Exploring the multifaceted role of NRF2 in brain physiology and cancer: A comprehensive review.

Chronic oxidative stress plays a critical role in the development of brain malignancies due to the high rate of brain oxygen utilization and concomitant production of reactive oxygen species. The nuclear factor-erythroid-2-related factor 2 (NRF2), a master regulator of antioxidant signaling, is a key factor in regulating brain physiology and the development of age-related neurodegenerative diseases. Also, NRF2 is known to exert a protective antioxidant effect against the onset of oxidative stress-induced diseases, including cancer, along with its pro-oncogenic activities through regulating various signaling pathways and downstream target genes. In glioblastoma (GB), grade 4 glioma, tumor resistance, and recurrence are caused by the glioblastoma stem cell population constituting a small bulk of the tumor core. The persistence and self-renewal capacity of these cell populations is enhanced by NRF2 expression in GB tissues. This review outlines NRF2's dual involvement in cancer and highlights its regulatory role in human brain physiology and diseases, in addition to the development of primary brain tumors and therapeutic potential, with a focus on GB.

Outlooks on using a mobile health intervention for supportive pain management for children and adolescents with cancer: a qualitative study.

BACKGROUND: Considerable improvements in the prognosis of pediatric cancer patients have been achieved over recent decades due to advances in treatment. Nevertheless, as the most common and distressing health issue for pediatrics with cancer, cancer-related pain is still a significant hurdle that impedes patients' journey to recovery, compromises their quality of life, and delays the positive outcome and effectiveness of their treatments. PURPOSE: Taking into consideration that acceptability studies are imperative for the design, evaluation, and implementation of healthcare interventions, this study aims to explore pediatric oncology patients' readiness to use a mobile health application that emphasizes social assistance and peer support in addition to conventional pain management methods. DESIGN AND METHODS: This study followed the Qualitative description approach. Twelve participants were chosen based on purposive sampling and maximum variation sampling. Interviews were analyzed using the conventional content analysis. RESULTS: Analysis of the interviews revealed four major categories: (A) The need for connectedness; (B) An innovative way to connect yet fearful; (C) A 3D approach; (D) Fears of the unfamiliar. CONCLUSIONS: This study is the first in Lebanon and the region to undertake an initiative towards introducing technology for pain assessment and management of children with cancer through a dedicated digital platform. The study results attested to the acceptability and potential utilization of this platform by children with cancer. PRACTICE IMPLICATIONS: Nurses need to be trained to play an essential role in teaching children with cancer about the significance of social support and assisting them to establish their social support network. Children with cancer are encouraged to voice out their need for help. Our proposed application can create an enabling environment to harness the power of social support and provide children with cancer the opportunity to connect on a deeper level in a supportive and pity-free space.

Nrf2 Downregulation Contributes to Epithelial-to-Mesenchymal Transition in Helicobacter pylori-Infected Cells.

BACKGROUND: Gastric cancer, the fifth most common cancer worldwide, is mainly linked to Helicobacter pylori infection. H. pylori induces chronic inflammation of the gastric mucosa associated with high oxidative stress. Our study aimed at assessing the implication of Nrf2, a major regulator of cellular redox homeostasis, in H. pylori-induced gastric carcinogenesis. METHODS: Using three different gastric epithelial cell lines, a non-cancerous (HFE-145) and two different subtypes of gastric cancer (AGS and MKN74), we analyzed the modulation of Nrf2 expression over time. After invalidation of Nrf2 by CRISPR-cas9, we assessed its role in H. pylori-induced epithelial-to-mesenchymal transition (EMT). Finally, we evaluated the expression of Nrf2 and ZEB1, a central EMT transcription factor, in human gastric tissues. RESULTS: We first demonstrated that the Nrf2 signaling pathway is differentially regulated depending on the infection stage. Rapidly and transiently activated, Nrf2 was downregulated 24 h post-infection in a VacA-dependent manner. We then demonstrated that Nrf2 invalidation leads to increased EMT, which is even exacerbated after H. pylori infection. Finally, Nrf2 expression tended to decrease in human patients' gastric mucosa infected with H. pylori. CONCLUSIONS: Our work supports the hypothesis that Nrf2 downregulation upon H. pylori infection participates in EMT, one of the most important events in gastric carcinogenesis.

Overcoming Drug Resistance in Advanced Prostate Cancer by Drug Repurposing.

Prostate cancer (PCa) is the second most common cancer in men. Common treatments include active surveillance, surgery, or radiation. Androgen deprivation therapy and chemotherapy are usually reserved for advanced disease or biochemical recurrence, such as castration-resistant prostate cancer (CRPC), but they are not considered curative because PCa cells eventually develop drug resistance. The latter is achieved through various cellular mechanisms that ultimately circumvent the pharmaceutical's mode of action. The need for novel therapeutic approaches is necessary under these circumstances. An alternative way to treat PCa is by repurposing of existing drugs that were initially intended for other conditions. By extrapolating the effects of previously approved drugs to the intracellular processes of PCa, treatment options will expand. In addition, drug repurposing is cost-effective and efficient because it utilizes drugs that have already demonstrated safety and efficacy. This review catalogues the drugs that can be repurposed for PCa in preclinical studies as well as clinical trials.

Central nervous system tumors and three-dimensional cell biology: Current and future perspectives in modeling.

Central nervous system (CNS) tumors are a variety of distinct neoplasms that present multiple challenges in terms of treatment and prognosis. Glioblastoma, the most common primary tumor in adults, is associated with poor survival and remains one of the least treatable neoplasms. These tumors are highly heterogenous and complex in their nature. Due to this complexity, traditional cell culturing techniques and methods do not provide an ideal recapitulating model for the study of these tumors' behavior in vivo. Two-dimensional models lack the spatial arrangement, the heterogeneity in cell types, and the microenvironment that play a large role in tumor cell behavior and response to treatment. Recently, scientists have turned towards three-dimensional culturing methods, namely spheroids and organoids, as they have been shown to recapitulate tumors in a more faithful manner to their in vivo counterparts. Moreover, tumor-on-a-chip systems have lately been employed in CNS tumor modeling and have shown great potential in both studying the pathophysiology and therapeutic testing. In this review, we will discuss the current available literature on in vitro three-dimensional culturing models in CNS tumors, in addition to presenting their advantages and current limitations. We will also elaborate on the future implications of these models and their benefit in the clinical setting.

The Use of Stem Cell-Derived Organoids in Disease Modeling: An Update.

Organoids represent one of the most important advancements in the field of stem cells during the past decade. They are three-dimensional in vitro culturing models that originate from self-organizing stem cells and can mimic the in vivo structural and functional specificities of body organs. Organoids have been established from multiple adult tissues as well as pluripotent stem cells and have recently become a powerful tool for studying development and diseases in vitro, drug screening, and host-microbe interaction. The use of stem cells-that have self-renewal capacity to proliferate and differentiate into specialized cell types-for organoids culturing represents a major advancement in biomedical research. Indeed, this new technology has a great potential to be used in a multitude of fields, including cancer research, hereditary and infectious diseases. Nevertheless, organoid culturing is still rife with many challenges, not limited to being costly and time consuming, having variable rates of efficiency in generation and maintenance, genetic stability, and clinical applications. In this review, we aim to provide a synopsis of pluripotent stem cell-derived organoids and their use for disease modeling and other clinical applications.

Thymoquinone anticancer activity is enhanced when combined with royal jelly in human breast cancer.

BACKGROUND: Breast cancer is the most common cause of the majority of cancer-related deaths in women, among which triple-negative breast cancer is the most aggressive type of breast cancer diagnosed with limited treatment options. Thymoquinone (TQ), the main bioactive constituent of Nigella sativa, has been extensively studied as a potent anticancer molecule against various types of cancers. Honeybee products such as the royal jelly (RJ), the nutritive secretion fed to honeybee queens, exhibit a variety of biological activities besides its anticancer effect. However, the anticancer activity of the combination of TQ and RJ against breast cancer is still unknown. AIM: To investigate cytotoxicity of RJ in FHs 74 Int cells and the anticancer effects of TQ, RJ, and their combinations in the MDA-MB-231 cell line. METHODS: Cells were treated with TQ, RJ, and their combinations for 24 h. Using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, we determined the half-maximal inhibitory concentration of TQ. Trypan blue and 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were then performed to assess the cell viability in response to different treatment conditions. Cell death and cycle regulation were investigated using propidium iodide deoxyribonucleic acid staining followed by flow cytometry in response to a single dose of TQ, RJ, and their combination. Immunostaining for cleaved caspase 3 and Ki67 expression was used to determine apoptosis induction and changes in cell proliferation. RESULTS: TQ alone inhibited cell viability in a dose-dependent manner at concentrations below and above the half-maximal inhibitory concentration. RJ exhibited relatively nontoxic effects against MDA-MB-231 cells and FHs 74 Int small intestinal cells at concentrations below 5 µg/mL. High doses of RJ (200 µg/mL) had greater toxicity against MDA-MB-231 cells. Interestingly, the inhibition of cell viability was most pronounced in response to 15 µmol/L TQ and 5 µg/mL RJ. A dose of 15 µmol/L TQ caused a significant increase in the PreG1 population, while a more pronounced effect on cell viability inhibition and PreG1 increase was observed in response to TQ and RJ combinations. TQ was the main inducer of caspase 3-dependent apoptosis when applied alone and in combination with RJ. In contrast, no significant regulation of Ki67 expression was observed, indicating that the decrease in cell viability was due to apoptosis induction rather than to inhibition of cell proliferation. CONCLUSION: This study is the first to report enhanced anticancer effects of TQ and RJ combination against MDA-MB-231 breast cancer cells, which could confer an advantage for cancer therapy.

Tumor Microenvironment in Prostate Cancer: Toward Identification of Novel Molecular Biomarkers for Diagnosis, Prognosis, and Therapy Development.

Prostate cancer (PCa) is by far the most commonly diagnosed cancer in men worldwide. Despite sensitivity to androgen deprivation, patients with advanced disease eventually develop resistance to therapy and may die of metastatic castration-resistant prostate cancer (mCRPC). A key challenge in the management of PCa is the clinical heterogeneity that is hard to predict using existing biomarkers. Defining molecular biomarkers for PCa that can reliably aid in diagnosis and distinguishing patients who require aggressive therapy from those who should avoid overtreatment is a significant unmet need. Mechanisms underlying the development of PCa are not confined to cancer epithelial cells, but also involve the tumor microenvironment. The crosstalk between epithelial cells and stroma in PCa has been shown to play an integral role in disease progression and metastasis. A number of key markers of reactive stroma has been identified including stem/progenitor cell markers, stromal-derived mediators of inflammation, regulators of angiogenesis, connective tissue growth factors, wingless homologs (Wnts), and integrins. Here, we provide a synopsis of the stromal-epithelial crosstalk in PCa focusing on the relevant molecular biomarkers pertaining to the tumor microenvironment and their role in diagnosis, prognosis, and therapy development.