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Purpose: microRNA-193a-5p is one of the well-known tumor suppressor miRNAs in the body but in many cases, its expression became reduced in patients suffering from gastric cancer (GC). The main purpose of this study was to restore the function of this miRNA in human GC cells and investigating the effects of enhanced expression of miR-193a-5p on proliferation, apoptosis, and migration of GC cells upon in vitro transfection. Methods: The KATO III GC cells were treated with 100 nM of miR-193a-5p or negative control sequences. Following that, the MTT assay, flow cytometry assay, and wound-healing assay were applied to estimate the impacts of enhanced expression of this miRNA on the viability, apoptosis, and migration rate of the cells, respectively. Moreover, the total RNA was isolated and alterations in the mRNA expression ratio of migratory genes were measured by qRT-PCR techniques. Results: The findings designated that enhanced expression of miR-193a-5p suppressed the migratory ability of the cells, but had no significant effects on cell survival or apoptosis of the transfected cells. In addition, this inhibitory function of miR-193a-5p on the migration rate of the KATO III cell line occurs with concurrent suppression of vimentin and MMP-9 gene expression. Conclusion: It can be concluded that miR-193a-5p negatively influences the migratory ability of the cancerous cells and restoring its effects can be regarded as a promising target of future therapeutic interventions, especially for GC metastasis. [ABSTRACT FROM AUTHOR]

The highly pathogenic, novel coronavirus disease (COVID-19) outbreak has emerged as a once-in-a-century pandemic with poor consequences, urgently calling for new therapeutics, cures, and supportive interventions. It has already affected over 250 million people worldwide; thereby, there is a need for novel therapies to alleviate the related complications. There is a paradigm shift in developing drugs and clinical practices to combat COVID-19. Several clinical trials have been performed or are testing diverse pharmacological interventions to alleviate viral load and complications such as cytokine release storm (CRS). Kinase-inhibitors have appeared as potential antiviral agents for COVID-19 patients due to their efficacy against CRS. Combination of kinase inhibitors with other therapies can achieve more efficacy against COVID-19. Based on the pre-clinical trials, kinase inhibitors such as Janus kinase-signal transducer and activator of transcription (JAK/STAT) inhibitors, Brutton's tyrosin kinase (BTK) inhibitors, p38 mitogen-activated protein kinases (p38 MAPK) inhibitors, Glycogen synthase kinase 3 (GSK-3) inhibitors can be a promising strategy against COVID-19. Kinase inhibitors possess crucial pharmacological properties for a successful re-purposing in terms of dual anti-inflammatory and anti-viral effects. This review will address the current clinical evidence and the newest discovery regarding the application of kinase inhibitors in COVID-19. An outlook on ongoing clinical trials (clinicaltrials.gov) and unpublished data is also presented here. Besides, Kinase inhibitors' function on COVID-19-mediated CRS is discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

• DC vaccine therapy in AML management. • Prospects of DC vaccination in AML. • AML patients improved via DC vaccine therapy. Acute myeloid leukemia (AML) is classified as a hematologic malignancy characterized by the proliferation of immature blood cells within the bone marrow (BM), resulting in an aberrant and unregulated cellular growth. The primary therapeutic modalities for AML include chemotherapy and hematopoietic stem cell transplantation. However, it is important to note that these treatments are accompanied by important adverse effects and mortality rates. Therefore, the need for more effective treatment options seems necessary, and dendritic cell (DC) vaccine therapy can be one of these options. In this study, we aim to investigate the effectiveness of DC vaccination therapy for the management of AML. PubMed, Scopus, ProQuest, Web of Science, and Google Scholar databases were searched for this systematic review. The articles were evaluated based on the inclusion criteria of this study and initially compared in terms of titles or abstracts. Finally, the articles related to the topic of this review were obtained in full text. The complete remission and partial remission, survival, correlative immune assays, and health-related metrics were used to evaluate this cellular immunotherapy effectiveness. The quality of the studies was assessed independently using the Cochrane risk-of-bias tools. The compiled data were input into a standard Excel spreadsheet. Each domain was evaluated as having either a "low risk," "high risk," or "unclear risk" of bias. Among the 3986 studies that were determined, a total of 11 correlated trials were selected for inclusion in this systematic review. DC vaccine therapy was effective in inducing complete and partial remission, and stabilization of the disease. Additionally, it was discovered that the treatment strengthened the immune system as seen by increased levels of CD4+ and CD8+ T cells, Th1 cytokines, WT1-specific T cells, and activated NK cells. We conducted a systematic review that supports the use of DC vaccine therapy as an effective treatment for AML. The therapy demonstrated potentials in achieving remission, enhancing the immune system function, and increasing overall survival. However, more studies are required to improve the methods of preparing and delivering the DC vaccine, and to confirm its long-term safety and effectiveness. [ABSTRACT FROM AUTHOR]

Introduction: Understanding the key role of the tumor microenvironment in specifying molecular markers of breast cancer subtypes is of a high importance in diagnosis and treatment. Therefore, the possibility of interconversion of luminal states and their specific markers alteration under the control of tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs) deserves to be further investigated. Methods: To activate normal human fibroblasts, liquid overlay technique or nemosis was used and a-SMA protein expression, CAFs marker, in fibroblastic spheroids was measured by blotting. The luminal A, MCF-7, and luminal B, MDA-MB 361, cell lines were treated with normal and spheroidal/activated fibroblast conditioned medium for 48 hours. The morphological changes of both luminal A and B cells were evaluated by invert light microscopy and analyzed through the shape factor formula. Moreover, chemo-sensitivity, proliferation, and changes in ER-related and proliferative genes expression levels were assessed respectively via MTT assay, Ki67 expression Immunofluorescence assay, real time PCR and Annexin V-FITC techniques. Results: Activated (spheroidal) fibroblasts, expressed aSMA marker two folds more than monolayer cultured fibroblasts. Our study indicated a significant increase in IC50 of both luminal A and B cell lines after being treated with conditioned medium particularly in treated group with spheroidal conditioned medium. Studying Morphological changes using shape factor formula demonstrated more aggressiveness with gaining mesenchymal features in both luminal A and B subtypes by increasing exposure time. Changes in the expression of Ki67 were observed following treatment with fibroblastic and spheroidal paracrine secretome. Driven Data from Ki67 assay supports the luminal A and B interconversion by elevated Ki67 expression in luminal A and lowered Ki67 expression in luminal B. Gene expression analysis revealed that anti-apoptotic Bcl2 gene expression in both luminal types treated with condition medium has been increased though there has seen no interchange in expression of ER-related and proliferative genes between luminal A (MCF7) and luminal B (MDA-MB361) subtypes, the results of Annexin V-FITC flow cytometry test indicated a decrease in the population of both early and late apoptotic cells in groups treated with both fibroblastic and spheroidal condition medium compared to of control group. Conclusion: Under the paracrine influence of fibroblast cells, both luminal A (MCF7) and luminal B (MDA-MB) subtypes of breast cancer gained invasive, anti-apoptotic, and chemoresistance features which are mostly increased by activated(spheroidal) fibroblasts conditioned medium mimicking CAFs. There was no strong proof for interconversion of luminal A and luminal B which share more similarities among breast cancer molecular subtypes. [ABSTRACT FROM AUTHOR]

Antigens in hydatid cyst fluid (HCF) have been discovered to bear a significant resemblance to antigens present in cancer cells. MicroRNA-1 (miR-1) is a well-known member of the tumor inhibitor miRNA family and has been shown to have pro-apoptotic and tumor-inhibitory functions. This study aimed to evaluate the ability of HCF to prevent breast cancer and to explore the underlying mechanisms that affect cancer cells. For this study, MDA-MB-231 and MCF-7 breast cancer cells were cultured and divided into two groups: one group received HCF treatment and the other group was untreated and served as the control group. The cytotoxicity and cell viability of various HCF concentrations on breast cancer cells were evaluated using the MTT assay. In addition, the expression level of miR-1 in HCF-treated and untreated breast cancer cells was analyzed using qRT-PCR. The study found that HCF treatment reduced the growth of MDA-MB-231 and MCF-7 breast cancer cells, indicating that it was cytotoxic to the cells. Specifically, the IC50 concentration of HCF after 24 hours of treatment was 7.32 µg/mL for MDA-MB-231 cells and 13.63 µg/mL for MCF-7 cells. In addition, qRT-PCR analysis revealed that the expression level of miR-1 was significantly increased in HCF-treated MDA-MB-231 (P = 0.0203) and MCF-7 (P = 0.0394) cell lines compared to untreated controls. Although HCF has been shown to inhibit the growth of breast cancer cells and to upregulate miR-1, a key tumor suppressor in cancer cells, the specific mechanisms responsible for this effect remain unclear. Further studies are needed to fully understand the molecular pathways underlying HCF's antitumor activity and its potential as a therapeutic agent in cancer therapy. [ABSTRACT FROM AUTHOR]

Introduction: Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. microRNAs are a group of regulatory non-coding RNAs that are involved in GC progression. miR-145 as a tumor suppressor and miR-21 as an oncomiR were shown to be dysregulated in many cancers including GC. This research aimed to enhance the expression of miR-145 while reducing the expression of miR-21 and examine their impact on the proliferation, apoptosis, and migration of GC cells. Methods: KATO III cells with high expression levels of miR-21-5p and low expression of miR-145-5p were selected. These cells were then transfected with either miR-145-5p mimics or anti-miR-21-5p, alone or in combination. Afterward, the cell survival rate was determined using the MTT assay, while apoptosis induction was investigated through V-FITC/PI and DAPI staining. Additionally, cell migration was examined using the wound healing assay, and cell cycle progression was analyzed through flow cytometry. Furthermore, gene expression levels were quantified utilizing the qRT-PCR technique. Results: The study's findings indicated that the co-replacement of miR-145-5p and anti-miR-21-5p led to a decrease in cell viability and the induction of apoptosis in GC cells. This was achieved via modulating the expression of Bax and Bcl-2 , major cell survival regulators. Additionally, the combination therapy significantly increased sub-G1 cell cycle arrest and reduced cell migration by downregulating MMP-9 expression as an epithelial-mesenchymal transition marker. This study provides evidence for the therapeutic possibility of the combination of miR-145-5p and anti-miR-21-5p and also suggests that they could inhibit cell proliferation by modulating the PTEN/AKT1 signaling pathway. Conclusion: Our research revealed that utilizing miR-145-5p and anti-miR-21-5p together could be a promising therapeutic approach for treating GC. [ABSTRACT FROM AUTHOR]

Scientific research over the past decades has proven the pivotal role of long non-coding RNAs (LncRNAs) in regulating gene expression. The immune responses are controlled through the interaction of pro-inflammatory (predominance of T helper 17 cells (Th17)) and anti-inflammatory cytokines excretion (predominance of Regulatory T cells (Treg)). Recent studies have marked the impact of many diverse LncRNAs on Treg/Th17 imbalances. Moreover, some of the roots and causes of human diseases can be associated with the alterations in the Th17/Treg ratio. In this review study, we overviewed the association between LncRNAs and Th17/Treg, with the potential of providing novel prognostic and diagnostic biomarkers and promising therapeutic targets in various diseases, particularly cancer. [ABSTRACT FROM AUTHOR]

Introduction: Trichomoniasis is the most common non-viral sexually transmitted infection that increases the risk of cervical cancer. Trichomonas vaginalis (T. vaginalis) can regulate the pro-inflammatory cytokine production in the host cells. Toll-like receptors (TLRs) are a family of the pattern recognition receptors (PRRs) of mammalian cells, expressed in various host cells and have an important role in recognizing pathogens, and pro-inflammatory responses. The aim of the present study is to investigate the role of TLR5 in cervical cancer cells (HeLa) and human vaginal epithelial cells (HVECs) exposed to T. vaginalis. Methodology: First, the cells and parasites were cultured in RPMI and trypticase yeast extract maltose (TYM), respectively. After adaption of parasite and epithelial cells by RPMI-TYM medium co-culture (9:1 vol/vol), HVECs and HeLa cells were stimulated with T. vaginalis trophozoites (24-hour incubation at 37 °C, 5% CO2). Following RNA extraction and cDNA synthesis, the gene expression levels of TLR5, IRAK1, and NF-kB were assessed using real-time PCR. Besides, the protein levels were measured using western blotting. All tests and controls were normalized using ß-actin as a housekeeping control. Results: Real-time PCR results showed an increased gene expression of TLR5, IRAK1, and NF-kB in T. vaginalis exposed HVECs and HeLa cells compared to the control group (p < 0.05). Additionally, western blot analysis showed a statistically significant increase in TLR5, and NF-kB proteins in both groups after exposure to the parasite (p < 0.05). Conclusions: These findings provide insight into the host-parasite interaction, and the results indicated that T. vaginalis could stimulate TLR5 and activate related pathways. [ABSTRACT FROM AUTHOR]

Bioactive micro- and macro-molecules (postbiotics) derived from gut beneficial microbes are among natural chemical compounds with medical significance. Currently, a unique therapeutic strategy has been developed with an emphasis on the small molecular weight biomolecules that are made by the microbiome, which endow the host with several physiological health benefits. A large number of postbiotics have been characterized, which due to their unique pharmacokinetic properties in terms of controllable aspects of the dosage and various delivery routes, could be employed as promising medical tools since they exert both prevention and treatment strategies in the host. Nevertheless, there are still main challenges for the in vivo delivery of postbiotics. Currently, scientific literature confirms that targeted delivery systems based on nanoparticles, due to their appealing properties in terms of high biocompatibility, biodegradability, low toxicity, and significant capability to carry both hydrophobic and hydrophilic postbiotics, can be used as a novel and safe strategy for targeted delivery or/and release of postbiotics in various (oral, intradermal, and intravenous) in vivo models. The in vivo delivery of postbiotics are in their emerging phase and require massive investigation and randomized double-blind clinical trials if they are to be applied extensively as treatment strategies. This manuscript provides an overview of the various postbiotic metabolites derived from the gut beneficial microbes, their potential therapeutic activities, and recent progressions in the drug delivery field, as well as concisely giving an insight on the main in vivo delivery routes of postbiotics. [ABSTRACT FROM AUTHOR]

Autoimmune diseases, especially among young people in the US, are one of the leading causes of morbidity and death. The immune responses are the fundamental pathogenicity of autoimmune disorders. The equilibrium between stimulatory and inhibitory signals is critical for the stimulation, migration, survival, and T cell‐related immune responses. The B7 family can substantially regulate T cell‐mediated immune responses. Nevertheless, recent breakthroughs in immune checkpoint blockade in cancer immunotherapy have facilitated autoimmune diseases, especially among the prone populations. In the current study, we tried to concisely review the role of the B7 family in regulating immune reactions and the influence of immune checkpoint inhibitors on autoimmunity development. [ABSTRACT FROM AUTHOR]

• There is a positive correlation between VISTA and CTLA-4 expression in Luminal A breast cancers. • Combined tumor-intrinsic VISTA/CTLA-4 knockdown increases T-cells' pro-inflammatory factors. • Combined tumor-intrinsic VISTA/CTLA-4 knockdown decreases MCF-7 stemness and cell cycle. • Combined tumor-intrinsic VISTA/CTLA-4 knockdown decreases MCF-7 cell migration. As inhibitory immune checkpoint molecules, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and V-domain Ig suppressor of T-cell activation (VISTA) can be expressed in tumoral cells and facilitate immune evasion of tumoral cells. Herein, we studied the significance of tumor-intrinsic CTLA-4 and VISTA silencing in tumor development and inflammatory factors expression in a co-culture system with MCF7 and T-cells. MCF7 cells were transfected with 60 pmol of CTLA-siRNA, VISTA-siRNA, and dual VISTA-/CTLA-4-siRNA. The MTT assay was performed to study the effect of CTLA-4 and VISTA knockdown on the viability of MCF7 cells. Colony formation and wound-healing assays were performed to investigate the effect of CTLA-4 and VISTA silencing on the clonogenicity and migration of MCF7 cells. Flow cytometry was used to study the significance of CTLA-4 and VISTA knockdown on the apoptosis and cell cycle of MCF7 cells. Also, a co-culture system with MCF7 and T-cells was developed to study the expression levels of IL-2, IFN-γ, TNF-α, TGF-β, and IL-10 following CTLA-4 and VISTA knockdown. The expression levels of caspase3, Bax, Bcl2, and MMP-9 were also investigated using quantitative real-time PCR. Finally, the TCGA Breast Cancer and GSE45827 datasets were analyzed to study the potential prognostic values of VISTA and CTLA-4, their expression difference in luminal A breast cancer and non-tumoral tissues, and their correlation in luminal A breast cancer tissues. Combined knockdown of tumor-intrinsic VISTA and CTLA-4 is superior in upregulating IL-2, IFN-γ, and TNF-α, downregulating TGF-β and IL-10 in T lymphocytes. Also, the combined silencing arrests the cell cycle at the sub-G1 phase, decreases migration, inhibits clonogenicity, and reduces cell viability of MCF7 cells. This combined treatment upregulates caspase 9 and BAX and downregulates MMP-9 in MCF7 cells. Our in-silico results have demonstrated a significant positive correlation between CTLA-4 and VISTA in luminal A breast cancer. The additive effect of the combined knockdown of tumor-intrinsic VISTA and CTLA-4 can substantially upregulate pro-inflammatory factors, downregulate anti-inflammatory factors, and inhibit tumor development in MCF7 cells. The significant positive correlation between VISTA and CTLA-4 in luminal A breast cancer might support the idea that a network of inhibitory immune checkpoint molecules regulates anti-tumoral immune responses; thus, combinational immune checkpoint molecules blockade can be suggested. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the commonest primary malignant brain tumor and has a remarkably weak prognosis. According to the aggressive form of GBM, understanding the accurate molecular mechanism associated with GBM pathogenesis is essential. Growth differentiation factor 15 (GDF‐15) belongs to transforming growth factor‐β superfamily with important roles to control biological processes. It affects cancer growth and progression, drug resistance, and metastasis. It also can promote stemness in many cancers, and also can stress reactions control, bone generation, hematopoietic growth, adipose tissue performance, and body growth, and contributes to cardiovascular disorders. The role GDF‐15 to develop and progress cancer is complicated and remains unclear. GDF‐15 possesses tumor suppressor properties, as well as an oncogenic effect. GDF‐15 antitumorigenic and protumorigenic impacts on tumor development are linked to the cancer type and stage. However, the GDF‐15 signaling and mechanism have not yet been completely identified because of no recognized cognate receptor. [ABSTRACT FROM AUTHOR]

Connective tissue diseases (CTDs) consist of an extensive range of heterogeneous medical conditions, which are caused by immune-mediated chronic inflammation and influences the various connective tissues of the body. They include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, Sjögren's syndrome, Behcet's disease, and many other autoimmune CTDs. To date, several anti-inflammatory approaches have been developed to reduce the severity of inflammation or its subsequent organ manifestations. As a logical mechanism to harnesses the undesired inflammation, some studies investigated the role of the intrinsic cholinergic anti-inflammatory pathway (CAP) in the modulation of chronic inflammation. Many different experimental and clinical models have been developed to evaluate the therapeutic significance of the CAP in CTDs. On the other hand, an issue that is less emphasized in this regard is the presence of autonomic neuropathy in CTDs, which influences the efficiency of CAP in such clinical settings. This condition occurs during CTDs and is a well-known complication of patients suffering from them. The advantages and limitations of CAP in the control of inflammatory responses and its possible therapeutic benefits in the treatment of CTDs are the main subjects of the current study. Therefore, this narrative review article is provided based on the recent findings of the complicated role of CAP in CTDs which were retrieved by searching Science Direct, PubMed, Google Scholar, and Web of Science. It seems that delineating the complex influences of CAP would be of great interest in designing novel surgical or pharmacological therapeutic strategies for CTDs therapy. [ABSTRACT FROM AUTHOR]

• HHLA2 silencing enhances the chemosensitivity of MG-63 cells to paclitaxel. • HHLA2 silencing increases paclitaxel antitumoral effect on MG-63 cell migration. • HHLA2 silencing increases paclitaxel antitumoral effect on MG-63 cell apoptosis. • HHLA2 silencing increases paclitaxel antitumoral effect on MG-63 cell cycle. Osteosarcoma is common type of bone cancer; however, the prognosis of patients with metastatic osteosarcoma is poor. As a new inhibitory immune checkpoint molecule, HHLA2 is upregulated in osteosarcoma. Herein, we studied the significance of tumor-intrinsic HHLA2 in MG-63 growth. Also, we examined the influence of combined therapy of HHLA2 knockdown with paclitaxel on the apoptosis, cell cycle, migration, and stemness of MG-63 cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was performed to study the half-maximal inhibitory concentration (IC50) of paclitaxel and the cytotoxicity of HHLA2-small interfering RNA (siRNA) on MG-63 cells. The apoptosis and cell cycle were analyzed using flow cytometry. The wound-healing and colony formation assays were conducted to investigate the effect of paclitaxel and HHLA2 knockdown on the migration and stemness of MG-63 cells, respectively. QRT-PCR was used to determine the Bax, caspase-3, and Bcl-2 mRNA expression levels. HHLA2 silencing has enhanced the chemosensitivity of MG-63 cells to paclitaxel. Besides, HHLA2 knockdown has increased the paclitaxel-induced cytotoxic effect on MG-63 cells. In terms of stimulating apoptosis, decreasing clonogenicity, halting the cell cycle at the sub G1 phase, and inhibiting migration, tumor-intrinsic HHLA2 silencing has increased these anti-tumor effects of paclitaxel on MG-63 cells. Besides, HHLA2 knockdown has potentiated paclitaxel-mediated Bcl-2 downregulation and paclitaxel-mediated caspase-3 and Bax upregulation in MG-63 cells. Tumor-intrinsic HHLA2 knockdown increases the anti-tumoral effect of paclitaxel on MG-63 cells and enhances the chemosensitivity of MG-63 cells to paclitaxel. [ABSTRACT FROM AUTHOR]

Immune checkpoints are vital molecules that regulate T-cell function by activation or inhibition. Among the immune checkpoint molecules, the B7-family proteins are significantly involved in the immune escape of tumor cells. By binding to inhibitory receptors, they can suppress T-cell-mediated immunity. B7-family proteins are found at various stages of tumor microenvironment formation and promote tumorigenesis and tumor progression. B7-H6 (encoded by gene NCR3LG1) is a prominent member of the family. It has unique immunogenic properties and is involved in natural killer (NK) cell immunosurveillance by binding to the NKp30 receptor. High B7-H6 expression in certain tumor types and shortage of or low expression in healthy cells – except in cases of inflammatory or microbial stimulation – have made the protein an attractive target of research activities in recent years. The avoidance of NK-mediated B7-H6 detection is a mechanism through which tumor cells escape immune surveillance. The stimulation of tumorigenesis occurs by suppressing caspase cascade initiation and anti-apoptosis activity stimulation via the STAT3 pathway. The B7-H6-NKp30 complex on the tumor membrane activates the NK cells and releases both tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). B7-H6 is highly expressed in a wide range of tumor cells, including glioma, hematologic malignant tumors, and breast cancer cells. Clinical examination of cancer patients indicated that the expression of B7-H6 is related to distant metastasis status and permits postoperative prognosis. Because of its unique properties, B7-H6 has a high potential be utilized as a biological marker for cancer diagnosis and prognosis, as well as a target for novel treatment options. [Display omitted] • Immune checkpoint molecules are vital molecules that regulate T-cell function by activation or inhibition. • B7-H6 is activated by binding to NKp30 on tumor cells and plays a prominent role in natural killer cell immunosurveillance. • High expression of B7-H6 in some tumors and low expression in healthy cells have made the protein an attractive target. [ABSTRACT FROM AUTHOR]

• Cancer stem cells (CSCs) are a small population of malignant cells that induce tumor onset and development. • Nanog, as a transcription factor, is one of the most critical markers in CSCs. • Nanog regulates multiple malignant phenotypes by modulating multiple signaling pathways, including AKT, STAT3 and P53 pathways. • Targeting Nang by miRNA may be effective approach in cancer treatment. Cancer stem cells (CSCs) are a small population of malignant cells that induce tumor onset and development. CSCs share similar features with normal stem cells in the case of self-renewal and differentiation. They also contribute to chemoresistance and metastasis of cancer cells, leading to therapeutic failure. To identify CSCs, multiple cell surface markers have been characterized, including Nanog, which is found at high levels in different cancers. Recent studies have revealed that Nanog upregulation has a substantial association with the advanced stages and poor prognosis of malignancies, playing a pivotal role through tumorigenesis of multiple human cancers, including leukemia, liver, colorectal, prostate, ovarian, lung, head and neck, brain, pancreatic, gastric and breast cancers. Nanog through different signaling pathways, like JAK/STAT and Wnt/β-catenin pathways, induces stemness, self-renewal, metastasis, invasiveness, and chemoresistance of cancer cells. Some of these signaling pathways are common in various types of cancers, but some have been found in one or two cancers. Therefore, this review aimed to focus on the function of Nanog in multiple cancers based on recent studies surveying the suitable approaches to target Nanog and inhibit CSCs residing in tumors to gain favorable results from cancer treatments. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells seem to be the most common innate lymphocyte subtypes, and they're known for their ability to guide anti-tumor and anti-viral responses, making them potentially therapeutic. Since NK cells lack polymorphic clonotypic receptors, they must rely on inhibitory receptors to develop, mature, and distinguish between "self" and "non-self." In the clinic, genetically engineered immune cells expressing a chimeric antigen receptor (CAR) that consists of an extracellular antigen recognizing domain connected to an intracellular signaling domain have gained interest. The U.S. food and drug administration (FDA) approved two CAR-T cells, anti-CD19 CARs, for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). Nevertheless, CAR-T cell therapy is linked to a series of negative side effects, including fatal cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), as well as a lack of regulatory control. CAR-transduced NK cells (CAR-NK) are thought to have many benefits, including clinical safety, the mechanisms by which they identify cancerous cells, and their abundance in clinical specimens, according to a growing number of studies. In pre-clinical and clinical trials, human primary NK cells and the NK-92 cell line were effectively transduced to express CARs against hematological cancers and solid tumors. Here, it is tried to summarize the development of CAR-NK cells, challenges and coping strategies, as well as managing the challenges and obstacles related to its protection, which promises to eliminate the shortcomings of conventional CARs. • Immune cells expressing a chimeric antigen receptor (CAR) connected to an intracellular signaling domain have gained interest. • CAR-transduced NK cells (CAR-NK) are thought to have many benefits, including clinical safety, the mechanisms by which they identify cancerous cells. • The practical implementation of CAR-NK cell treatments is linked to significant challenges that must be overcome for them to realize their greatest capacity. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) can present tumoral antigens to T-cells and stimulate T-cell-mediated anti-tumoral immune responses. In addition to uptaking, processing, and presenting tumoral antigens to T-cells, co-stimulatory signals have to be established between DCs with T-cells to develop anti-tumoral immune responses. However, most of the tumor-infiltrated immune cells are immunosuppressive in the tumor microenvironment (TME), paving the way for immune evasion of tumor cells. This immunosuppressive TME has also been implicated in suppressing the DC-mediated anti-tumoral immune responses, as well. Various factors, i.e., immunoregulatory cells, metabolic factors, tumor-derived immunosuppressive factors, and inhibitory immune checkpoint molecules, have been implicated in developing the immunosuppressive TME. Herein, we aimed to review the biology of DCs in developing T-cell-mediated anti-tumoral immune responses, the significance of immunoregulatory cells in the TME, metabolic barriers contributing to DCs dysfunction in the TME, tumor-derived immunosuppressive factors, and inhibitory immune checkpoint molecules in DC-based cell therapy outcomes. With reviewing the ongoing clinical trials, we also proposed a novel therapeutic strategy to increase the efficacy of DC-based cell therapy. Indeed, the combination of DC-based cell therapy with monoclonal antibodies against novel immune checkpoint molecules can be a promising strategy to increase the response rate of patients with cancers. The immune checkpoint molecules play a critical role in the dendritic cell dysfunction and decrease the efficacy of dendritic cell-based anti-cancer immunotherapies. Therefore, the development of combination therapies such as the use of immune checkpoint inhibitors along with dendritic cell vaccines can be considered as a promising strategy to fight cancer. [Display omitted] • Immunosuppressive TME inhibits DCs' activity in inducing anti-tumoral T cell responses. • Immune checkpoints expression on DCs is one of the major causes of DCs dysfunction in the TME. • Combination therapy with ICIs improves the efficiency of DC-based therapy. • ICIs combination therapy with DC-based therapeutics are evaluating in numerous clinical trials. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular trap (NETosis), the web-like structures induced by neutrophil death, is an important inflammatory mechanism of the immune system leading to reactive oxygen species production/coagulopathy, endothelial dysfunction, atherosclerosis, and ischemia. NETosis exerts its role through different mechanisms such as triggering Toll-like receptors, inflammatory cytokines, platelet aggregation, neutrophil activation/infiltration, and vascular impairment. NETosis plays a key role in the prognosis of coronary artery disease, ischemic injury of kidney, lung, gastrointestinal tract and skeletal muscles. In this review, we explored the molecular mechanisms involved in NETosis, and ischemic/reperfusion injuries in body organs. [Display omitted] [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are among the abundant cell populations of the tumor microenvironment (TME), which have pivotal roles in tumor development, chemoresistance, immune evasion, and metastasis. Growing evidence indicates that TAMs and the cross-talk between TAMs and tumoral endothelial cells can substantially contribute to tumor angiogenesis, which is considered a vital process for cancer development. Besides, tumoral endothelial cells can regulate the leukocyte infiltration to the TME in solid cancers and contribute to immune evasion. Therefore, targeting the immunosuppressive TAMs and the cross-talk between them can be a promising strategy for improving anti-tumoral immune responses. This review aims to summarize the biology of TAMs, their recently identified roles in tumor development/angiogenesis, and recent advances in macrophage-based cancer immunotherapy approaches for treating cancers. [ABSTRACT FROM AUTHOR]

The growth and development of cancer are directly correlated to the suppression of the immune system. A major breakthrough in cancer immunotherapy depends on various mechanisms to detect immunosuppressive factors that inhibit anti-tumor immune responses. Immune checkpoints are expressed on many immune cells such as T-cells, regulatory B cells (Bregs), dendritic cells (DCs), natural killer cells (NKs), regulatory T (Tregs), M2-type macrophages, and myeloid-derived suppressor cells (MDSCs). Immune inhibitory molecules, including CTLA-4, TIM-3, TIGIT, PD-1, and LAG-3, normally inhibit immune responses via negatively regulating immune cell signaling pathways to prevent immune injury. However, the up-regulation of inhibitory immune checkpoints during tumor progression on immune cells suppresses anti-tumor immune responses and promotes immune escape in cancer. It has recently been indicated that cancer cells can up-regulate various pathways of the immune checkpoints. Therefore, targeting immune inhibitory molecules through antibodies or miRNAs is a promising therapeutic strategy and shows favorable results. Immune checkpoint inhibitors (ICIs) are introduced as a new immunotherapy strategy that enhance immune cell-induced antitumor responses in many patients. In this review, we highlighted the function of each immune checkpoint on different immune cells and therapeutic strategies aimed at using monoclonal antibodies and miRNAs against inhibitory receptors. We also discussed current challenges and future strategies for maximizing these FDA-approved immunosuppressants' effectiveness and clinical success in cancer treatment. [Display omitted] • Inhibitory immune checkpoints are the primary cause of immune cells dysfunction. • Elevated levels of inhibitory immune checkpoints on immune cells induce tumor immune escape. • The utilization of immune checkpoint inhibitor (ICI) therapy assists cancer treatment. • ICI, in combination with other cancer treatment approaches, promotes the immune response rate. • The miRNAs control the antitumor response by regulating inhibitory immune checkpoints. [ABSTRACT FROM AUTHOR]

Tumoral programmed cell death ligand 1 (PD-L1) has been implicated in the immune evasion and development of colorectal cancer. Although monoclonal immune checkpoint inhibitors can exclusively improve the prognosis of patients with microsatellite instability-high (MSI-H) and tumor mutational burden-high (TMB-H) colorectal cancer, specific tumor-suppressive microRNAs (miRs) can regulate multiple oncogenic pathways and inhibit the de novo expression of oncoproteins, like PD-L1, both in microsatellite stable (MSS) and MSI-H colorectal cancer cells. This scoping review aimed to discuss the currently available evidence regarding the therapeutic potentiality of PD-L1-inhibiting miRs for colorectal cancer. For this purpose, the Web of Science, Scopus, and PubMed databases were systematically searched to obtain peer-reviewed studies published before 17 March 2021. We have found that miR-191–5p, miR-382–3p, miR-148a-3p, miR‐93–5p, miR-200a-3p, miR-200c-3p, miR-138–5p, miR-140–3p, and miR-15b-5p can inhibit tumoral PD-L1 in colorectal cancer cells. Besides inhibiting PD-L1, miR-140–3p, miR-382–3p, miR-148a-3p, miR‐93–5p, miR-200a-3p, miR-200c-3p, miR-138–5p, and miR-15b-5p can substantially reduce tumor migration, inhibit tumor development, stimulate anti-tumoral immune responses, decrease tumor viability, and enhance the chemosensitivity of colorectal cancer cells regardless of the microsatellite state. Concerning the specific, effective, and safe delivery of these miRs, the single-cell sequencing-guided biocompatible-based delivery of these miRs can increase the specificity of miR delivery, decrease the toxicity of traditional nanoparticles, transform the immunosuppressive tumor microenvironment into the proinflammatory one, suppress tumor development, decrease tumor migration, and enhance the chemosensitivity of tumoral cells regardless of the microsatellite state. [Display omitted] • Besides being an immune checkpoint, tumoral PD-L1 stimulates oncogenic pathways. • Immune checkpoint inhibitors do not substantially regulate oncogenic pathways. • Besides inhibiting PD-L1, PD-L1-inhibiting miRs can regulate tumoral pathways. • Biocompatible nanoparticles are safe and non-toxic carriers for miR delivery. • Single-cell sequencing data can facilitate personalized and specific miR delivery. [ABSTRACT FROM AUTHOR]

The immunosuppressive tumor microenvironment has been implicated in attenuating anti-tumoral immune responses and tumor growth in various cancers. Inhibitory immune checkpoints have been introduced as the primary culprits for developing the immunosuppressive tumor microenvironment. Therefore, a better understanding of the cross-talk between inhibitory immune checkpoints in the tumor microenvironment can pave the way for introducing novel approaches for treating affected patients. Growing evidence indicates that CD39 and CD73, as novel checkpoints, can transform adenosine triphosphate (ATP)-mediated pro-inflammatory tumor microenvironment into an adenosine-mediated immunosuppressive one via the purinergic signaling pathway. Indeed, enzymatic processes of CD39 and CD73 have crucial roles in adjusting the extent, intensity, and chemical properties of purinergic signals. This study aims to review the biological function of CD39 and CD73 and shed light on their significance in regulating anti-tumoral immune responses in various cancers. [Display omitted] [ABSTRACT FROM AUTHOR]

Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC. [ABSTRACT FROM AUTHOR]