Epigenetic and metabolic reprogramming in inflammatory bowel diseases: diagnostic and prognostic biomarkers in colorectal cancer.

BACKGROUND AND AIM: "Inflammatory bowel disease" (IBD) is a chronic, relapsing inflammatory disease of the intestinal tract that typically begins at a young age and might transit to colorectal cancer (CRC). In this manuscript, we discussed the epigenetic and metabolic change to present a extensive view of IBDs transition to CRC. This study discusses the possible biomarkers for evaluating the condition of IBDs patients, especially before the transition to CRC. RESEARCH APPROACH: We searched "PubMed" and "Google Scholar" using the keywords from 2000 to 2022. DISCUSSION: In this manuscript, interesting titles associated with IBD and CRC are discussed to present a broad view regarding the epigenetic and metabolic reprogramming and the biomarkers. CONCLUSION: Epigenetics can be the main reason in IBD transition to CRC, and Hypermethylation of several genes, such as VIM, OSM4, SEPT9, GATA4 and GATA5, NDRG4, BMP3, ITGA4 and plus hypomethylation of LINE1 can be used in IBD and CRC management. Epigenetic, metabolisms and microbiome-derived biomarkers, such as Linoleic acid and 12 hydroxy 8,10-octadecadienoic acid, Serum M2-pyruvate kinase and Six metabolic genes (NAT2, XDH, GPX3, AKR1C4, SPHK and ADCY5) expression are valuable biomarkers for early detection and transition to CRC condition. Some miRs, such as miR-31, miR-139-5p, miR -155, miR-17, miR-223, miR-370-3p, miR-31, miR -106a, miR -135b and miR-320 can be used as biomarkers to estimate IBD transition to CRC condition.

Complete Blood Count Test in Rheumatology: Not Just a Screening Test.

BACKGROUND: Rheumatic disorders are chronic and common diseases, which especially involve connective tissue and may be associated with the damage to vital organs such as heart and kidney. Diagnosis, prognosis, determining the probability of severe complications, monitoring and evaluation of the response to treatment in such patients require specialized, expensive and time-consuming laboratory tests. METHODS: In this review article, we assessed the value of parameters of routine, inexpensive, and available Complete Blood Count (CBC) in detecting disease activity and explaining the prognosis of a number of rheumatic disorders, including systemic lupus erythematosus and rheumatoid arthritis by reviewing the results of searching Google Scholar search engine and PubMed databases over 2000 - 2021. RESULTS: Review of previous articles showed that while traditional Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) tests do not have sufficient specificity to appraise disease activity, CBC derived inflammatory biomarker Neutrophil-to-Lymphocyte Ratio (NLR) is able to assess disease activity and response to treatment in Rheumatoid Arthritis (RA). Also, Mean Platelet Volume (MPV) and NLR can determine the prognosis of renal involvement in Systemic lupus erythematosus (SLE). CONCLUSIONS: Although CBC-based parameters are not completely specific and sensitive to rheumatic disorders, but based on the results of previous studies, these parameters, particularly red cell distribution width (RDW), MPV, NLR and platelet to lymphocyte ratio (PLR) are inflammatory biomarkers with a prognostic role in rheumatic disorders that can also assess activity of the disease.

Essential thrombocythemia: a hemostatic view of thrombogenic risk factors and prognosis.

Essential thrombocythemia (ET) is a classical myeloproliferative neoplasm that is susceptible to hypercoagulable state due to impaired hemostatic system, so that thrombotic complications are the leading cause of mortality in ET patients. The content used in this article has been obtained by the PubMed database and Google Scholar search engine from English-language articles (2000-2019) using the following keywords: "Essential thrombocythemia," "Thrombosis," "Risk factors" and "Hemostasis. In this neoplasm, the count and activity of cells such as platelets, leukocytes, endothelial cells, as well as erythrocytes are increased, which can increase the risk of thrombosis through rising intercellular interactions, expression of surface markers, and stimulation of platelet aggregation. In addition to these factors, genetic polymorphisms in hematopoietic stem cells (HSCs), including mutations in JAK2, CALR, MPL, or genetic abnormalities in other genes associated with the hemostatic system may be associated with increased risk of thrombotic events. Moreover, disruption of coagulant factors can pave the way for thrombogeneration. Therefore, the identification of markers related to cell activation, genetic abnormalities, or alternation in the coagulant system can be used together as diagnostic and prognostic markers for the occurrence of thrombosis among ET patients. Thus, because thrombotic complications are the main factors of mortality in ET patients, a hemostatic viewpoint and risk assessment of cellular, genetic, and coagulation factors can have prognostic value and contribute to the choice of effective treatment and prevention of thrombosis.

Role of bone marrow adipocytes in leukemia and chemotherapy challenges.

Adipose tissue (AT) is an extramedullary reservoir of normal hematopoietic stem cells (HSCs). Adipocytes prevent the production of normal HSCs via secretion of inflammatory factors, and adipocyte-derived free fatty acids may contribute to the development and progression of leukemia via providing energy for leukemic cells. In addition, adipocytes are able to metabolize and inactivate therapeutic agents, reducing the concentrations of active drugs in adipocyte-rich microenvironments. The aim of this study was to detect the role of adipocytes in the progression and treatment of leukemia. Relevant literature was identified through a PubMed search (2000-2018) of English-language papers using the following terms: leukemia, adipocyte, leukemic stem cell, chemotherapy, and bone marrow. Findings suggest the striking interplay between leukemic cells and adipocytes to create a unique microenvironment supporting the metabolic demands and survival of leukemic cells. Based on these findings, targeting lipid metabolism of leukemic cells and adipocytes in combination with standard therapeutic agents might present novel treatment options.

Strategies to inhibit arsenic trioxide-induced cardiotoxicity in acute promyelocytic leukemia.

OBJECTIVE: Arsenic trioxide (ATO) is a drug commonly used for the treatment of acute promyelocytic leukemia (APL). Although ATO has been shown to cause significant improvement in patients, it is associated with serious side effects, which sometimes lead to the patient's death. In this review paper, we examine the reports of ATO-induced cardiotoxicity in APL patients and evaluate the strategies to reduce the incidence of such toxicity. METHODS: The key search terms were "arsenic trioxide," "acute promyelocytic leukemia," "cardiotoxicity," "molecular pathway," and "biomarker." RESULTS: Studies have indicated the involvement of several molecular pathways in ATO-induced cardiotoxicity. These pathways increase the production of reactive oxygen species by interfering with intracellular calcium homeostasis as well as impairing the transfer of calcium into endoplasmic reticulum and mitochondria. On the other hand, increasing or decreasing expressions of some microRNAs (miRs) have been shown to play a role in cardiotoxicity. CONCLUSION: Finally, it can be stated that given the essential role of molecular pathways in cardiotoxicity and considering the fact these pathways impair the regulation of miRs expression, identification of molecular pathways involved in ATO-induced cardiotoxicity aimed at targeting miRs could be a new therapeutic strategy to prevent cardiotoxicity.

Protective role of heat shock transcription factor 1 in heart failure: A diagnostic approach.

OBJECTIVE: Nonexpression or expression inhibition of protective factors has been determined in the occurrence of heart failure (HF). Heat shock transcription factor 1 (HSF1) is among such factors, which reduces the incidence of HF by controlling cardiac hypertrophy and fibrosis. In this study, molecular mechanisms for nonexpression of HSF1 in HF patients have been investigated. MATERIALS AND METHODS: This review paper is based on the material obtained via PubMed search of 1996-2018. The key search terms were "heart failure," "heat shock transcription factor 1," "hypertrophy", "fibrosis," and "apoptosis." RESULTS: Although factors such as janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and heat shock proteins (HSPs) may respectively increase and decrease susceptibility to HF, in some circumstances, these factors may unexpectedly prevent HF progression. CONCLUSION: Finally, identification of molecular pathways expressed by various factors could be used to design appropriate treatments or to employ strategies inducing the expression of HSF1 to prevent HF.

Chronic myeloid leukemia with complex karyotypes: Prognosis and therapeutic approaches.

OBJECTIVE AND BACKGROUND: Chronic myeloid leukemia (CML) is a neoplastic disease whose genetic and cytogenetic changes play important roles in prognosis and treatment strategies. Philadelphia (Ph) translocation t(9;22)(q34;q11) is a diagnostic and prognostic biomarker in CML. METHODS: Pubmed and Google Scholar databases were searched for English language articles from 1975 to 2017 containing the terms CML; Additional chromosomal abnormalities; Philadelphia translocation; Prognosis; and Treatment. DISCUSSION: Approximately 10-12% of CML patients exhibit additional chromosomal aberrations (ACAs) in chronic phase and blast crisis. ACAs emergence may cause different features in CML patients according to Ph pattern. For instance, deletion of chromosome 9 derivation is associated to patient's bad survival, whereas monosomy 7 develops myeloid dysplastic syndrome (MDS) or acute myeloid leukemia (AML) in CML patients with Ph-negative pattern. And ACAs in Ph-positive CML is considered as a failure in the management of CML with imatinib. CONCLUSION: CML classification using different features such as Ph and ACAs can play a decisive role in the evaluation of treatment responses in patients, for example, CML patients with Ph negative and monosomy 7 develop MDS or CML patient -Y and extra copy of Ph have a good response to tyrosine kinase inhibitors, therefore, classifications according to Ph and ACAs play an important role in choosing better treatment protocols and therapeutic strategies. Karyotype analysis in CML patients with complex karyotype shows unrandom pattern so ACAs can be great clue in medical guidelines.

Clonal hematopoiesis: Genes and underlying mechanisms in cardiovascular disease development.

The clonal hematopoiesis when occurring without hematologic abnormalities is defined as clonal hematopoiesis of indeterminate potential (CHIP). Aging causes accumulation of somatic mutations, and hematopoietic stem cells (HSCs) can develop clonal expansion of different lineages by these mutations. CHIP has a correlation with cancer and cardiovascular disease (CVD) through acquired mutations in genes. DNMT3A, TET2, ASXL1, and JAK2 genes as well as other genes are the most common somatic mutations causing CHIP and CVD in an older age. Other factors such as cholesterol level, laboratory tests and indexes also affect CVD. In addition, mutations in adenosine triphosphate-binding cassette transporters and also chronic stress in nervous system can result in HSCs proliferation and CVD. However, laboratory tests and indexes are not sensitive for CVD diagnosis. But the therapeutic interventions can be helpful to prevent CVD cases by targeting somatic mutations, chemokine receptors, and growth factors in HSCs. Also, new drugs can control CVD by targeting of cells and their signaling pathways in HSCs. Therefore, more investigations are needed and more questions should be answered for the relationship between CHIP and CVD as a challenging issue in future.

Flip-flops of natural killer cells in autoimmune diseases versus cancers: Immunologic axis.

Natural killer (NK) cells play an essential role in the immune response to infections, inflammations, and malignancies. Recent studies suggest that NK cell surface receptors and cytokines are the key points of the disease development and protection. We hypothesized that the interactions between NK cell receptors and targeted cells construct an eventual niche, and this niche has an eventual profile in various autoimmune diseases and cancers. The NK cells preactivated with cytokines, such as interleukin-2 (IL-2), IL-12, IL-15, and IL-18 can have higher cytotoxicity; however, the toxic side effect of IL-2 should be considered. The vicissitudes of NK cell profile and its receptors obey the environmental communications and cell interactions. Our vision around the NK cells as an immune axis remained dual, and we still cannot judge the immune responses based on the NK cell flip-flop. A design of eventual niche to monitor the NK cell and targeted cell interaction is needed to strengthen our ability in diagnosis and treatment approaches based on the NK cells. Here, we have reviewed the shifts in the NK cells and their surface receptors in autoimmune diseases, solid tumors, and leukemia, and also discussed the effective chemokines that affect NK cell activation and proliferation. The main aim of this review is to present a broader vision of the NK cell changes in autoimmune disease and cancers.

Autophagy regulation and its role in normal and malignant hematopoiesis.

Autophagy, the molecular machinery of self-eating, plays a dual role of a tumor promoter and tumor suppressor. This mechanism affects different clinical responses in cancer cells. Autophagy is targeted for treating patients resistant to chemotherapy or radiation. Limited reports investigate the significance of autophagy in cancer therapy, the regulation of hematopoietic and leukemic stem cells and leukemia formation. In the current review, the role of autophagy is discussed in various stages of hematopoiesis including quiescence, self-renewal, and differentiation.

Wnt/ß-catenin in ischemic myocardium: interactions and signaling pathways as a therapeutic target.

Cardiovascular disease (CVD) is still a factor of mortality in the whole world. Through canonical and noncanonical pathways and with different receptors, the Wnt/ß-catenin signaling pathway plays an essential role in response to heart injuries. Wnt regulates the mobilization and proliferation of cells in endothelium and epicardium in an infarcted heart. Therefore, with its profibrotic effects as well as its antagonism with other proteins, Wnt/ß-catenin signaling pathway leads to beneficial effects on fibrosis and cardiac remodeling in myocardium. In addition, Wnt increases the proliferation and differentiation of cardiac progenitors in an ischemic heart. Complex interactions and dual activity of Wnt, the changes in its expression, and mutations that can change its activity during heart development have an adverse effect on cardiac myocardium after injury. However, targeting the Wnt in myocardium with cellular and molecular pathways can be suggested to improve and repair ischemic heart. Given these challenges, in this review article, we deal with the role of Wnt/ß-catenin signaling pathway as well as its interactions with other cells and molecules in an ischemic myocardium.

Expression and Activity of Matrix Metalloproteinases in Leukemia.

Matrix metalloproteinases (MMPs) are responsible for the degradation of extracellular matrix components and hence play a crucial role in physiological and pathologic processes. The imbalance between the expression of MMPs and their inhibitors can be effective in leukemic cell processes such as migration, angiogenesis, survival, and apoptosis, playing a key role in the progression and prognosis of leukemia. In this review, we discuss the potential involvement of MMPs and their inhibitors in the pathogenesis and progression of leukemia by examining their role in the prognosis of leukemia. Inducing leukemic cell growth, migration, invasiveness, and angiogenesis are the main roles of MMPs in leukemia progression mediated by their degradative activity. Given the important role of MMPs in leukemia progression, further clinical trials are needed to confirm the link between MMPs' expressions and leukemia prognosis. It is hoped to use MMPs as therapeutic targets to improve patients' health by recognizing the prognostic value of MMPs in leukemia and their effect on the progression of these malignancies and their response to treatment.

Aberrant DNA Methylation in Chronic Myeloid Leukemia: Cell Fate Control, Prognosis, and Therapeutic Response.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell malignancy characterized by the expression of the BCR-ABL1 fusion gene with different chimeric transcripts. Despite the crucial impact of constitutively active tyrosine kinase in CML pathogenesis, aberrant DNA methylation of certain genes plays an important role in disease progression and the development of drug resistance. This article reviews recent findings relevant to the effect of DNA methylation pattern of regulatory genes on various cellular activities such as cell proliferation and survival, as well as cell-signaling molecules in CML. These data might contribute to defining the role of aberrant DNA methylation in disease initiation and progression. However, further studies are needed on the validation of specific aberrant methylation markers regarding the prognosis and prediction of response among the CML patients.

MicroRNA Modulation during the In vitro Culture of Hematopoietic Stem Cells Prior to Transplantation.

BACKGROUND: Human umbilical cord blood (HUCB) is an acceptable and readily accessible source of stem cells. There is an ongoing interest in cord blood stem cell therapies; however, little is known about the possible unfavorable effects of laboratory modifications on the isolated HUCB cells. The involvement of miRNAs in several biological processes has been shown. The aim of this study was to evaluate the possible changes in miRNA expression profiles in CD133+ hematopoietic cells after in vitro culture. METHODS: HUCBCD133+ hematopoietic stem cells were isolated by magnetic-activated cell sorting, and then the cells were counted using flow cytometry. The cells were divided into 2 groups. In the first group, RNA was extracted and the cells of the second group were cultured in vitro for 12 days and then these cells were used to assay miRNAs expression using real-time qPCR. RESULTS: The results showed that the expression of 349 out of 1,151 screened miRNAs was upregulated following a 12-day in vitro culture of CD133+ cells, whereas the expression of 293 miRNAs was downregulated. In addition, the expression of 509 miRNAs was not significantly altered. Another in-silico analysis involving the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to the selected miRNAs was also conducted. CONCLUSION: Based on our results, the in vitro expansion of HUCB resulted in altered expression levels of miRNAs. This study provides information on the effects of 2-dimensional culture of hematopoietic cells prior to transplantation for more successful transplantation.

Wnt/ß-catenin signaling in bone marrow niche.

The bone marrow (BM) niche is a specific physiological environment for hematopoietic and non-hematopoietic stem cells (HSCs). Several signaling pathways (including Wnt/ß-catenin) regulate various aspects of stem cell growth, function and death in the BM niche. In addition, the canonical Wnt pathway is crucial for directing self-renewal and differentiation as important mechanisms in many types of stem cells. We review the role of the Wnt/ß-catenin pathway in the BM niche and its importance in stem cells. Relevant literature was identified by a PubMed search (1997-2014) of English-language literature by using the following keywords: BM niche, Wnt/ß-catenin signaling, osteoblast, osteoclast and bone disease. The Wnt/ß-catenin pathway regulates the stability of the ß-catenin proto-oncogene. The stabilized ß-catenin then translocates to the nucleus, forming a ß-catenin-TCF/LEF complex regulating the transcription of specific target genes. Stem cells require ß-catenin to mediate their response to Wnt signaling for maintenance and transition from the pluripotent state during embryogenesis. In adult stem cells, Wnt signaling functions at various hierarchical levels to contribute to the specification of the diverse tissues. Aberrant Wnt/ß-catenin signaling and its downstream transcriptional regulators are observed in several malignant stem cells and human cancers. Because Wnt signaling can maintain stem cells and cancer cells, the ability to modulate the Wnt pathway either positively or negatively may be of therapeutic relevance. The controlled activation of Wnt signaling might allow us to enhance stem and progenitor cell activity when regeneration is needed.

Role of stem cell factor in the placental niche.

Stem cell factor (SCF) is a cytokine found in hematopoietic stem cells (HSCs) and causes proliferation and differentiation of cells by binding to its receptor (c-kit). It is produced in the yolk sac, fetal liver and bone marrow during the development of the fetus and, together with its signaling pathway, plays an important role in the development of these cells. The placenta, an important hematopoiesis site before the entry of cells into the liver, is rich in HSCs, with definitive hematopoiesis in a variety of HSC types and embryonic stem cells. Chorionic-plate-derived mesenchymal stem cells (CP-MSCs) isolated from the placenta show stem cell markers such as CD41 and cause the self-renewal of cells under hypoxic conditions. In contrast, hypoxia can result in apoptosis and autophagy via oxidative stress in stem cells. As a hypoxia-induced factor, SCF causes a balance between cell survival and death by autophagy in CP-MSCs. Stromal cells and MSCs have a crucial function in the development of HSCs in the placenta via SCF expression in the placental vascular niche. Defects in hematopoietic growth factors (such as SCF and its signaling pathways) lead to impaired hematopoiesis, resulting in fetal death and abortion. Therefore, an awareness of the role of the SCF/c-kit pathway in the survival, apoptosis and development of stem cells can significantly contribute to the exploration of stem cell production pathways during the embryonic period and in malignancies and in the further generation of these cells to facilitate therapeutic approaches. In this review, we discuss the role of SCF in the placental niche.

Mesenchymal stem cells as a double-edged sword in suppression or progression of solid tumor cells.

Tumor cells are able to attract mesenchymal stem cells (MSCs) to primary tumor site. On the other hand, MSCs secrete various factors to attract tumor cells towards BM. In this review, in addition to assessment of MSCs function at tumor sites and their impact on growth and metastasis of tumor cells, the importance of MSC in attraction of malignant cells to BM and their involvement in drug resistance of tumor cells have also been studied. Relevant literature was identified by a PubMed search (2000-2015) of English-language literature using the terms mesenchymal stem cells, cancer cell, metastasis, and tumor microenvironment. MSCs migrate towards tumor microenvironment and are involved in both pro-tumorigenic and antitumorigenic functions. The dual function of MSCs at tumor sites is dependent upon a variety of factors, including the type and origin of MSCs, the cancer cell line under study, in vivo or in vitro conditions, the factors secreted by MSCs and interactions between MSCs, host immune cells and cancer cells. Therefore, MSCs can be regarded both as friends and enemies of cancer cells. Although the role of a number of pathways, including IL-6/STAT3 pathway, has been indicated in controlling the interaction between MSCs and tumor cells, other mechanisms by which MSCs can control the tumor cells are not clear yet. A better understanding of these mechanisms through further studies can determine the exact role of MSCs in cancer progression and identify them as important therapeutic agents or targets.

Significance of oncogenes and tumor suppressor genes in AML prognosis.

Acute myeloid leukemia (AML) is a heterogeneous disorder among hematologic malignancies. Several genetic alterations occur in this disease, which cause proliferative progression, reducing differentiation and apoptosis in leukemic cells as well as increasing their survival. In the genetic study of AML, genetic translocations, gene overexpression, and mutations effective upon biology and pathogenesis of this disease have been recognized. Proto-oncogenes and tumor suppressor genes, which are important in normal development of myeloid cells, are involved in the regulation of cell cycle and apoptosis, undergo mutation in this type of leukemia, and are effective in prognosis of AML subtypes. This review deals with these genes, the assessment of which can be important in the diagnosis and prognosis of patients as well as therapeutic outcome.

Bone marrow niche in immune thrombocytopenia: a focus on megakaryopoiesis.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased bleeding tendency and thrombocytopenia. In fact, the precise pathogenesis of this disease is still not clear. Megakaryopoiesis involves complete differentiation of megakaryocyte (MK) progenitors to functional platelets. This complex process occurs in specific bone marrow (BM) niches composed of several hematopoietic and non-hematopoietic cell types, soluble factors, and extracellular matrix proteins. These specialized microenvironments sustain MK maturation and localization to sinusoids as well as platelet release into circulation. However, MKs in ITP patients show impaired maturation and signs of degradation. Intrinsic defects in MKs and their extrinsic environment have been implicated in altered megakaryopoiesis in this disease. In particular, aberrant expression of miRNAs directing MK proliferation, differentiation, and platelet production; defective MK apoptosis; and reduced proliferation and differentiation rate of the MSC compartment observed in these patients may account for BM defects in ITP. Furthermore, insufficient production of thrombopoietin is another likely reason for ITP development. Therefore, identifying the signaling pathways and transcription factors influencing the interaction between MKs and BM niche in ITP patients will contribute to increased platelet production in order to prevent incomplete MK maturation and destruction as well as BM fibrosis and apoptosis in ITP. In this review, we will examine the interaction and role of BM niches in orchestrating megakaryopoiesis in ITP patients and discuss how these factors can be exploited to improve the quality of patient treatment and prognosis.

Regulatory effect of chemokines in bone marrow niche.

Chemokines secreted from different cellular components of bone marrow (BM) play an important role in the formation of the BM niche system. The hematopoietic stem cell (HSC) pool located in specialized anatomical sites within the BM is subjected to a complex network of chemokines, such that the produced chemokines affect the fate of these cells. Expression of different chemokine receptors on leukemic stem cells (LSCs) uncovers the critical role of chemokines in the maintenance, survival and fate of these cells in the leukemic niche. As a pre-metastatic niche rich in a variety of chemokines, the BM niche is turned into a locus of tumor cell development and division. The chemokine receptors expressed on the surface of metastatic cells lead to their metastasis and homing to the BM niche. Knowledge of chemokines and their receptors leads to the production of various therapeutic antagonists at chemokine receptors expressed on leukemic and tumor cells, enabling interference with chemokine function as a therapeutic tool. New findings suggest that miRNAs, with their specific inhibitory function, affect the ability of producing and expressing chemokines and chemokine receptors. This review focuses on the emerging role of chemokines and their receptors in normal and pathologic conditions of the BM niche, and also discusses the new therapeutic methods with this background.