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Background: Identification of the factors that result in academic achievement and prevent academic failure is of extreme importance due to the effective role of nursing in the health and wellbeing of human beings. Objectives: This study is done with regards to the important role of academic emotions in academic achievement and the double effect of academic engagement mediators and cognitive strategies in the process; Therefore, the focus of this investigation is the influential role of academic emotions in academic achievement of the nursing students of Zanjan University of Medical Sciences through mediation of academic engagement and cognitive strategies. Methods: This research is causal-comparative in nature, covering a statistical population of 178 male and female students of nursing in Zanjan University of Medical Sciences, who were found qualified for this study. Questionnaire was used as an instrument for collection of data, which was then analyzed using SPSS24 and LISREL 8.8. Results: The findings showed that academic engagement with a coefficient of 0.58 and cognitive strategies with a coefficient of 0.22 mediated academic achievement and academic emotion. Moreover, the adequacy of the model was above 0.90 through the Goodness-of-Fit Indices. Moreover, the adequacy of the model was proved through such Goodness-of-Fit Indices as the Chi-square test, which equaled 6.12, the six degrees of freedom (6DoF) and the 0.40 level of statistical significance (p). Conclusion: Therefore, it is concluded that mediation of academic engagement and cognitive strategies will enhance effect of academic emotion in academic achievement and the variables have well proved their mediation role

Dendritic cells (DCs) are essential for promoting T lymphocyte responses since they are specialist antigen-presenting cells. In order to maintain tolerance or initiate immune responses, DCs must be activated in a balanced and regulated manner via diverse signaling pathways. By using a variety of pharmacological components, we can interfere with their different signaling pathways such as the mammalian target of rapamycin (mTOR) to appropriately modulate DC activity. In the current study, we administered RAD001 to DCs to examine the impact of mTOR inhibition on both the maturation stage and the expression of inflammatory and anti-inflammatory molecules in DCs. Pure monocytes were cultivated and stimulated with GM-CSF and IL-4 to generate immature DCs, which were then treated with RAD001. The phenotype of the DCs was determined by labeling surface markers and analyzing them using flow cytometry. Afterward, real-time PCR was carried out to evaluate the expression of inflammatory and anti-inflammatory genes. The administration of RAD001 to DCs led to a significant upregulation in the gene expression of inflammatory molecules such as IL-12, IL-1β, tumor necrosis factor (TNF)-α, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB). Conversely, RAD001 treatment resulted in a decrease in the gene expression of anti-inflammatory factors IL-10 and indoleamine 2,3-dioxygenase (IDO). However, the expression of differentiation and antigen presentation-related markers CD11c and human leukocyte antigens (HLA)-DR in RAD001-treated DCs was lower and higher compared to the control group that did not receive the treatment, respectively. Taken together, our findings indicated that RAD001 treatment of DCs can be a promising therapeutic approach for the generation of immunogenic DCs in order to barricade tumor growth. However, there is a need for further investigation to evaluate the impacts of mTOR inhibition by RAD001 in DCs on cellular immune responses in vitro and in vivo., Competing Interests: Declarations. Ethics approval: All experiments and procedures were conducted in accordance with the ethical principles of Tabriz University of Medical Science, Tabriz, Iran, and approved by the regional ethical committee for medical research (Ethical code: IR.TBZMED.REC.1401.405). Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Arginine vasopressin (AVP) has disparate impacts on immune responses by divergent receptors on cells including DCs. This study was conducted with the aim of investigating the impact of AVP on the maturation and expression of the inhibitory immune checkpoint molecules in tolerogenic monocyte-derived DCs. CD14 marker was used to separate monocytes from peripheral blood mononuclear cells (PBMCs) by MACS method. To differentiate monocytes from DCs, we utilized GM-CSF and IL-4 cytokines. Tolerogenic DCs were generated using vitamin D3 and dexamethasone. We added LPS and AVP to the culture medium on day 6 after incubation of DCs at 37 °C. Finally, we assessed the surface molecules by flow cytometry and used real-time PCR to evaluate the expression of genes related to the inhibitory immune checkpoints. Based on the obtained data, AVP increased the expression of CD11c (P ≤ 0.0001), HLA-DR (P ≤ 0.01), and CD86 (P ≤ 0.01) in AVP-mDCs. Also, the expression of all the immune checkpoint genes including CTLA-4 (P ≤ 0.001), BTLA (P ≤ 0.001), PDL-1 (P ≤ 0.05), B7H7 (P ≤ 0.001), LAG3 (P ≤ 0.01), and VISTA (P ≤ 0.001) in AVP-mDCs was increased in comparison to the control group. Vasopressin caused the generation of mature and tolerogenic DCs. Our data may help to consider AVP-mDCs to take part in autoimmune disease therapy, transplanted tissue rejection impedance, and allergies., Competing Interests: Declarations. Ethics approval and consent to participate: The studies involving human participants were reviewed and approved by ethical code: IR.TBZMED.REC.1401.506. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

VISTA is a newly discovered immune checkpoint whose functional mechanisms have become increasingly important to study due to its brilliant results in cancer immunotherapy. Despite VSIG-3/IGSF11 being identified as an inhibitory ligand for VISTA with potential as a target for cancer immunotherapy, very little is known of its functions. This study aimed to conduct a detailed analysis of VSIG-3/IGSF11 in melanoma, as well as to study the effects of its silencing on melanoma cell line progression and human T cell functions. Online databases were used to investigate VSIG-3/IGSF11 expression, its relationships, and prognostic value in melanoma. Then, the effects of VSIG-3/IGSF11 silencing on proliferation, migration, cell cycle arrest, and apoptosis in A2058 melanoma cells were assessed using MTT, colony formation, wound healing, cell cycle, and Annexin-V FITC/PI assays, respectively. Finally, A2058 cells transfected with VSIG-3/IGSF11 siRNA were co-cultured with human T cells, and the expression levels of T cell cytokines were evaluated using qRT-PCR. VSIG-3/IGSF11 expression was significantly increased in melanoma patients and cell lines; however, no correlation was found between VSIG-3/IGSF11 expression levels and clinicopathological characteristics, survival, or immune cell infiltration. Following VSIG-3/IGSF11 silencing in A2058 cells, viability, proliferation, and migration rates were decreased, while apoptosis was increased. T cells co-cultured with VSIG-3/IGSF11 siRNA-transfected A2058 cells exhibited increased expression levels of IFN-γ and IL-12 and decreased expression levels of IL-10, TGF-β, and TNF-α. The inhibitory effect of VSIG-3/IGSF11 silencing on A2058 melanoma cell progression, along with the alteration of T cell cytokines towards a pro-inflammatory phenotype, suggests that VSIG-3/IGSF11 is primarily involved in melanoma progression and modulating immune responses. Therefore, it may be a valuable target for immunotherapy in melanoma patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Anticancer immunotherapies with a dendritic Cell (DC) basis are becoming more popular. However, it has been suggested that the tumor's immunosuppressive mechanisms, such as inhibitory immunological checkpoint molecules, reduce the effectiveness of anticancer immunogenicity mediated by DC. Thus, overcoming immune checkpoints and inducing effective antigen-specific T-cell responses uniquely produced with malignant cells represent the key challenges. Among the inhibitory immune checkpoints, DCs' ability to mature and present antigens is decreased by CTLA-4 expression. Consequently, we hypothesized that by expressing CTLA-4 cells on DCs, the T cells' activation against tumor antigens would be suppressed when confronted with these antigens presented by DCs. In this research, by loading cell lysate of breast cancer (BC) on DCs and the other hand by inhibiting the induction of CTLA-4 using small interfering RNA (siRNA), we assessed the functional activities and phenotypes of DCs, and also the responses associated with T-cells following co-culture DC/T cell. Our research has shown that the suppression of CTLA-4 enhanced the stimulating capabilities of DCs. Additionally, CTLA-4-suppressed BC cell lysate-loaded DCs produced more IL-4 and IFN-ϒ and increased T cell induction in contrast to DCs without CTLA-4 suppression. Together, our data point to CTLA-4-suppressed DCs loaded with BC cell lysate as a potentially effective treatment method. However, further research is required before employing this method in therapeutic contexts., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Apelin, a bioactive peptide that serves as an endogenous ligand for the apelin receptor (APJ), is overexpressed in various types of cancers and contributes to cancer cell proliferation, viability, migration, angiogenesis, and metastasis, as well as immune deviation. Noncoding RNAs (ncRNAs) regulate gene expression, and there is growing evidence suggesting a bidirectional crosstalk between ncRNAs (including long noncoding RNAs [lncRNAs], circular RNAs [circRNAs], and microRNAs [miRNAs]) and apelin in cancers. Certain miRNAs can directly target the apelin and inhibit its expression, thereby suppressing tumor growth. It has been indicated that miR-224, miR-195/miR-195-5p, miR-204-5p, miR-631, miR-4286, miR-637, miR-4493, and miR-214-3p target apelin mRNA and influence its expression in prostate cancer, lung cancer, esophageal cancer, chondrosarcoma, melanoma, gastric cancer, glioma, and hepatocellular carcinoma (HCC), respectively. Moreover, circ-NOTCH1, circ-ZNF264, and lncRNA BACE1-AS upregulate apelin expression in gastric cancer, glioma, and HCC, respectively. On the other hand, apelin has been shown to regulate the expression of certain ncRNAs to affect tumorigenesis. It was revealed that apelin affects the expression of circ_0000004/miR-1303, miR-15a-5p, and miR-106a-5p in osteosarcoma, lung cancer, and prostate cancer, respectively. This review explains a bidirectional interplay between ncRNAs and apelin in cancers to provide insights concerning the molecular mechanisms underlying this crosstalk and potential implications for cancer therapy., (© 2024 John Wiley & Sons Ltd.)

Proper and functional immune response requires a complex interaction between innate and adaptive immune cells, which dendritic cells (DCs) are the primary actors in this coordination as professional antigen-presenting cells. DCs are armed with numerous pattern recognition receptors (PRRs) such as nucleotide-binding and oligomerization domain-like receptors (NLRs) like NLRP3, which influence the development of their activation state upon sensation of ligands. NLRP3 is a crucial component of the immune system for protection against tumors and infectious agents, because its activation leads to the assembly of inflammasomes that cause the formation of active caspase-1 and stimulate the maturation and release of proinflammatory cytokines. But, when NLRP3 becomes overactivated, it plays a pathogenic role in the progression of several autoimmune disorders. So, NLRP3 activation is strictly regulated by diverse signaling pathways that are mentioned in detail in this review. Furthermore, the role of NLRP3 in all of the diverse immune cells' subsets is briefly mentioned in this study because NLRP3 plays a pivotal role in modulating other immune cells which are accompanied by DCs' responses and subsequently influence differentiation of T cells to diverse T helper subsets and even impact on cytotoxic CD8 + T cells' responses. This review sheds light on the functional and therapeutic role of NLRP3 in DCs and its contribution to the occurrence and progression of autoimmune disorders, prevention of diverse tumors' development, and recognition and annihilation of various infectious agents. Furthermore, we highlight NLRP3 targeting potential for improving DC-based immunotherapeutic approaches, to be used for the benefit of patients suffering from these disorders., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: It is well-known that TH1 and Treg cells exert anti- and pro-tumorigenic activity, respectively. Thus, TH1 cell suppression together with Treg cell hyperactivation contribute to tumor development. Glycyrrhiza glabra (G. glabra) has various immunomodulatory and anti-tumorigenic properties., Objective: To explore the impacts of G. glabra extract on different parameters related to TH1 and Treg cells using a breast cancer (BC) model., Methods: Four groups of Balb/C mice bearing 4T1 cell-induced BC were treated intraperitoneally with either saline or G. glabra extract at dosages of 50, 100 and 150 mg/kg (G. glabra-50, G. glabra-100, and G. glabra-150, respectively). After sacrificing animals on day 26, the frequency of splenic TH1 and Treg cells, the levels of serum IFN-γ, TGF-β, and IL-12, and intra-tumoral expressions of granzyme-B, T-bet, and FOXP3 were assessed., Results: Compared to untreated tumor control (UTC) group, treatment with G. glabra-50, G. glabra-100, or G. glabra-150 increased the survival rate, percentage of TH1 cells, and T-bet expression. Conversely, they reduced the percentage of Treg cells, and serum TGF-β levels. In comparison to the UTC group, treatment with G. glabra-50 and G. glabra-150 increased the serum IL-12 levels. Treatment with G. glabra-100 and G. glabra-150 boosted granzyme-B expression. Treatment with G. glabra-150 elevated IFN-γ levels, while treatment with G. glabra-50 decreased the FOXP3 expression. IL-12 levels were higher in mice treated with G. glabra-150 compared to those treated with G. glabra-100., Conclusion: Treatment of mice with BC using G. glabra extract improved survival rate, reduced tumor growth, and modulated T cell-mediated immune responses.

Gene silencing through RNA interference (RNAi) technology has provided forceful therapeutic modalities to specific knockdown of the genes' expression related to diseases. Small interfering RNAs (siRNAs) can start a process that specifically degrades and silences the expression of cognate mRNAs. These RNA interference processes could effectively adjust many biological processes, including immune responses. Dendritic cells (DCs) are specialist antigen-presenting cells with potent functions in regulating innate and adaptive immunity. SiRNAs performed vital roles in coordinating immune processes mediated by DCs. This review describes the findings that shed light on the significance of siRNAs in DC immune regulation and highlight their potential applications for improving DC-based immunotherapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Dendritic cells (DCs) are known as antigen-presenting cells that are capable of regulating immune responses. DCs and T cells can interact mutually to induce antigen-specific T-cell responses. Cabergoline, which is a dopamine (DA) receptor agonist, seems to implement anti-inflammatory properties in the immune system, and therefore in the present study the impact of a DA receptor agonist cabergoline on the monocyte-derived DCs (moDCs) was assessed. Immature moDCs were treated with lipopolysaccharide to produce mature DCs (mDCs). The expression of DCs' related surface markers namely: CD11c, HLA-DR, and CD86 was measured by utilizing of flow cytometry. Real-time PCR was the technique of choice to determine the levels at which diverse inflammatory and anti-inflammatory factors in cabergoline-treated and control mDC groups were expressed. DCs treated with cabergoline displayed a significant decrease in CD86 and HLA-DR expression, markers linked to maturation and antigen presentation, respectively. In addition, the cabergoline-mDC group showed a considerable decline in terms of the levels at which IL-10, TGF-β, and IDO genes were expressed, and an increase in the expression of TNF-α and IL-12 in comparison to the mDC control group. Our findings revealed that cabergoline as an immunomodulatory agent can relatively shift DCs into an immunogenic state, and there is a requirement for further investigations to evaluate the effects of cabergoline-treated DCs on the T cell responses in vitro, and also in various diseases including cancer in animal models., (© 2024 John Wiley & Sons Ltd.)

Introduction: Signal transducer and activator of transcriptions (STATs) factors as critical proteins in cell signaling regulate diverse biological processes such as differentiation and proliferation of cells. STATs have been shown to play distinct roles in modulating immune responses mediated by innate and adaptive immune cell subsets due to their significant roles in cytokine signaling., Methods: In the current study, we review recent studies on the contribution of individual STAT proteins to cytokine signaling, development, and activity of diverse immune cells that constitute the whole immune system and help its performance against endogenous or exogenous agents with a particular focus on meaningful STAT factor in each of innate and adaptive immune cells' subsets to clarify their function in favor of the tumor or against it., Results: Dysregulation of signaling pathways in the immune cells is associated with various immune disorders, such as the inability of immune system cells in the effective destruction of cancerous cells. Increase of knowledge about these pathways' functions is essential to understand how they can be effectively targeted to eliminate tumors., Conclusion: The majority of immune cells use the Jak/STAT signaling pathway, which is one of the most important signaling pathways with a role in induction of proper immune responses. Since each of the STAT factors has a specific role in diverse immune cells' subsets, appropriate targeting of them can be a promising strategy for patients who suffer from immune system disorders; specifically it can be beneficial as an approach for cancer immunotherapy., Competing Interests: The authors declare that there is no conflict of interest., (© 2025 The Author(s).)

Dendritic cells (DCs) are professional antigen-presenting cells (APCs), including heterogenous populations with phenotypic and functional diversity that coordinate bridging innate and adaptive immunity. Signal transducer and activator of transcriptions (STAT) factors as key proteins in cytokine signaling were shown to play distinct roles in the maturation and antigen presentation of DCs and play a pivotal role in modulating immune responses mediated by DCs such as differentiation of T cells to T helper (Th) 1, Th2 or regulatory T (Treg) cells. This review sheds light on the importance of STAT transcription factors' signaling pathways in different subtypes of DCs and highlights their targeting potential usages for improving DC-based immunotherapies for patients who suffer from cancer or diverse autoimmune conditions according to the type of the STAT transcription factor and its specific activating or inhibitory agent.

Purpose: In dendritic cells (DCs), leptin as an immune-regulating hormone, increases the IL-12 generation whereas it reduces the IL-10 production, thus contributing to TH1 cell differentiation. Using a murine model of breast cancer (BC), we evaluated the impacts of the Leptin and/or lipopolysaccharide (LPS)-treated DC vaccine on various T-cell-related immunological markers., Materials and Methods: Tumors were established in mice by subcutaneously injecting 7 × 10 5 4T1 cells into the right flank. Mice received the DC vaccines pretreated with Leptin, LPS, and both Leptin/LPS, on days 12 and 19 following tumor induction. The animals were sacrificed on day 26 and after that the frequency of the splenic cytotoxic T lymphocytes (CTLs) and TH1 cells; interferon gamma (IFN-γ), interleukin 12 (IL-12) and tumor growth factor beta (TGF-β) generation by tumor lysate-stimulated spleen cells, and the mRNA expression of T-bet, FOXP3 and Granzyme B in the tumors were measured with flow cytometry, ELISA and real-time PCR methods, respectively., Results: Leptin/LPS-treated mDC group was more efficient in blunting tumor growth ( p  = .0002), increasing survival rate ( p  = .001), and preventing metastasis in comparison with the untreated tumor-bearing mice (UT-control). In comparison to the UT-control group, treatment with Leptin/LPS-treated mDC also significantly increased the splenic frequencies of CTLs ( p  < .001) and TH1 cells ( p  < .01); promoted the production of IFN-γ ( p  < .0001) and IL-12 ( p  < .001) by splenocytes; enhanced the T-bet ( p  < .05) and Granzyme B ( p  < .001) expression, whereas decreased the TGF-β and FOXP3 expression ( p  < .05)., Conclusion: Compared to the Leptin-treated mDC and LPS-treated mDC vaccines, the Leptin/LPS-treated mDC vaccine was more effective in inhibiting BC development and boosting immune responses against tumor.

Tolerogenic dendritic cells (TolDCs) are attractive therapeutic options for autoimmune disorders because they suppress autologous T-cell responses. Dendritic cells (DCs) are equipped with pattern recognition receptors (PRR), including nucleotide-binding and oligomerization domain-like receptors (NLRs) such as NLRP3. Abnormal NLRP3 activation has been reported to be correlated with the occurrence of autoimmune disorders. Accordingly, we hypothesized that glyburide treatment of DCs by blocking the ATP-sensitive K+ (kATP) channels generates TolDCs by inhibiting NLRP3. Insulin was even loaded on a group of glyburide-treated mature DCs (mDCs) to investigate the antigen (Ag) loading effects on glyburide-treated mDCs' phenotypical and functional features. Consequently, T lymphocytes' mediated responses ensuing co-culture of them with control mDCs, insulin loaded and unloaded glyburide treated mDCs were evaluated to determine generated TolDCs' capacity in inhibition of T cell responses that are inducer of destruction in insulin-producing pancreatic beta cells in Type 1 Diabetes Mellitus (T1DM). Our findings indicated that glyburide generates desirable TolDCs with decreased surface expression of maturation and Ag presentation related markers and diminished level of inflammatory but increased level of anti-inflammatory cytokines, which even insulin loading demonstrated more anti-inflammatory functions. In addition, co-cultured T cells showed regulatory or T helper 2 phenotype instead of T helper 1 features. Our findings suggested that insulin-loaded and unloaded glyburide-treated DCs are promising therapeutic approaches for autoimmune patients, specifically DCs loaded with insulin for T1DM patients. However, further research is required before this technique can be applied in clinical practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Gastric cancer, ranked as the fifth most common cancer worldwide, presents multiple treatment challenges. These obstacles often arise due to cancer stem cells, which are associated with recurrence, metastasis, and drug resistance. While dendritic cell (DC)-based immunotherapy has shown promise as a therapeutic strategy, its efficacy can be limited by the tumor microenvironment and certain inhibitory immune checkpoint molecules, such as B7H7. SiRNA-medicated knockdown of B7H7 in tumor cell lysate-pulsed DCs can increase cytokine secretion and autologous T lymphocyte expansion. This study aimed to evaluate the impact of B7H7 suppression in gastric cancer cell lysate-pulsed DCs on the stimulatory potential of autologous CD3 + T lymphocytes., Methods: Peripheral blood mononuclear cells (PBMCs) were isolated and monocytes were obtained; then, they were differentiated to immature DCs (iDCs) by GM-CSF and IL-4. Tumor cell lysates from human gastric cancer cell lines were harvested, and iDCs were transformed into mature DCs (mDCs) by stimulating iDCs with tumor cell lysate and lipopolysaccharide. B7H7-siRNA was delivered into mDCs using electroporation, and gene silencing efficiency was assessed. The phenotypic characteristics of iDCs, mDCs, and B7H7-silenced mDCs were evaluated using specific surface markers, an inverted light microscope, and flow cytometry. CD3 + T cells were isolated via magnetically activated cell sorting. They were labeled with CFSE dye and co-cultured with mDCs and B7H7-silenced mDCs to evaluate their ability to induce T-cell proliferation. T-cell proliferation was assessed using flow cytometry. The concentration of TGF-β, IL-4, and IFN-γ secreted from CD3 + T cells in the co-cultured supernatant was evaluated to investigate the cytokine secretory activity of the cells., Results: Transfection of B7H7 siRNA into mDCs was performed in optimal conditions, and the siRNA transfection effectively reduced B7H7 mRNA expression in a dose-dependent manner. SiRNA-mediated B7H7 knockdown in mDCs enhanced maturation and activation of the DCs, as demonstrated by an increased surface expression of CD11c, CD86, and CD40. Co-culture experiments revealed that B7H7-silenced mDCs had more capacity to induce T cell proliferation compared to non-transfected mDCs. The cytokine production patterns of T cells were also altered. Upon examining the levels of TGF-β, IL-4, and IFN-γ released by CD3 + T cells in the co-culture supernatant, we found that silencing B7H7 in mDCs resulted in a rise in IL-4 secretion and a reduction in TGF-β levels compared to mDCs that were not transfected., Conclusions: The study found that suppressing B7H7 expression in DCs significantly enhances their maturation and stimulatory activity when exposed to gastric cancer cell lysate. These B7H7-silenced DCs can substantially increase cytokine production and promote co-cultured T-cell expansion. Consequently, inhibiting B7H7 in DCs may offer a practical strategy to enhance the ability of DCs to initiate T lymphocyte responses and improve the effectiveness of DC-based cell therapy for cancer patients.

A functional immune system is crucial for a healthy life, protecting from infections, tumors, or autoimmune disorders; these are accomplished by the interaction between various immune cells. Nourishment, particularly micronutrients, are very important components in the immune system balance, therefore this review emphasizes the vitamins (D, E, A, C) and Dendritic cells' subsets due to vitamins' roles in immune processes, especially on dendritic cells' functions, maturation, and cytokine production. Current studies reveal significant benefits related to vitamins, including vitamin E, which can contribute to the control of dendritic cells' function and maturation. Furthermore, vitamin D plays an immunoregulatory and anti-inflammatory role in the immune system. Metabolite of vitamin A which is called retinoic acid leads to T cells' differentiation to T helper 1 or T helper 17, so low levels of this vitamin exacerbate the menace of infectious diseases, and vitamin C has anti-oxidant effects on dendritic cells and modulate their activation and differentiation program. Additionally, the correlation between the amount of vitamin and the occurrence or progression of allergic diseases and autoimmunity disorders is discussed according to the results of previous studies., (© 2023 Wiley-VCH GmbH.)

Dendritic cells (DCs) release nanometer-sized membrane vesicles known as dexosomes, containing different molecules, particularly proteins, for presenting antigens, i.e., major histocompatibility complex (MHC)-I/II and CD86. Dexosomes can, directly and indirectly, stimulate antigen-reactive CD8 + and CD4 + T cell responses. Antigen-loaded dexosomes can lead to the development of potent anti-tumoral immune responses. Notably, developing dexosome-based cell-free vaccines could serve as a new vaccination platform in the era of immunotherapy for various cancers. Furthermore, combining dexosomes vaccination strategies with other treatment approaches can considerably increase tumor-specific T cell responses. Herein, we aimed to review how dexosomes interact with immune cells, e.g., CD4 + and CD8 + T cells and natural killer (NK) cells. Besides, we discussed the limitations of this approach and suggested potential strategies to improve its effectiveness for affected patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Apelin/APJ axis plays a critical role in cancer progression, thus its targeting inhibits tumor growth. However, blocking of Apelin/APJ axis in combination with immunotherapeutic approaches may be more effective. This study aimed to investigate the effects of APJ antagonist ML221 in combination with a DC vaccine on angiogenic, metastatic and apoptotic-related factors in a breast cancer (BC) model. Four groups of female BALB/c mice with 4T1-induced BC were treated with PBS, APJ antagonist ML221, DC vaccine, and "ML221 + DC vaccine". After completion of the treatment, the mice were sacrificed and the serum levels of IL-9 and IL-35 as well as the mRNA expression of angiogenesis (including VEGF, FGF-2, and TGF-β), metastasis (including MMP-2, MMP-9, CXCR4) and apoptosis-related markers (Bcl-2, Bax, Caspase-3) in tumor tissues were determined using ELISA and real-time PCR, respectively. Angiogenesis was also evaluated by co-immunostaining of tumor tissues with CD31 and DAPI. Primary tumor metastasis to the liver was analyzed using hematoxylin-eosin staining. The efficiency of combination therapy with "ML221 + DC vaccine" was remarkably higher than single therapies in preventing liver metastasis compared to the control group. In comparison with the control group, combination therapy could significantly reduce the expression of MMP-2, MMP-9, CXCR4, VEGF, FGF-2, and TGF-β in tumor tissues (P < 0.05). It also decreased the serum level of IL-9 and IL-35 compared with the control group (P < 0.0001). Moreover, vascular density and vessel diameter were significantly reduced in the combination therapy group compared with the control group (P < 0.0001). Overall, our findings demonstrate that combination therapy using a blocker of the apelin/APJ axis and DC vaccine can be considered a promising therapeutic program in cancers., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Prostaglandin E2 (PGE2), a product of cyclooxygenase (COX) pathway of arachidonic acid, exerts inhibitory impacts on dendritic cell (DC) activity to repress anti-tumor immune responses. Therefore, targeting COX during DC vaccine generation may enhance DC-mediated antitumor responses. We aimed to investigate the impacts of DC vaccine treated with celecoxib (CXB), a selective COX2 inhibitor, on some T cell-related parameters., Materials and Methods: Breast cancer (BC) was induced in BALB/c mice, and then they received DC vaccine treated with lipopolysaccharide (LPS-mDCs), LPS with a 5 ​μM dose of CXB (LPS/CXB5-mDCs) and LPS with a 10 ​μM dose of CXB (LPS/CXB10-mDCs). The frequency of splenic Th1 and Treg cells and amounts of IFN-γ, IL-12 and TGF-β production by splenocytes, as well as, the expression of Granzyme-B, T-bet and FOXP3 in tumors were determined using flow cytometry, ELISA, and real-time PCR, respectively., Results: Compared with untreated tumor group (T-control), treatment with LPS/CXB5-mDCs and LPS/CXB10-mDCs decreased tumor growth (P ​= ​0.009 and P ​< ​0.0001), escalated survival rate (P ​= ​0.002), increased the frequency of splenic Th1 cells (P ​= ​0.0872, and P ​= ​0.0155), increased the IFN-γ (P ​= ​0.0003 and P ​= ​0.0061) and IL-12 (P ​= ​0.001 and P ​= ​0.0009) production by splenocytes, upregulated T-bet (P ​= ​0.062 and P ​< ​0.0001) and Granzyme-B (P ​= ​0.0448 and P ​= ​0.4485), whereas decreased the number of Treg cells (P ​= ​0.0014, and P ​= ​0.0219), reduced the amounts of TGF-β production by splenocytes (P ​= ​0.0535 and P ​= ​0.0169), and reduced the expression of FOXP3 (P ​= ​0.0006 and P ​= ​0.0057) in comparison with T-control group., Conclusions: Our findings show that LPS/CXB-treated DC vaccine potently modulated antitumor immune responses in a mouse BC model., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2023 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Antigen recognition and presentation are highlighted as the first steps in developing specialized antigen responses. Dendritic cells (DCs) are outstanding professional antigen-presenting cells (APCs) responsible for priming cellular immunity in pathological states, including cancer. However, the diminished or repressed function of DCs is thought to be a substantial mechanism through which tumors escape from the immune system. In this regard, DCs obtained from breast cancer (BC) patients represent a notably weakened potency to encourage specific T-cell responses. Additionally, impaired DC-T-cell cross-talk in BC facilitates the immune evade of cancer cells and is connected with tumor advancement, immune tolerance, and adverse prognosis for patients. In this review we aim to highlight the available knowledge on DC-T-cell interactions in BC aggressiveness and show its therapeutic potential in BC treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2022 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Dendritic cell (DC)-based immunotherapy has increased interest among anti-cancer immunotherapies. Nevertheless, the immunosuppressive mechanisms in the tumor milieu, e.g., inhibitory immune checkpoint molecules, have been implicated in diminishing the efficacy of DC-mediated anti-tumoral immune responses. Therefore, the main challenge is to overcome inhibitory immune checkpoint molecules and provoke efficient T-cell responses to antigens specifically expressed by cancerous cells. Among the inhibitory immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression on DCs diminishes their maturation and antigen presentation capability. Accordingly, we hypothesized that the expression of CTLA-4 on DCs inhibits the T cell-mediated anti-tumoral responses generated following the presentation of tumor antigens by DCs to T lymphocytes. In this study, we loaded colorectal cancer (CRC) cell lysate on DCs and inhibited the expression of CTLA-4 by small interfering RNA (siRNA) in them to investigate the DCs' functional and phenotypical features, and T-cell mediated responses following DC/T cell co-culture. Our results demonstrated that blockade of CTLA-4 could promote stimulatory properties of DCs. In addition, CTLA-4 silenced CRC cell lysate-loaded DCs compared to the DCs without CTLA-4 silencing resulted in augmented T cell proliferation and cytokine production, i.e., IFN-γ and IL-4. Taken together, our findings suggest CTLA-4 silenced CRC cell lysate-loaded DCs as a promising therapeutic approach however further studies are needed before this strategy can be used in clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ghorbaninezhad, Masoumi, Bakhshivand, Baghbanzadeh, Mokhtarzadeh, Kazemi, Aghebati-Maleki, Shotorbani, Jafarlou, Brunetti, Santarpia, Baradaran and Silvestris.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The immunosuppressive microenvironment of tumors reduces the effectiveness of immunotherapies. Apelin as an immunosuppressor peptide is expressed in the microenvironment of many tumors. Thus, inhibition of apelin-related protumor activities can promote the effectiveness of cancer immunotherapy. Here, we investigated the efficacy of a dendritic cell (DC) vaccine in combination with an apelin receptor antagonist, ML221, to modulate Th1 and Th2 cell-related responses in breast cancer-bearing mice., Materials and Methods: Tumor was induced in female BALB/c mice by injecting 7 ​× ​10 5 4T1 cells in the right flank. Tumor-bearing mice were then given PBS, ML221, DC vaccine and "ML221 + DC vaccine" for 21 days. On day 37, mice were sacrificed and the frequency of Th1/Th2 cells in spleen and serum levels of IFN-γ/IL-10 were determined using flow cytometry and ELISA, respectively. Lung metastasis was evaluated in lung tissues stained with hematoxylin and eosin. Finally, the obtained data were analyzed using appropriate statistical tests., Results: Combination therapy with ML221 + DC vaccination was more effective in reducing tumor growth (P ​< ​0.0001), preventing lung metastasis (P ​< ​0.0001) and increasing survival rate (P ​< ​0.01) compared to the control group. Moreover, combination treatment substantially increased the frequency of Th1 cells while decreasing the frequency of Th2 cells in the spleen compared to the control group (P ​< ​0.01). It also reduced serum levels of IL-10 compared with the control group (P ​< ​0.05)., Conclusion: Our findings showed that combination therapy using ML221 + DC vaccine can be considered as an effective cancer therapeutic program to potentiate anti-tumor immune responses., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Past researches indicate that some types of antibiotics, apart from their antimicrobial effects, have some other important effects which indirectly are exerted by modulating and regulating the immune system's mediators. Among the compounds with antimicrobial effects, fluoroquinolones (FQs) are known as synthetic antibiotics, which exhibit the property of decomposing of DNA and prevent bacterial growth by inactivating the enzymes involved in DNA twisting, including topoisomerase II (DNA gyrase) and IV. Interestingly, immune responses are indirectly modulated by FQs through suppressing pro-inflammatory cytokines, such as interleukin 1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α), and super-inducing IL-2, which tend to increase both the growth and activity of T and B lymphocytes. In addition, they affect the development of immune responses by influencing of expression of other cytokines and mediators. This study aims to review past research on the immunomodulatory effects of FQs on the expression of cytokines, especially IL-2 and to discuss controversial investigations.

Metformin, cimetidine, and ibuprofen separately exhibit immunomodulatory and anti-tumorigenic effects. Herein, the impacts of metformin alone and in combination with cimetidine/ibuprofen on some Th1- and regulatory T (Treg) cell-related parameters were evaluated using a breast cancer (BC) model. For establishing the BC model, four groups of Balb/c mice were challenged with the carcinoma cell line. After 11-30 days post-induction, they were treated intraperitoneally (with metformin (200 mg/kg), "metformin plus cimetidine (20 mg/kg)"; "metformin plus ibuprofen (20 mg/kg)", or with all three drugs in mentioned doses. Untreated BC and without tumor mice were enrolled as control groups. On day 31, splenic Th1 and Treg cell frequencies, serum interferon-gamma (IFN-γ), and transforming growth factor-beta (TGF-β) concentration, and intra-tumoral T-bet, TGF-β, and forkhead box protein P3 (FOXP3) expression were measured; using flow cytometry, enzyme-linked immunosorbent assay (ELISA), and real-time-PCR, respectively. Treatment of the BC mice with metformin alone and in combination with cimetidine and/or ibuprofen enhanced the frequency of Th1 cells, and IFN-γ concentration, while it resulted in a decrease in the frequency of Treg cells, serum TGF-β concentration, and the expression of FOXP3 and TGF-β compared with un-treated BC mice. FOXP3 expression in the metformin-treated group was lower in mice who received combination therapy. Survival rate and body weight were increased, while tumor size and spleen index were reduced in mice treated with metformin alone and its combination with cimetidine and/or ibuprofen. No remarkable differences were found between metformin-treated mice and those who received combination therapies regarding Th1 and Treg cell percentages, TGF-β expression, body weight, tumor size, and spleen index. The benefits of combinational therapy may be largely attributed to metformin. Immunotherapeutic potentials of metformin in cancers need further considerations.

Cancer stem cells (CSCs) with their self-renewal ability are accepted as cells which initiate tumors. CSCs are regarded as interesting targets for novel anticancer therapeutic agents because of their association with tumor recurrence and resistance to conventional therapies, including radiotherapy and chemotherapy. Chimeric antigen receptor (CAR)-T cells are engineered T cells which express an artificial receptor specific for tumor associated antigens (TAAs) by which they accurately target and kill cancer cells. In recent years, CAR-T cell therapy has shown more efficiency in cancer treatment, particularly regarding blood cancers. The expression of specific markers such as TAAs on CSCs in varied cancer types makes them as potent tools for CAR-T cell therapy. Here we review the CSC markers that have been previously targeted with CAR-T cells, as well as the CSC markers that may be used as possible targets for CAR-T cell therapy in the future. Furthermore, we will detail the most important obstacles against CAR-T cell therapy and suggest solutions., Competing Interests: Authors declare that there are no potential conflicts of interest., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Proprotein convertase subtilisin/kexin type 9 (PCSK9), as a vital modulator of low-density lipoprotein cholesterol (LDL-C) , is raised in hepatocytes and released into plasma where it binds to LDL receptors (LDLR), leading to their cleavage. PCSK9 adheres to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR which is confirmed by crystallography. LDLR expression is adjusted at the transcriptional level through sterol regulatory element binding protein 2 (SREBP-2) and at the post translational stages, specifically through PCSK9, and the inducible degrader of the LDLR PCSK9 inhibition is an appealing new method for reducing the concentration of LDL-C. In this review the role of PCSK9 in lipid homeostasis was elucidated, the effect of PCSK9 on atherosclerosis was highlighted, and contemporary therapeutic techniques that focused on PCSK9 were summarized. Several restoration methods to inhibit PCSK9 have been proposed which concentrate on both extracellular and intracellular PCSK9, and they include blockage of PCSK9 production by using gene silencing agents and blockage of it's binding to LDLR through antibodies and inhibition of PCSK9 autocatalytic processes by tiny molecule inhibitors., (© 2020 The Authors.)

Apelin is an endogenous peptide, which is expressed in a vast board of organs such as the brain, placenta, heart, lungs, kidneys, pancreas, testis, prostate and adipose tissues. The apelin receptor, called angiotensin-like-receptor 1 (APJ), is also expressed in the brain, spleen, placenta, heart, liver, intestine, prostate, thymus, testis, ovary, lungs, kidneys, stomach, and adipose tissue. The apelin/APJ axis is involved in a number of physiological and pathological processes. The apelin expression is increased in various kinds of cancer and the apelin/APJ axis plays a key role in the development of tumors through enhancing angiogenesis, metastasis, cell proliferation and also through the development of cancer stem cells and drug resistance. The apelin also stops the apoptosis of cancer cells. The apelin/APJ axis was considered in this review as an attractive therapeutic target for cancer treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2020 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Background: Recent evidence has indicated that beta-secretase 1 (BACE1) is involved in the production of amyloid beta (Aβ) in patients affected with Alzheimer's disease (AD). Therefore; the purpose of this study was to measure mRNA and plasma levels of BACE1 in AD patients, as an early diagnosis biomarker for such individuals., Methods: A total number of thirty AD patients and thirty normal subjects as controls were recriuted in the present study. Plasma levels of BACE1 were then examined via enzyme-linked immunosorbent assay (ELISA) and also mRNA expression of BACE1 in total blood was measured using real-time PCR technique., Results: The findings revealed a significant difference in gene expression of BACE1 in the peripheral blood of AD patients compared with that in controls (p<0.0001). Additionally, elevated plasma levels of BACE1 were found in AD patients compared with those in normal subjects (p<0.01). Statistical analyses also demonstrated no correlation between expression (mRNA and protein) of BACE1 in both AD patients and controls and age or the results of Mini-Mental State Examination (MMSE) scale (p>0.05)., Conclusion: Given the importance of early diagnosis of AD patients, it was suggested that the measurement of plasma levels and also mRNA expression of BACE1 might be a valuable blood-based biomarker used in preference to other invasive diagnostic methods such as cerebrospinal fluid (CSF) analysis., Competing Interests: All of the authors declare that they have no conflict of interest.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with high outbreak rates. It is estimated that about 35 million individuals around the world suffered from dementia in 2010. AD is expected to increase twofold every 20 years and, by 2030, approximately 65 million people could suffer from this illness. AD is determined clinically by a cognitive impairment and pathologically by the production of amyloid beta (Aβ), neurofibrillary tangles, toxic free radicals and inflammatory mediators in the brain. There is still no treatment to cure or even alter the progressive course of this disease; however, many new therapies are being investigated and are at various stages of clinical trials. Neuropeptides are signaling molecules used by neurons to communicate with each other. One of the important neuropeptides is apelin, which can be isolated from bovine stomach. Apelin and its receptor APJ have been shown to broadly disseminate in the neurons and oligodendrocytes of the central nervous system. Apelin-13 is known to be the predominant neuropeptide in neuroprotection. It is involved in the processes of memory and learning as well as the prevention of neuronal damage. Studies have shown that apelin can directly or indirectly prevent the production of Aβ and reduce its amounts by increasing its degradation. Phosphorylation and accumulation of tau protein may also be inhibited by apelin. Apelin is considered as an anti-inflammatory agent by preventing the production of inflammatory mediators such as interleukin-1β and tumor necrosis factor alpha. It has been shown that in vivo and in vitro anti-apoptotic effects of apelin have prevented the death of neurons. In this review, we describe the various functions of apelin associated with AD and present an integrated overview of recent findings that, in general, recommend apelin as a promising therapeutic agent in the treatment of this ailment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Clinical features of infantile diarrhea were studied among 603 infants from birth to 12 months of age to determine the predominant clinical feature(s) seen in infantile diarrhea associated with a specific enteric pathogen. Among the major clinical features, fever was most often seen in diarrhea due to Yersinia spp. (61.5%) followed by that in rotavirus (26.1%). Vomiting was mostly associated with Vibrio cholerae infection (90.9%) and shigellosis (64.6%). Dehydration was predominant in Vibrio cholerae (90.9%) and Salmonella (84.9%) infections. Bloody diarrhea was mostly due to Shigella infection (74.3%). As regards diarrhea with multiple pathogens, vomiting and dehydration were most frequent with Campylobacter+Enteropathogenic Escherichia coli (EPEC) (88.9% and 77.8%, respectively), while fever was more common with rotavirus+Shigella+Escherichia coli and rotavirus+Giardia. Infection with invasive organisms lead to vomiting, 4-10 stools per day and dehydration significantly more often as compared to infections with non-invasive organisms. Similarly more stools of patients infected with invasive organisms showed presence of blood and more than 5 leukocytes/HPF as compared to those infected with non-invasive organisms.