Search

Background: MicroRNAs have gained attention as key immunomodulators, with miR-155 specifically shown in various studies to drive macrophage polarization toward the classical phenotype. This polarization is crucial, as classical macrophages play a well-recognized role in differentiating type-1 immune responses and resisting Leishmania infection. Objective: The present study aims to evaluate the anti-leishmanial immunoadjuvant effects of the miR-155 chitosan polyplex (miR-155 CP). Methods: The anti-leishmanial immunoadjuvant activity of miR-155 CP synthesized by the coacervation method was assessed against L. major (MRHO/IR/75/ER) by analyzing the infectivity rate on RAW 264.7 cells in vitro.MiR-155 CP as an adjuvant co-administrated with soluble Leishmania antigen (SLA) for immunization of BALB/c mice, then the challenge was performed by subcutaneous injection of 1 × 106L. major promastigotes. Eight weeks following the challenge, lesion size, parasite load, cytokine assay, and nitric oxide production were evaluated. Results: The nanoparticles were produced with a size of 233.87 ± 8 nm and a zeta potential of + 22.6 ± 2 mV with good transfection efficiency. The mean infection index among pretreated cells with miR-155 CP (72±1.1) decreased significantly compared to the control group (420 ± 2.8). The parasite burden and the size of the lesions were significantly reduced in the immunized infected mice. Vaccination by miR-155 CP/SLA triggered the production of IFN-γ and NO and changed the cytokine profile of antigen-specific cells.Conclusion:The effectiveness of the SLA vaccine can be enhanced by including miR-155 CP as an adjuvant. SLA and miR-155 CP co-administration improve the type-1 immune response. This enhanced immune response helps prevent severe leishmaniasis. [ABSTRACT FROM AUTHOR]

The complex interplay between ferroptosis and efferocytosis in cancer has attracted significant interest recently. Efferocytosis, the process of eliminating apoptotic cells, is essential for preserving tissue homeostasis and reducing inflammation. However, dysregulation of efferocytosis can have profound effects on cancer. Apoptotic cells accumulate because of impaired efferocytosis, which triggers chronic inflammation and the release of pro-inflammatory chemicals. Surprisingly, accumulating evidence suggests that dysregulation of ferroptosis- a form of controlled cell death characterized by lipid peroxidation and the buildup iron-dependent reactive oxygen species (ROS)-can influence efferocytic activities within the tumor microenvironment. Dysfunctional iron metabolism and increased lipid peroxidation, are associated with ferroptosis, resulting in inadequate apoptotic cell clearance. Conversely, apoptotic cells can activate ferroptotic pathways, increasing oxidative stress and inducing cell death in cancer cells. This reciprocal interaction emphasizes the complex relationship between efferocytosis and ferroptosis in cancer biology. Understanding and managing the delicate balance between cell clearance and cell death pathways holds significant therapeutic potential in cancer treatment. Targeting the efferocytosis and ferroptosis pathways may offer new opportunities for improving tumor clearance, reducing inflammation, and sensitizing cancer cells to therapeutic interventions. Further research into the interaction between efferocytosis and ferroptosis in cancer will provide valuable insights for the development of novel therapies aimed at restoring tissue homeostasis and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Despite remarkable progress in contemporary medical technology and enhanced survival outcomes for various cancer types, pancreatic cancer (PC) continues to stand out as a particularly deadly gastrointestinal malignancy. Given a persistent rise in both incidence and the corresponding mortality rates of PC globally, evaluations of PC burden by sex are of great importance. Here, we used the illness‐death multi‐state model (IDM) to forecast the prevalence of PC through the year 2040. Methods: IDM was established based on obtainable data to predict the future prevalence of PC on global, regional, and national scales from 2019 to 2040. Analyses were also performed regarding sex and 95% confidence intervals (CIs) are presented for all estimates. Results: The projected prevalence rate for 2040 is anticipated to be 6.093 ([95% CI 5.47–6.786] per 100,000) worldwide, indicating a significant increase of 31.45% since 1990, and a 12.29% increase since 2019. The estimated average annual increase since 2020 was 0.5%. Considering sex differences, females are expected to have a steeper slope in prevalence rate than males. Intriguingly, when considering the percentage changes between the periods of 2019–2040 and 1990–2019 for both sexes, females exhibited 29% and 11% increase relative to males (2.6‐fold greater increase). Conclusions: By 2040, it is predicted that the prevalence of PC will increase globally, with women being at higher risk of developing the disease. Considering the percentage changes, regions with lower socioeconomic status are anticipated to face a greater risk of experiencing PC compared to other geographical areas. [ABSTRACT FROM AUTHOR]

Treatment with melatonin is routinely prescribed for its potent antioxidant and cognitive‐promoting effects, nevertheless, it has yet to find neuromodulatory effects in normal and disease conditions. Therefore, to investigate its neuromodulatory mechanisms, melatonin was systemically administered over 10 consecutive days to both intracortical normal saline‐ and amyloid‐β 1‐42 (Aβ) peptide‐injected rats. At the behavioral level, treatment with melatonin was associated with reduced efficacy in restoring Aβ‐induced deficit in passive‐avoidance memory. Whole‐cell patch‐clamp recordings from CA1 pyramidal neurons revealed that melatonin treatment reduced spontaneous and evoked intrinsic excitability in control rats while exerting a reduction of spontaneous, but not evoked activity, in the Aβ‐injected group. Interestingly, treatment with melatonin enhances after‐hyperpolarization in control, but not Aβ‐injected rats. In contrast, our voltage‐clamp study showed that Ih current is significantly enhanced by Aβ injection, and this effect is further strengthened by treatment with melatonin in Aβ‐injected rats. Finally, we discovered that the transcription of melatonin receptors 1 (MT1) and 2 (MT2) is significantly upregulated in the hippocampi of Aβ‐injected rats. Collectively, our study demonstrates that systemic treatment with melatonin has differential neuromodulation on CA1 neuronal excitability, at least in part, via differential effects on after‐hyperpolarization and Ih currents due to Aβ‐induced neurotoxicity. Summary: The molecular and cellular underpinnings of AD pathology are accompanied by developing aberrant neuronal excitability. These neuronal properties are also a part of melatonin effectors by which melatonin exerts its cognitive‐promoting and anti‐seizure effects. In this paper, we answer the question of how melatonin may influence neuronal excitability in healthy and AD‐like conditions. Answering this query is important considering the fact that melatonin effectiveness is altered with the development of AD. This may be due to, as we demonstrate, the deregulation of melatonin receptors in the hippocampus of AD rats. These findings are significant because shed further light on the cellular mechanisms of melatonin and help us to understand AD pathophysiology. [ABSTRACT FROM AUTHOR]

Introduction: The PI3K/AKT/mTOR signaling pathway plays a significant role in the development of T-cell acute lymphoblastic leukemia (T-ALL). Rapamycin is a potential therapeutic strategy for hematological malignancies due to its ability to suppress mTOR activity. Additionally, microRNAs (miRNAs) have emerged as key regulators in T-ALL pathophysiology and treatment. This study aimed to investigate the combined effects of rapamycin and miRNAs in inhibiting the PI3K/AKT/mTOR pathway in T-ALL cells. Methods: Bioinformatic algorithms were used to find miRNAs that inhibit the PI3K/AKT/mTOR pathway. Twenty-five bone marrow samples were collected from T-ALL patients, alongside five control bone marrow samples from non-leukemia patients. The Jurkat cell line was chosen as a representative model for T-ALL. Gene and miRNA expression levels were assessed using quantitative real-time PCR (qRT-PCR). Two miRNAs exhibiting down-regulation in both clinical samples and Jurkat cells were transfected to the Jurkat cell line to investigate their impact on target gene expression. Furthermore, in order to evaluate the potential of combination therapy involving miRNAs and rapamycin, apoptosis and cell cycle assays were carried out. Results: Six miRNAs (miR-3143, miR-3182, miR-99a/100, miR-155, miR-576-5p, and miR- 501- 3p) were predicted as inhibitors of PI3K/AKT/mTOR pathway. The expression analysis of both clinical samples and the Jurkat cell line revealed a simultaneous downregulation of miR- 3143 and miR-3182. Transfection investigation demonstrated that the exogenous overexpression of miR- 3143 and miR-3182 can effectively inhibit PI3K/AKT/mTOR signaling in the Jurkat cell line. Moreover, when used as a dual inhibitor along with rapamycin, miR-3143 and miR-3182 significantly increased apoptosis and caused cell cycle arrest in the Jurkat cell line. Conclusion: These preliminary results highlight the potential for improving T-ALL treatment through multi-targeted therapeutic strategies involving rapamycin and miR-3143/miR-3182. [ABSTRACT FROM AUTHOR]