The sensitivity of acute myeloid leukemia cells to cytarabine is increased by suppressing the expression of Heme oxygenase-1 and hypoxia-inducible factor 1-alpha.

BACKGROUND: Acute myeloid leukemia (AML), a malignancy Often resistant to common chemotherapy regimens (Cytarabine (Ara-c) + Daunorubicin (DNR)), is accompanied by frequent relapses. Many factors are involved in causing chemoresistance. Heme Oxygenase-1 (HO-1) and Hypoxia-Inducible Factor 1-alpha (HIF-1α) are two of the most well-known genes, reported to be overexpressed in AML and promote resistance against chemotherapy according to several studies. The main chemotherapy agent used for AML treatment is Ara-c. We hypothesized that simultaneous targeting of HO-1 and HIF-1α could sensitize AML cells to Ara-c. METHOD: In this study, we used our recently developed, Trans-Activator of Transcription (TAT) - Chitosan-Carboxymethyl Dextran (CCMD) - Poly Ethylene Glycol (PEG) - Nanoparticles (NPs), to deliver Ara-c along with siRNA molecules against the HO-1 and HIF-1α genes to AML primary cells (ex vivo) and cell lines including THP-1, KG-1, and HL-60 (in vitro). Subsequently, the effect of the single or combinational treatment on the growth, proliferation, apoptosis, and Reactive Oxygen Species (ROS) formation was evaluated. RESULTS: The designed NPs had a high potential in transfecting cells with siRNAs and drug. The results demonstrated that treatment of cells with Ara-c elevated the generation of ROS in the cells while decreasing the proliferation potential. Following the silencing of HO-1, the rate of apoptosis and ROS generation in response to Ara-c increased significantly. While proliferation and growth inhibition were considerably evident in HIF-1α-siRNA-transfected-AML cells compared to cells treated with free Ara-c. We found that the co-inhibition of genes could further sensitize AML cells to Ara-c treatment. CONCLUSIONS: As far as we are aware, this study is the first to simultaneously inhibit the HO-1 and HIF-1α genes in AML using NPs. It can be concluded that HO-1 causes chemoresistance by protecting cells from ROS damage. Whereas, HIF-1α mostly exerts prolific and direct anti-apoptotic effects. These findings imply that simultaneous inhibition of HO-1 and HIF-1α can overcome Ara-c resistance and help improve the prognosis of AML patients.

Investigation of L-carnitine effects on CD44+ cancer stem cells from MDA-MB-231 breast cancer cell line as anti-cancer therapy.

Breast cancer stem cells (BCSCs) are a small subpopulation of breast cancer cells, capable of metastasis, recurrence, and drug resistance in breast cancer patients. Therefore, targeting BCSCs appears to be a promising strategy for the treatment and prevention of breast cancer metastasis. Mounting evidence supports the fact that carnitine, a potent antioxidant, modulates various mechanisms by enhancing cellular respiration, inducing apoptosis, and reducing proliferation and inflammatory responses in tumor cells. The objective of this study was to investigate the impact of L-carnitine (LC) on the rate of proliferation and induction of apoptosis in CD44+ CSCs. To achieve this, the CD44+ cells were enriched using the Magnetic-activated cell sorting (MACS) isolation method, followed by treatment with LC at various concentrations. Flow cytometry analysis was used to determine cell apoptosis and proliferation, and western blotting was performed to detect the expression levels of proteins. Treatment with LC resulted in a significant decrease in the levels of p-JAK2, p-STAT3, Leptin receptor, and components of the leptin pathway. Moreover, CD44+ CSCs-treated cells with LC exhibited a reduction in the proliferation rate, accompanied by an increase in the percentage of apoptotic cells. Hence, it was concluded that LC could potentially influence the proliferation and apoptosis of CD44+ CSC by modulating the expression levels of specific protein.

The prognostic and therapeutic potential of HO-1 in leukemia and MDS.

BACKGROUND: Heme oxygenase-1 (HO-1), a heme-degrading enzyme, is proven to have anti-apoptotic effects in several malignancies. In addition, HO-1 is reported to cause chemoresistance and increase cell survival. Growing evidence indicates that HO-1 contributes to the course of hematological malignancies as well. Here, the expression pattern, prognostic value, and the effect of HO-1 targeting in HMs are discussed. MAIN BODY: According to the recent literature, it was discovered that HO-1 is overexpressed in myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), acute myeloblastic leukemia (AML), and acute lymphoblastic leukemia (ALL) cells and is associated with high-risk disease. Furthermore, in addition to HO-1 expression by leukemic and MDS cells, CML, AML, and ALL leukemic stem cells express this protein as well, making it a potential target for eliminating minimal residual disease (MRD). Moreover, it was concluded that HO-1 induces tumor progression and prevents apoptosis through various pathways. CONCLUSION: HO-1 has great potential in determining the prognosis of leukemia and MDS patients. HO-1 induces resistance to several chemotherapeutic agents as well as tyrosine kinase inhibitors and following its inhibition, chemo-sensitivity increases. Moreover, the exact role of HO-1 in Chronic Lymphocytic Leukemia (CLL) is yet unknown. While findings illustrate that MDS and other leukemic patients could benefit from HO-1 targeting. Future studies can help broaden our knowledge regarding the role of HO-1 in MDS and leukemia. Video abstract.

A sustainable supply chain network considering lot sizing with quantity discounts under disruption risks: centralized and decentralized models.

This study proposes a framework for the main parties of a sustainable supply chain network considering lot-sizing impact with quantity discounts under disruption risk among the first studies. The proposed problem differs from most studies considering supplier selection and order allocation in this area. First, regarding the concept of the triple bottom line, total cost, environmental emissions, and job opportunities are considered to cover the criteria of sustainability. Second, the application of this supply chain network is transformer production. Third, applying an economic order quantity model lets our model have a smart inventory plan to control the uncertainties. Most significantly, we present both centralized and decentralized optimization models to cope with the considered problem. The proposed centralized model focuses on pricing and inventory decisions of a supply chain network with a focus on supplier selection and order allocation parts. This model is formulated by a scenario-based stochastic mixed-integer non-linear programming approach. Our second model focuses on the competition of suppliers based on the price of products with regard to sustainability. In this regard, a Stackelberg game model is developed. Based on this comparison, we can see that the sum of the costs for both levels is lower than the cost without the bi-level approach. However, the computational time for the bi-level approach is more than for the centralized model. This means that the proposed optimization model can better solve our problem to achieve a better solution than the centralized optimization model. However, obtaining this better answer also requires more processing time. To address both optimization models, a hybrid bio-inspired metaheuristic as the hybrid of imperialist competitive algorithm (ICA) and particle swarm optimization (PSO) is utilized. The proposed algorithm is compared with its individuals. All employed optimizers have been tuned by the Taguchi method and validated by an exact solver in small sizes. Numerical results show that striking similarities are observed between the results of the algorithms, but the standard deviations of PSO and ICA-PSO show better behavior. Furthermore, while PSO consumes less time among the metaheuristics, the proposed hybrid metaheuristic named ICA-PSO shows more time computations in all small instances. Finally, the provided results confirm the efficiency and the performance of the proposed framework and the proposed hybrid metaheuristic algorithm.

The prognostic and therapeutic potentials of CTLA-4 in hematological malignancies.

INTRODUCTION: Hematological Malignancies (HMs) are a group of progressive, difficult-to-treat, and highly recurrent diseases. A suppressed phenotype of the immune system is present in HMs and growing evidence indicates the role of Cytotoxic T lymphocyte-Associated protein 4 (CTLA-4) in the course of HMs. AREAS COVERED: This article reviews the recent literature on the role of CTLA-4 in different subtypes of HMs. Here, the studies on the expression pattern, its effect on the prognosis of different HMs, and polymorphisms of CTLA-4 have been elaborated. Finally, the effect of targeting CTLA-4 in vitro and in vivo, as well as in clinical trials, is discussed. EXPERT OPINION: According to the recent literature, CTLA-4 is overexpressed in different HMs, which is correlated with poor survival, while it is associated with better a prognosis in Chronic Lymphocytic Leukemia (CLL). Targeting CTLA-4 in Acute Myeloid Leukemia (AML), Sezary Syndrome (SS), Hodgkin's Lymphoma (HL), and so on, is helpful. While this is not recommended and may even be harmful in multiple myeloma (MM) and CLL. Also, it seems that certain CTLA-4 gene polymorphisms are efficient factors in the course of HMs. Future studies may broaden our knowledge regarding the role of CTLA-4 in HMs.

Combined Feedback Feedforward Control of a 3-Link Musculoskeletal System Based on the Iterative Training Method.

The investigation and study of the limbs, especially the human arm, have inspired a wide range of humanoid robots, such as movement and muscle redundancy, as a human motor system. One of the main issues related to musculoskeletal systems is the joint redundancy that causes no unique answer for each angle in return for an arm's end effector's arbitrary trajectory. As a result, there are many architectures like the torques applied to the joints. In this study, an iterative learning controller was applied to control the 3-link musculoskeletal system's motion with 6 muscles. In this controller, the robot's task space was assumed as the feedforward of the controller and muscle space as the controller feedback. In both task and muscle spaces, some noises cause the system to be unstable, so a forgetting factor was used to a convergence task space output in the neighborhood of the desired trajectories. The results show that the controller performance has improved gradually by iterating the learning steps, and the error rate has decreased so that the trajectory passed by the end effector has practically matched the desired trajectory after 1000 iterations.

A fuzzy rule-based multi-criterion approach for a cooperative green supplier selection problem.

Multi-criterion decision-making models are widely used in supplier selection problems. This study contributes to a green supplier selection problem considering the green manufacturing, green transportation, and green procurement. This study contributes to reverse logistics, eco-design, reusing, recycling, and remanufacturing with their high impact on the industries. In addition to the logistics costs and transportation costs, the carbon emissions are considered. With regard to the game theory, this paper uses a cooperative green supplier selection model. If transportation requirements of two or more companies are combined, it will help manufacturers to have less [Formula: see text] emissions with lower cost. After creating the optimization model to consider the uncertainty, this cooperative game theory model is established in a fuzzy environment. In this regard, a fuzzy rule-based (FRB) system is deployed and the set of fuzzy IF-THEN rules is considered. The proposed FRB model is contributed for the first time in the area of green supplier selection problem. Finally, some sensitivity analyses are conducted in a numerical example to evaluate the proposed model. With regard to the findings, although the cost of CO2 emission of horizontal cooperation is increased, the cost saving of companies is increased. It means our total cost is optimal in a logistic network using the cooperative game theory. The results also indicate that horizontal cooperation in logistic network causes less cost and benefits for each company.

Sustainable closed-loop supply chain network under uncertainty: a response to the COVID-19 pandemic.

This study proposes a sustainable closed-loop supply chain under uncertainty to create a response to the COVID-19 pandemic. In this paper, a novel stochastic optimization model integrating strategic and tactical decision-making is presented for the sustainable closed-loop supply chain network design problem. This paper for the first time implements the concept of sustainable closed-loop supply chain for the application of ventilators using a stochastic optimization model. To make the problem more realistic, most of the parameters are considered to be uncertain along with the normal probability distribution. Since the proposed model is more complex than majority of previous studies, a hybrid whale optimization algorithm as an enhanced metaheuristic is proposed to solve the proposed model. The efficiency of the proposed model is tested in an Iranian medical ventilator production and distribution network in the case of the COVID-19 pandemic. The results confirm the performance of the proposed algorithm in comparison with two other similar algorithms based on different multi-objective criteria. To show the impact of sustainability dimensions and COVID-19 pandemic for our proposed model, some sensitivity analyses are done. Generally, the findings confirm the performance of the proposed sustainable closed-loop supply chain for the pandemic cases like COVID-19.

Effect of Cellular-Based Artificial Antigen Presenting Cells Expressing ICOSL, in T-cell Subtypes Differentiation and Activation.

Purposes: Effective and selective T-cell activation and proliferation during the T-cell expansion phase of a cellular adoptive immunotherapy method, challenging because recent studies revealed the importance of each subtype of T-cells in different immunologic strategies against tumors, like CAR-T cell therapies. Artificial antigen presenting cells (aAPCs) regarded as a natural way to manipulate T-cell subtypes activation and specific proliferation. In the current study, we utilized K562 cells based aAPC method expressing the ICOSL molecule, to evaluate T-cell subtypes differentiation rate and functional status. Methods: CD3+T-cells isolated and, co-cultured with ICOSL expressing K562 cells. After 4, 6, and 10 days selective CD markers of T-cell subtypes and each subtype's activity-related genes levels evaluated by qPCR methods. Results: During the culture period, CD4+ Th related phenotype reduced continuously, and in day 10th of culture CD4+ T-cell's population significantly reduced (P =0.029). In contrast, the CD8+ population ratio was ascending during the study period but was not statistically significant. FoxP3+CD25-, Treg population ratio was significantly increased during the time in comparison with the control group, as well as memory T-cell phenotypic marker, CD127+, expressing cells ratio. T-cell subpopulations activity-related genes expression levels evaluated too, and the Th1 related IL-2 and INF-γ reductions observed alongside regulatory T-cells gene (IL-10) and Cytotoxic T-cell's related gene (Geranzym-A) elevations. Conclusion: We concluded that the K562-ICOSL based aAPC system is working and effective in T-cell short to medium culture periods, and this approach preparing relatively selective milieu for CD8+ T-Cell differentiation and much less Treg differentiation.

The Optimal Adaptive-Based Neurofuzzy Control of the 3-DOF Musculoskeletal System of Human Arm in a 2D Plane.

Each individual performs different daily activities such as reaching and lifting with his hand that shows the important role of robots designed to estimate the position of the objects or the muscle forces. Understanding the body's musculoskeletal system's learning control mechanism can lead us to develop a robust control technique that can be applied to rehabilitation robotics. The musculoskeletal model of the human arm used in this study is a 3-link robot coupled with 6 muscles which a neurofuzzy controller of TSK type along multicritic agents is used for training and learning fuzzy rules. The adaptive critic agents based on reinforcement learning oversees the controller's parameters and avoids overtraining. The simulation results show that in both states of with/without optimization, the controller can well track the desired trajectory smoothly and with acceptable accuracy. The magnitude of forces in the optimized model is significantly lower, implying the controller's correct operation. Also, links take the same trajectory with a lower overall displacement than that of the nonoptimized mode, which is consistent with the hand's natural motion, seeking the most optimum trajectory.

Acellular Wharton's Jelly, Potentials in T-Cell Subtypes Differentiation, Activation and Proliferation.

Purpose: Because of different potentials of T-cell subtypes in T-cell based cellular immunotherapy approaches such as CAR-T cell therapies; Regarding the high cost of the serum-free specific culture media, having distinct control on T-cell subset activation, expansion and differentiation seem crucial in T-cell expansion step of cell preparation methods. By the way, there was no clear data about the effect of acellular Wharton's Jelly (AWJ) on T-cells expansion, activation or differentiation status. So, we have launched to study the effect of AWJ on T-cell's immunobiological properties. Methods: CD3+ T-cells were isolated from healthy bone marrow allogeneic donors, sorted by FACS method and cultured on either routine phyto-hemagglutinin complemented and different concentrations of AWJ, lag phase and doubling time of the cells calculated from cell growth curve. After 3, 7 and 14-days T-cell subtypes cell markers and cell activity related genes expression rate have been evaluated by flow cytometry and real-time polymerase chain reaction (PCR) methods respectively. Results: AWJ in a 1:1 ratio compared with contemporary lymphocyte culture media showed significant activating and proliferative capacities. The introduced condition has not affected the frequency of CD4+ subpopulation of T-cells, but significantly increased even CD8+ cells and immune-activator genes in T-cells. The regulatory and memory subsets of T-cells in this study have not affected significantly. Conclusion: the study results revealed that AWJ can be utilized as a supportive substance to increase the memory properties of the T-cells, gives control to design a selective medium for expanding and differentiating memory T-cells, relatively.

Low-Rank and Sparse Recovery of Human Gait Data.

Due to occlusion or detached markers, information can often be lost while capturing human motion with optical tracking systems. Based on three natural properties of human gait movement, this study presents two different approaches to recover corrupted motion data. These properties are used to define a reconstruction model combining low-rank matrix completion of the measured data with a group-sparsity prior on the marker trajectories mapped in the frequency domain. Unlike most existing approaches, the proposed methodology is fully unsupervised and does not need training data or kinematic information of the user. We evaluated our methods on four different gait datasets with various gap lengths and compared their performance with a state-of-the-art approach using principal component analysis (PCA). Our results showed recovering missing data more precisely, with a reduction of at least 2 mm in mean reconstruction error compared to the literature method. When a small number of marker trajectories is available, our findings showed a reduction of more than 14 mm for the mean reconstruction error compared to the literature approach.

The role of XIAP in resistance to TNF-related apoptosis-inducing ligand (TRAIL) in Leukemia.

The treatment for leukemic malignancies remains a challenge despite the wide use of conventional chemotherapies. Therefore, new therapeutic approaches are highly demanded. TNF-related apoptosis-inducing ligand (TRAIL) represents a targeted therapy against cancer because it induces apoptosis only in tumor cells. TRAIL is currently under investigation for the treatment of leukemia. Preclinical studies evaluated the potential therapeutic efficacy of TRAIL on cell lines and clinical samples and showed promising results. However, like most anti-cancer drugs, resistance to TRAIL-induced apoptosis may limit its clinical efficacy. It is critical to understand the molecular mechanisms of TRAIL. Therefore, rational therapeutic drug combinations for clinical trials of TRAIL-based therapies might be achieved. In a variety of leukemic cells, overexpression of X-linked inhibitor of apoptosis protein (XIAP), a negative regulator of apoptosis pathway, has been discovered. Implication of XIAP in the ineffective induction of cell death by TRAIL in leukemia has been explored in several resistant cell lines. XIAP inhibitors restored TRAIL sensitivity in resistant cells and primary leukemic blasts. Moreover, TRAIL resistance in leukemic cells could be overcome by the effects of several anti-leukemic agents via the mechanisms of XIAP downregulation. Here, we discuss targeting XIAP, a strategy to restore TRAIL sensitivity in leukemia to acquire more insights into the mechanisms of TRAIL resistance. The concluding remarks may lead to identify putative ways to resensitize tumors.

Down-regulation of intracellular anti-apoptotic proteins, particularly c-FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily that induces apoptosis in different types of cancer cells via activation of caspase cascade. TRAIL interacts with its cognate receptors that placed on cancer cells surface, including TRAIL-R1 (death receptor 4, DR4), TRAIL-R2 (death receptor 5, DR5), TRAIL-R3 (decoy receptor 1, DcR1), TRAIL-R4 (decoy receptor 2, DcR2), and osteoprotegerin (OPG). Despite high apoptosis-inducing ability of TRAIL, various cancerous cells gain resistance to TRAIL gradually, and consequently TRAIL potential for apoptosis stimulation in these cells diminishes intensely. According to diverse ranges of examinations, intracellular anti-apoptotic proteins, such as cellular-FLICE inhibitory protein (c-FLIP), apoptosis inhibitors (IAPs), myeloid cell leukemia sequence 1 (MCL-1), BCL-2, BCL-XL, and survivin play key role in cancer cells resistance to TRAIL. These proteins attenuate cancer cells sensitivity to TRAIL via various functions, importantly through caspase cascade suppression. The c-FLIP avoids from caspase 8 activation by FADD via binding to caspase 8 cleavage of FADD. Moreover, it activates signaling pathways that involved in cancer cells survival and proliferation. Intriguingly, it appears that the down-regulation of intracellular anti-apoptotic proteins, particularly c-FLIP is effectiveness goal for TRAIL-resistant cancers therapy, because their up-regulation in association with poor prognosis has been observed in various types of TRAIL-resistant cancers. In this review, we tried to collect and examine investigations that researchers have been able to sensitize cancer cells to TRAIL through targeting of c-FLIP alone or with other intracellular anti-apoptotic proteins directly or indirectly. It seems that co-treatment of resistant cells by TRAIL with other therapeutic agents with the aim of intracellular anti-apoptotic proteins inhibition is hopeful and attractive approach to overcome various TRAIL-resistant cancers.

Promoter Methylation Status of Survival-Related Genes in MOLT- 4 Cells Co-Cultured with Bone Marrow Mesenchymal Stem Cells under Hypoxic Conditions.

OBJECTIVES: DNA methylation is a well-studied epigenetic mechanism that is a potent arm of the gene expression controlling machinery. Since the hypoxic situation and the various cells of bone marrow microenvironment, e.g. mesenchymal stem cells, play a role in the in vivo and in vitro biology of leukemic cells, we decided to study the effects of hypoxia and mesenchymal stem cells (MSCs) on the promoter methylation pattern of BAX and BCL2 genes. MATERIALS AND METHODS: In this experimental study, the co-culture of MOLT-4 cells with MSCs and treatment with CoCl2 was done during 6, 12, and 24 hour periods. Total DNA was extracted using commercial DNA extraction kits, and sodium bisulfite (SBS) treatment was performed on the extracted DNA. Methylation specific polymerase chain reaction (MSP) was used to evaluate the methylation status of the selected genes' promoter regions. RESULTS: The BAX and BCL2 promoters of untreated MOLT-4 cells were in partial methylated and fully unmethylated states, respectively. After incubating the cancer cells with CoCl2 and MSCs, the MSP results after 6, 12, and 24 hours were the same as untreated MOLT-4 cells. In other words, the exposure of MOLT-4 cells to the hypoxia-mimicry agent and MSCs in various modes and different time frames showed that these factors have exerted no change on the methylation signature of the studied fragments from the promoter region of the mentioned genes. CONCLUSIONS: Hypoxia and MSCs actually have no notable effect on the methylation status of the promoters of BAX and BCL2 in the specifically studied regions. DNA methylation is probably not the main process by which MSCs and CoCl2 induced hypoxia regulate the expression of these genes. Finally, we are still far from discovering the exact functional mechanisms of gene expression directors, but these investigations can provide new insights into this field for upcoming studies.

Co-delivery of insulin-like growth factor 1 receptor specific siRNA and doxorubicin using chitosan-based nanoparticles enhanced anticancer efficacy in A549 lung cancer cell line.

Here, we investigated the effects of dual delivery of IGF-1R siRNA and doxorubicin by chitosan nanoparticles on viability of A549 lung cancer cells line by utilization of MTT and qRT-PCR. Furthermore apoptosis and migration of treated cells were assessed by Annexin-PI and wound healing assays, respectively. The chitosan nanoparticles had about 176 nm size with zeta potential and polydispersive index about 11 mV and 0.3, respectively. The IGF-1R siRNA had synergistic effect on DOX-induced cytotoxicity and apoptosis in tumour cells. In addition, siRNA/DOX-loaded chitosan nanoparticles could significantly decrease migration and expressions of mmp9, VEGF and STAT3 in A549 cells.

The acute lymphoblastic leukemia prognostic scoring whether it is possible by BCL-2, BAX gene promoter genotyping.

BACKGROUND: BCL-2 is the most important anti-apoptotic regulator and Bax is a pro-apoptotic protein. The status of these parameters or the ration of BCL-2 to BAX is important in malignant cell fate as well as normal cells. METHODS: Sixty-two ALL patients and 62 healthy sex-and age-matched controls were studied. After genotyping, the promoter region of the BAX and BCL-2 genes by RFLP-PCR method the patients were classified in nine prognostic groups, after that, the overall survival ratio of each score was compared with others pair-wise or between groups. RESULTS: The frequencies of the AA, AC, CC alleles of the BCL-2 C-938A polymorphism in patient group were 33 (53.23%), 18 (29.03%), 11 (17.74%), and in the control group were 13 (21.0%), 27 (43.5%), 22 (35.5%), respectively (P=0.003). Also, the frequencies of AA, AG, GG alleles of the BAX G-248A SNP were 15 (24.2%), 24 (38.7%), 23 (37.1%) in ALL group and 13 (21.0%), 25 (40.3%), 24 (38.7%) (p>0.05) in the control group. The survival time estimation and ratio were significantly different between different SNPs in BCL-2 (P=0.002). CONCLUSION: These findings showed that the BCL-2 promoter region polymorphism is more reliable than BAX gene promoter polymorphism in any ALL scoring system. But the establishment of complete scoring system requires further more clinical and laboratory findings along with genetic polymorphisms is necessary.

The Effect of Baicalin as A PPAR Activator on Erythroid Differentiation of CD133(+)Hematopoietic Stem Cells in Umbilical Cord Blood.

OBJECTIVE: The peroxisome proliferator-activated receptors (PPARs) are a group of nu- clear receptor proteins whose functions as transcription factors regulate gene expres- sions. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. This study attempts to determine the effect of baicalin, a PPARγ activator, on erythroid differentiation of cluster of differentiation 133(+)(CD133(+)) cord blood hematopoietic stem cells (HSCs). MATERIALS AND METHODS: In this experimental study, in order to investigate the effects of the PPARγ agonists baicalin and troglitazone on erythropoiesis, we isolated CD133(+) cells from human umbilical cord blood using the MACS method. Isolated cells were cultured in erythroid-inducing medium with or without various amounts of the two PPARγ activa- tors (baicalin and troglitazone). Erythroid differentiation of CD133(+)cord blood HSCs were assessed using microscopic morphology analysis, flow cytometric analysis of erythroid surface markers transferrin receptor (TfR) and glycophorin A (GPA) and bycolony forming assay. RESULTS: Microscopic and flow cytometric analysis revealed the erythroid differentiation of CD133(+)cord blood HSCs under applied erythroid inducing conditions. Our flow cytometric data showed that the TfR and GPA positive cell population diminished significantly in the presence of either troglitazone or baicalin. The suppression of erythroid differentiation in response to PPARγ agonists was dose-dependent. Erythroid colony-forming ability of HSC decreased significantly after treatment with both PPARγ agonists but troglitazone had a markedly greater effect. CONCLUSION: Our results have demonstrated that PPARγ agonists modulate erythroid dif- ferentiation of CD133(+)HSCs, and therefore play an important role in regulation of normal erythropoiesis under physiologic conditions. Thus, considering the availability and applica- tion of this herbal remedy for treatment of a wide range of diseases, the inhibitory effect of baicalin on erythropoiesis should be noted.