The role of exhausted natural killer cells in the immunopathogenesis and treatment of leukemia.

The immune responses to cancer cells involve both innate and acquired immune cells. In the meantime, the most attention has been drawn to the adaptive immune cells, especially T cells, while, it is now well known that the innate immune cells, especially natural killer (NK) cells, play a vital role in defending against malignancies. While the immune cells are trying to eliminate malignant cells, cancer cells try to prevent the function of these cells and suppress immune responses. The suppression of NK cells in various cancers can lead to the induction of an exhausted phenotype in NK cells, which will impair their function. Recent studies have shown that the occurrence of this phenotype in various types of leukemic malignancies can affect the prognosis of the disease, and targeting these cells may be considered a new immunotherapy method in the treatment of leukemia. Therefore, a detailed study of exhausted NK cells in leukemic diseases can help both to understand the mechanisms of leukemia progression and to design new treatment methods by creating a deeper understanding of these cells. Here, we will comprehensively review the immunobiology of exhausted NK cells and their role in various leukemic malignancies. Video Abstract.

Blockade of HIF-1α and STAT3 by hyaluronate-conjugated TAT-chitosan-SPION nanoparticles loaded with siRNA molecules prevents tumor growth.

HIF-1α and STAT3 are two of the critical factors in the growth, proliferation, and metastasis of cancer cells and play a crucial role in inhibiting anti-cancer immune responses. Therefore, we used superparamagnetic iron oxide (SPION) nanoparticles (NPs) coated with thiolated chitosan (ChT) and trimethyl chitosan (TMC) and functionalized with hyaluronate (H) and TAT peptide for delivery of siRNA molecules against STAT3 and HIF-1α to cancer cells both in vivo and in vitro. The results indicated that tumor cell transfection with siRNA-encapsulated NPs robustly inhibited proliferation and migration and induced apoptosis in tumor cells. Furthermore, simultaneous silencing of HIF-1α and STAT3 significantly repressed cancer development in two different tumor types (4T1 breast cancer and CT26 colon cancer) which were associated with upregulation of cytotoxic T lymphocytes and IFN-γ secretion. The findings suggest inhibiting the HIF-1α/STAT3 axis by SPION-TMC-ChT-TAT-H NPs as an effective way to treat cancer.

Small dense low-density lipoprotein-lowering agents.

Metabolic disorders, including obesity, diabetes, and hyperlipidemia, as well as cardiovascular diseases (CVD), particularly atherosclerosis, are still leading causes of death worldwide. Plasma levels of low-density lipoprotein (LDL) are currently being considered as a critical risk factor for the diseases mentioned above, especially atherosclerosis. Because of the heterogeneous nature of LDL, many studies have already been conducted on its subclasses, especially small dense LDL (sdLDL). According to available evidence, sdLDL levels can be considered as an ideal alternative to LDL levels for monitoring CVD and early diagnosis of atherosclerosis. Recently, several researchers have focused on factors that are able to decrease sdLDL levels and improve health quality. Therefore, the purpose of this study is to describe the production process of sdLDL particles and review the effects of pharmaceutical and dietary agents as well as lifestyle on sdLDL plasma levels. In brief, their mechanisms of action are discussed. Apparently, cholesterol and LDL-lowering compounds are also effective in the reduction of sdLDL levels. In addition, improving lipid profile, especially the reduction of triglyceride levels, appropriate regimen, and lifestyle can decrease sdLDL levels. Therefore, all the aforementioned parameters should be taken into consideration simultaneously in sdLDL levels reducing strategies.

MicroRNA-372 acts as a double-edged sword in human cancers.

MicroRNAs (miRNAs or miRs) are non-coding, single-stranded, endogenous RNAs that regulate various biological processes, most notably the pathophysiology of many human malignancies. It process is accomplished by binding to 3'-UTR mRNAs and controlling gene expression at the post-transcriptional level. As an oncogene, miRNAs can either accelerate cancer progression or slow it down as a tumor suppressor. MicroRNA-372 (miR-372) has been found to have an abnormal expression in numerous human malignancies, implying that the miRNA plays a role in carcinogenesis. It is both increased and downregulated in various cancers, and it serves as both a tumor suppressor and an oncogene. This study examines the functions of miR-372 as well as the LncRNA/CircRNA-miRNA-mRNA signaling pathways in various malignancies and analyses its potential prognostic, diagnostic, and therapeutic implications.

Dual role of microRNA-1297 in the suppression and progression of human malignancies.

MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded and tiny RNAs that modulate several biological functions, more importantly, the pathophysiology of numerous human cancers. They are bound with target mRNAs and thereby regulate gene expression at post-transcriptional levels. MiRNAs can either trigger cancer progression as an oncogene or alleviate it as a tumor suppressor. Abnormal expression of microRNA-1297 (miR-1297) has been noticed in several human cancers suggesting a distinct role for the miRNA in tumorigenesis. More specifically, it is both up-regulated and down-regulated in various cancers suggesting that it can act as both tumor suppressor and oncogene. This review systematically highlights the different roles of miR-1297 in the pathophysiology of human cancers, explains the mechanisms underlying miR-1297-mediated tumorigenesis, and discusses its potential prognostic, diagnostic, and therapeutic importance.

MicroRNA-154: A Novel Candidate for Diagnosis and Therapy of Human Cancers.

MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded, tiny RNAs with 21-23 nucleotides that regulate several biological functions through binding to target mRNAs and modulating gene expression at post-transcriptional levels. Recent studies have described crucial roles for miRNAs in pathophysiology of numerous human cancers. They can act as an oncogene and promote cancer or as a tumor suppressor and alleviate the disease. Recently discovered microRNA-154 (miR-154) has been proposed to be involved in multiple physiological and pathological processes including cancer. With this aspect, aberrant expression of miR-154 has been demonstrated in variety of human malignancies, suggesting an important role for miR-154 in tumorigenesis. To be specific, it is considered as a tumor suppressor miRNA and exerts its beneficial effects by targeting several genes. This review systematically summarizes the recent advances done on the role of miR-154 in different cancers and discusses its potential prognostic, diagnostic and therapeutic values.

Dysregulation of microRNAs regulating survivin in CD4+ T cells in multiple sclerosis.

BACKGROUND: Impaired elimination mechanisms of the autoreactive lymphocytes, like T lymphocytes, via apoptosis may be the cause of continues inflammatory state in multiple sclerosis (MS). BIRC5 gene codify for the survivin, which participates in the modulation of apoptosis and cell survival. The objective of this study was investigation of the role of important confirmed miRNAs, including miR-335, miR-485, miR-542, and miR-708, in the regulation of survivin mRNA in the CD4+ T cells of MS cases. METHODS: In this study, 50 RRMS patients as well as 50 healthy matched controls were recruited. The peripheral blood mononuclear cells (PBMCs) were isolated from whole blood samples and CD4+ T cells were prepared. After that, RNA was extracted, cDNA was synthesized, and the expression levels of miR-335, miR-485, miR-542, and miR-708 were measured using Real-time PCR. Moreover, the mRNA expression of survivin was detected. Serum level of survivin was detected using ELISA. RESULTS: The mRNA of survivin was 2-folds upregulated in the CD4+ T cells from MS patients in comparison to the healthy controls (P = 0.0053). Serum level of survivin was higher in patients than controls. There was statistically significant downregulation of miR-485 (P = 0.001) and miR-708 (P = 0.011) in CD4+ T cells of patients compared with controls. The miR-485 downregulation had statistically significant correlation with the mRNA expression and serum level of survivin. CONCLUSION: miRNAs play a role in the regulation of survivin, and therefore apoptosis of CD4+ T cells, and hence are probably participating in a persistent inflammatory condition in MS patients.

Inhibition of CD73 using folate targeted nanoparticles carrying anti-CD73 siRNA potentiates anticancer efficacy of Dinaciclib.

Conventional therapeutic methods against cancer, including chemotherapy, radiotherapy, surgery, and combination therapy, have exhibited different toxicity levels due to their unspecific mechanism of action. To overcome the challenges facing conventional cancer therapies, newly developed methods are being investigated. Significant levels of specificity, remarkable accumulation at the tumor site, limited side effects, and minimal off-target effects enable the newly synthesized nanoparticles (NPs) to become the preferred drug delivery method in anticancer therapeutic approaches. According to the literature, CD73 has a pivotal role in cancer progression and resistance to chemotherapy and radiotherapy. Therefore, CD73 has attracted considerable attention among scientists to target this molecule. Accordingly, FDA approved CDK inhibitors such as Dinaciclib that blocks CDK1, 2, 5, and 9, and exhibits significant anticancer activity. So in this study, we intended to simultaneously suppress CD73 and CDKs in cancer cells by using the folic acid (FA)-conjugated chitosan-lactate (CL) NPs loaded with anti-CD73 siRNA and Dinaciclib to control tumor progression and metastasis. The results showed that NPs could effectively transfect cancer cells in a FA receptor-dependent manner leading to suppression of proliferation, survival, migration, and metastatic potential. Moreover, the treatment of tumor-bearing mice with this combination strategy robustly inhibited tumor growth and enhanced survival time in mice. These findings imply the high potential of FA-CL NPs loaded with anti-CD73 siRNA and Dinaciclib for use in cancer treatment shortly.