Decoding contextual crosstalk: revealing distinct interactions between non-coding RNAs and unfolded protein response in breast cancer.

Breast cancer is significantly influenced by endoplasmic reticulum (ER) stress, impacting both its initiation and progression. When cells experience an accumulation of misfolded or unfolded proteins, they activate the unfolded protein response (UPR) to restore cellular balance. In breast cancer, the UPR is frequently triggered due to challenging conditions within tumors. The UPR has a dual impact on breast cancer. On one hand, it can contribute to tumor growth by enhancing cell survival and resistance to programmed cell death in unfavorable environments. On the other hand, prolonged and severe ER stress can trigger cell death mechanisms, limiting tumor progression. Furthermore, ER stress has been linked to the regulation of non-coding RNAs (ncRNAs) in breast cancer cells. These ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play essential roles in cancer development by influencing gene expression and cellular processes. An improved understanding of how ER stress and ncRNAs interact in breast cancer can potentially lead to new treatment approaches. Modifying specific ncRNAs involved in the ER stress response might interfere with cancer cell survival and induce cell death. Additionally, focusing on UPR-associated proteins that interact with ncRNAs could offer novel therapeutic possibilities. Therefore, this review provides a concise overview of the interconnection between ER stress and ncRNAs in breast cancer, elucidating the nuanced effects of the UPR on cell fate and emphasizing the regulatory roles of ncRNAs in breast cancer progression.

Concise review: The heterogenous roles of BATF3 in cancer oncogenesis and dendritic cells and T cells differentiation and function considering the importance of BATF3-dependent dendritic cells.

The transcription factor, known as basic leucine zipper ATF-like 3 (BATF3), is a crucial contributor to the development of conventional type 1 dendritic cells (cDC1), which is definitely required for priming CD8 + T cell-mediated immunity against intracellular pathogens and malignancies. In this respect, BATF3-dependent cDC1 can bring about immunological tolerance, an autoimmune response, graft immunity, and defense against infectious agents such as viruses, microbes, parasites, and fungi. Moreover, the important function of cDC1 in stimulating CD8 + T cells creates an excellent opportunity to develop a highly effective target for vaccination against intracellular pathogens and diseases. BATF3 has been clarified to control the development of CD8α+ and CD103+ DCs. The presence of BATF3-dependent cDC1 in the tumor microenvironment (TME) reinforces immunosurveillance and improves immunotherapy approaches, which can be beneficial for cancer immunotherapy. Additionally, BATF3 acts as a transcriptional inhibitor of Treg development by decreasing the expression of the transcription factor FOXP3. However, when overexpressed in CD8 + T cells, it can enhance their survival and facilitate their transition to a memory state. BATF3 induces Th9 cell differentiation by binding to the IL-9 promoter through a BATF3/IRF4 complex. One of the latest research findings is the oncogenic function of BATF3, which has been approved and illustrated in several biological processes of proliferation and invasion.

Glyburide-treated human monocyte-derived dendritic cells loaded with insulin represent tolerogenic features with anti-inflammatory responses and modulate autologous T cell responses in vitro.

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.

STATs signaling pathways in dendritic cells: As potential therapeutic targets?

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.

What is the context?Multiple disorders, including different infectious and autoimmune diseases and cancers, have affected many individuals all around the world. One of the main methods for combating such diseases is immunotherapy based on the dendritic cell (DC) vaccine. DCs are the most potent antigen-presenting cells for developing T lymphocytes' potential to eliminate external and internal harmful factors. Manipulating DCs' different signaling pathways, such as activating or blocking inhibitory or activatory pathways, based on our purpose is a great method for achieving efficient DC vaccines. The signal transducer and activator of transcription (STAT) is a protein with six subtypes that exists in DCs and conducts specific signaling pathways. Changing the activity of each STAT via various methods and drugs can affect DCs differently. Furthermore, each DC-existing STAT can play a specific role in establishing a special kind of disease. Thus, STAT proteins and their related signaling pathways have attracted many scientists' attention.What does the review highlight?We provide a comprehensive overview of different STATs' roles in DC subsets. Moreover, we conducted this review to identify if DC-associated STATs have any role in starting a special kind of disease. The effects of different drugs on STATs in DCs were also investigated.What is the impact?Generalabsly, STAT1, STAT2, and STAT4 with activatory roles, STAT3 with inhibitory roles, and STAT5 and STAT6 with both inhibitory and activatory roles can affect DCs in different conditions. Targeting different STATs in DCs with specific drugs contributes to alleviating various disease symptoms.

Efficacy of Simultaneous Administration of Nimodipine, Progesterone, and Magnesium Sulfate in Patients with Severe Traumatic Brain Injury: A Randomized Controlled Trial.

OBJECTIVE: To investigate the safety and efficacy of simultaneous administration of nimodipine, progesterone, magnesium sulfate in patients suffering from severe traumatic brain injury (TBI). METHODS: Overall, 90 patients with blunt head trauma who were admitted to the Besat hospital, Hamadan University of Medical Sciences, Iran through the Emergency Department in 2017 to 2018 were randomly assigned to the study or control groups each containing 45 patients. In the study group, intravenous nimodipine 60 mg every 12 hours for 5 days, intramuscular progesterone 1 mg/kg daily for 5 days, and magnesium sulfate 5 grams stat followed by 2.5 grams every 4 hours for 21 days were administered. Daily GCS and jugular venous oxygen saturation (SjvO2) of the patients were measured on admission day (day 0) through hospitalization day 4 at the intensive care unit. Then, all patients were visited at three months after discharge. RESULTS: The mean age of the patients was 31.4 ± 12.8 years including 59 (65.6%) men with no significant difference between the groups. The baseline GCS and SjvO2 of the patients were comparable in both groups, however, GCS of the patients in the study group were significantly higher in the next 4 hospitalization days compared to the controls. Whereas, the SjvO2 of the patients were not significantly different between the groups during these days. Three-month mortality rate of the patients in the study group was significantly lower than the three-month mortality rate of the patients in the control groups (22.2% vs. 42.2%, p=0.042). CONCLUSION: Administration of combined protocol of magnesium sulfide, progesterone and nimodipine may be safe and effective in patients suffering from severe TBI. CLINICAL TRIAL REGISTRY: IRCT201210229534N2.