic review and meta-analysis of controlled trials.

Chronic inflammation has been considered as the main cause of chronic diseases. Zn has anti-inflammatory effects by decreasing the expression of inflammatory markers. The present systematic review and meta-analysis study aims to evaluate the impact of Zn supplementation on inflammation. PubMed (Medline), Scopus, Web of Science, and Embase databases were searched up to 10 December 2020. Controlled trials which have investigated the effects of Zn supplementation on serum/plasma levels of inflammatory cytokines in subjects aged >15 years were included. A pooled meta-analysis was performed using a random effect model. Sensitivity analysis was performed to determine the robustness of the observed effect sizes. A total of twelve studies was included in meta-analysis. Zn could decrease IL-6 levels (standardised mean difference (SMD) = -0·76 pg/ml; 95 % CI -1·28, -0·24; P = 0·004). There was no significant change in TNF-α (SMD = 0·42 pg/ml; 95 % CI -0·31, 1·16; P = 0·257) and IL-2 levels (SMD = 1·64 pg/ml; 95 % CI -1·31, 4·59; P = 0·277) following Zn supplementation. However, Zn could increase IL-2 significantly after the deletion of one arm in sensitivity analysis (SMD = 2·96 pg/ml; 95 % CI 2·03, 3·88; P < 0·05). Conclusively, Zn supplementation can decrease the IL-6 level. Zn increased IL-2 level after the sensitivity analysis. Zn supplementation has not ameliorative effects on TNF-α.

The associations between dietary pattern of chronic obstructive pulmonary disease patients and depression: a cross-sectional study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common lung disease during middle age which one of its complications is depression. Depression is considered one of the major causes of severe disability worldwide. One of the factors that affect the severity and incidence of this disease is a lifestyle, especially dietary pattern. On the other hand, some studies showed the relationship between dietary patterns and depression. The present study aims to investigate the dietary patterns of people with chronic obstructive pulmonary disease and its association with depression. METHODS: The present cross-sectional study was performed on 220 patients (mean ± SD age = 54.58 ± 5.08) with chronic obstructive pulmonary disease (56.6% men, 43.4% women) from Tabriz, Iran. Questionnaires of general information, food frequency, Beck depression and physical activity were completed. The dominant dietary patterns were determined by factor analysis, and their relationship with depression was discussed by regression analysis. RESULTS: Three dominant dietary patterns were identified as healthy, unhealthy, and mixed dietary patterns. An inverse relationship was found between healthy and mixed dietary patterns with depression. There is no meaningful connection between unhealthy dietary patterns and depression. Depression had a significant inverse relationship with physical activity. There was no relationship between dietary patterns and Forced Expiratory Volume for 1 s (FEV1) and Forced Vital Capacity (FVC) criteria. A positive and significant relationship was observed between mixed dietary patterns with FEV1/FVC. CONCLUSION: Inverse relationships exist between healthy dietary patterns and depression in patients with COPD, and improves the function of the lungs. Further studies are needed to show the exact relationship between diet and COPD depression.

Preventive and Tumor-Suppressive Effects of Lactobacillus Paracasei X12 in Rat Model of Colorectal Cancer.

The paper in hand seeks to evaluate the tumor-suppressive and apoptotic effects of L. paracasei X12 in 1, 2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. The rats were divided into three groups (n = 8-12 per group); L. paracasei X12 was administrated to these animals for forty weeks. The findings of this study indicated that L. paracasei X12 administration prevented severe weight loss in DMH-treated rats. It was also determined that L. paracasei X12 administration could prevent the neoplasia incidence, cell proliferation and it also could suppress the tumors' growth. Additionally, a significant improvement was observed in apoptosis indexes and cell proliferation in probiotic-treated rats. In conclusion, this study provides insights into the therapeutic potential of L. paracasei X12 with emphasis on the issue that modulation of apoptosis pathway could leave beneficial effects in the prevention and suppression of colorectal cancer (CRC). However, further studies are in support to clarify the mechanisms involved in the tumor-suppressive effect of probiotics.