Mechanistic insights into mesenchymal-amoeboid transition as an intelligent cellular adaptation in cancer metastasis and resistance.

Malignant cell plasticity is an important hallmark of tumor biology and crucial for metastasis and resistance. Cell plasticity lets cancer cells adapt to and escape the therapeutic strategies, which is the leading cause of cancer patient mortality. Epithelial cells acquire mobility via epithelial-mesenchymal transition (EMT), whereas mesenchymal cells enhance their migratory ability and clonogenic potential by acquiring amoeboid characteristics through mesenchymal-amoeboid transition (MAT). Tumor formation, progression, and metastasis depend on the tumor microenvironment (TME), a complex ecosystem within and around a tumor. Through increased migration and metastasis of cancer cells, the TME also contributes to malignancy. This review underscores the distinction between invasion pattern morphological manifestations and the diverse structures found within the TME. Furthermore, the mechanisms by which amoeboid-associated characteristics promote resistance and metastasis and how these mechanisms may represent therapeutic opportunities are discussed.

Pre-adolescence repeat exposure to sub-anesthetic doses of ketamine induces long-lasting behaviors and cognition impairment in male and female rat adults.

In pre-adolescence, repeated anesthesia may be required for therapeutic interventions. Adult cognitive and neurobehavioral problems may result from preadolescent exposure to anesthetics. This study examined the long-term morphological and functional effects of repeated sub-anesthetic doses of ketamine exposure on male and female rat adults during pre-adolescence. Weaned 48 pre-adolescent rats from eight mothers and were randomly divided into four equal groups: control group and the ketamine group of males and females (20 mg/kg daily for 14 days); then animals received care for 20-30 days. Repeated exposure to sub-anesthetic doses of ketamine on cognitive functions was assayed using Social discrimination and novel object tests. Besides, an elevated plus maze and fear conditioning apparatus were utilized to determine exploratory and anxiety-like behavior in adults. Toluidine blue stain was used to evaluate the number of dead neurons in the hippocampus, and the effects of ketamine on synaptic plasticity were compared in the perforant pathway of the CA1 of the hippocampus. Our study indicates that repeated exposure to sub-anesthetic doses of ketamine during pre-adolescence can result in neurobehavioral impairment in male and female rat adulthood but does not affect anxiety-like behavior. We found a significant quantifiable increase in dark neurons. Recorded electrophysiologically, repeat sub-anesthetic doses of ketamine resulted in hampering long-term potentiation and pair pulse in male adult animals. Our results showed that repeated exposure to sub-anesthetic doses of ketamine during pre-adolescence can induce hippocampus and neuroplasticity changes later in adulthood. This study opens up a new line of inquiry into potential adverse outcomes of repeated anesthesia exposure in pre-adolescent rats.

The obesity-autophagy-cancer axis: Mechanistic insights and therapeutic perspectives.

Autophagy, a self-degradative process vital for cellular homeostasis, plays a significant role in adipose tissue metabolism and tumorigenesis. This review aims to elucidate the complex interplay between autophagy, obesity, and cancer development, with a specific emphasis on how obesity-driven changes affect the regulation of autophagy and subsequent implications for cancer risk. The burgeoning epidemic of obesity underscores the relevance of this research, particularly given the established links between obesity, autophagy, and various cancers. Our exploration delves into hormonal influence, notably INS (insulin) and LEP (leptin), on obesity and autophagy interactions. Further, we draw attention to the latest findings on molecular factors linking obesity to cancer, including hormonal changes, altered metabolism, and secretory autophagy. We posit that targeting autophagy modulation may offer a potent therapeutic approach for obesity-associated cancer, pointing to promising advancements in nanocarrier-based targeted therapies for autophagy modulation. However, we also recognize the challenges inherent to these approaches, particularly concerning their precision, control, and the dual roles autophagy can play in cancer. Future research directions include identifying novel biomarkers, refining targeted therapies, and harmonizing these approaches with precision medicine principles, thereby contributing to a more personalized, effective treatment paradigm for obesity-mediated cancer.

The role of BCL2L13 in glioblastoma: turning a need into a target.

Glioblastoma (GBM) is the most common aggressive central nervous system cancer. GBM has a high mortality rate, with a median survival time of 12-15 months after diagnosis. A poor prognosis and a shorter life expectancy may result from resistance to standard treatments such as radiation and chemotherapy. Temozolomide has been the mainstay treatment for GBM, but unfortunately, there are high rates of resistance with GBM bypassing apoptosis. A proposed mechanism for bypassing apoptosis is decreased ceramide levels, and previous research has shown that within GBM cells, B cell lymphoma 2-like 13 (BCL2L13) can inhibit ceramide synthase. This review aims to discuss the causes of resistance in GBM cells, followed by a brief description of BCL2L13 and an explanation of its mechanism of action. Further, lipids, specifically ceramide, will be discussed concerning cancer and GBM cells, focusing on ceramide synthase and its role in developing GBM. By gathering all current information on BCL2L13 and ceramide synthase, this review seeks to enable an understanding of these pieces of GBM in the hope of finding an effective treatment for this disease.

Metastatic outgrowth via the two-way interplay of autophagy and metabolism.

Metastasis represents one of the most dangerous issue of cancer progression, characterized by intricate interactions between invading tumor cells, various proteins, and other cells on the way towards target sites. Tumor cells, while undergoing metastasis, engage in dynamic dialogues with stromal cells and undertake epithelial-mesenchymal transition (EMT) phenoconversion. To ensure survival, tumor cells employ several strategies such as restructuring their metabolic needs to adapt to the alterations of the microenvironmental resources via different mechanisms including macroautophagy (autophagy) and to circumvent anoikis-a form of cell death induced upon detachment from the extracellular matrix (ECM). This review focuses on the puzzling connections of autophagy and energetic metabolism within the context of cancer metastasis.

Modulating Wnt/ß-Catenin Signaling Pathway on U251 and T98G Glioblastoma Cell Lines Using a Combination of Paclitaxel and Temozolomide, A Molecular Docking Simulations and Gene Expression Study.

One of the most lethal cancers, glioblastoma (GBM), affects 14.5% of all central nervous system (CNS) tumors. Patients diagnosed with GBM have a meager median overall survival (OS) of 15 months. Extensive genetic analysis has shown that many dysregulated pathways, including the Wnt/ß-catenin signaling system, contribute to the pathogenicity of GBM. Paclitaxel (PTX) and temozolomide (TMZ) are recognized to have therapeutic potential in several types of cancer, including GBM. This work aimed to examine the impact of PTX and TMZ on the human glioma cell lines U251 and T98G using molecular docking simulations and gene expression profiles in the Wnt/ß-catenin signaling pathway. Standard procedure for Molecular Docking simulation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay, and Flow Cytometry assay was used. Genes implicated in the Wnt/ß-catenin signaling pathway, including Dvl, Axin, APC, ß-catenin, and glycogen synthase kinase3-ß (GSK3ß), were subjected to real-time PCR. The estimated parameters for targets revealed that the average binding energy and inhibition constant (Ki) for the DVL, ß-Catenin, and GSK3ß, when targeted by PTX, were - 5.01 kcal/mol, - 5.4 kcal/mol, and - 9.06 kcal/mol, respectively. This energy range was - 6.34 kcal/mol for DVL, - 5.52 kcal/mol for ß-Catenin, and - 5.66 kcal/mol for GSK3ß as a result of TMZ's inhibitory actions. Gene expression analyses indicated that PTX and PTX/TMZ suppressed GSK3ß (p < 0.05). GSK3ß from the Wnt/ß-catenin signaling pathway was significantly targeted by PTX alone, and adding TMZ to PTX may improve the efficacy of glioblastoma treatment. In addition, the GSK3ß gene may help GBM therapy strategies as a potential PTX target.

Molecular mechanisms of microRNAs in glioblastoma pathogenesis.

Glioblastoma (GBM) is human's most prevalent and severe brain cancer. Epigenetic regulators, micro(mi)RNAs, significantly impact cellular health and disease because of their wide range of targets and functions. The "epigenetic symphony" in which miRNAs perform is responsible for orchestrating the transcription of genetic information. The discovery of regulatory miRNA activities in GBM biology has shown that various miRNAs play a vital role in disease onset and development. Here, we summarize our current understanding of the current state-of-the-art and latest findings regarding the interactions between miRNAs and molecular mechanisms commonly associated with GBM pathogenesis. Moreover, by literature review and reconstruction of the GBM gene regulatory network, we uncovered the connection between miRNAs and critical signaling pathways such as cell proliferation, invasion, and cell death, which provides promising hints for identifying potential therapeutic targets for the treatment of GBM. In addition, the role of miRNAs in GBM patient survival was investigated. The present review, which contains new analyses of the previous literature, may lead to new avenues to explore in the future for the development of multitargeted miRNA-based therapies for GBM.

Apigenin-coated gold nanoparticles as a cardioprotective strategy against doxorubicin-induced cardiotoxicity in male rats via reducing apoptosis.

Aims: Cardiotoxicity is associated with doxorubicin (DOX), an effective anticancer drug. Apigenin has cardioprotective properties; it may be employed as a capping and reducing agent in synthesizing gold nanoparticles (AuNPs). This study examined the cardioprotective impact of AuNPs synthesized with apigenin (Api) in DOX-induced cardiotoxicity (DIC). Main methods: Api-AuNPs were synthesized in a single pot without needing additional reagents for reducing gold ions or stabilizing the NPs. The cytotoxicity of Api-AuNPs on H9c2 heart cells was subsequently determined using the MTT assay. In the animal investigation, 40 male rats were randomly assigned to one of four groups: control, cardiotoxicity (DOX), DOX treated with apigenin (DOX + Api), or DOX treated with Api-AuNPs (DOX + Api-AuNPs). To examine heart function, echocardiography was conducted. Blood samples were obtained to evaluate injury indicators (Lactate dehydrogenase (LDH), creatine kinase MB (CK-MB), Cardiac Troponin I (cTn-I), Alanine transaminase (ALT), and Aspartate transaminase (AST)). The heart was removed under general anesthetic, weighed, and preserved in formalin solution. Six micrometer-thick cardiac tissue sections were stained with hematoxylin, eosin (H&E), and immunohistochemistry to identify cardiomyocyte apoptotic markers (Bax, Bcl-2, and caspase3). Key findings: Api-AuNPs have an average size of 21.4 ± 11.6 nm and are stable in physiological environments. Api-AuNPs therapy substantially reduced body and heart weight loss compared to the DOX group. Injury indicators were reduced dramatically by Api-AuNPs treatment. Api-AuNPs inhibited myocardial apoptosis via modulating Bax, caspase3, and Bcl-2 and ameliorating tissue damage caused by DOX. Significance: Api-AuNPs' anti-apoptotic activities provide cardioprotection against DIC. It has the potential to reduce cardiotoxicity and boost myocardial performance.

Tailoring drug co-delivery nanosystem for mitigating U-87 stem cells drug resistance.

Glioblastoma multiforme (GBM) is the most prevalent form of brain tumor, which generally has a poor prognosis. According to consensus, recurrence of the tumor and chemotherapy resistance acquisition are the two distinguishing features of GBM originated from glioblastoma stem cells (GSCs). To eliminate these obstacles inherent in GBM chemotherapy, targeting GSCs through a smart drug delivery system has come to the front position of GBM therapeutics. In this study, B19 aptamer (Apt)-conjugated polyamidoamine (PAMAM) G4C12 dendrimer nanoparticles (NPs), called Apt-NPs, were formulated for the co-delivery of paclitaxel (PTX) and temozolomide (TMZ) to U-87 stem cells. These drugs were loaded using a double emulsification solvent evaporation method. As a result, drug-loaded Apt-NPs significantly inhibited the tumor growth of U-87 stem cells, by the initiation of apoptosis via the downregulation of autophagic and multidrug resistance (MDR) genes. Additionally, by their downregulation by qPCR of CD133, CD44, SOX2, and the canonical Wnt/ß-catenin pathway, cell proliferation has substantially decreased. Altogether, the results demonstrate that this intelligent drug co-delivery system is capable of effectively transferring PTX and TMZ to U-87 stem cells and without any toxic effect on Apt-NPs alone to U-87 stem cells. Furthermore, the designed dendrimer-based pharmaceutical system along with single-stranded B19 aptamer might be utilized as a new therapeutic strategy for the treatment of U-87 stem cells drug resistance in the GBM.

Could We Address the Interplay Between CD133, Wnt/ß-Catenin, and TERT Signaling Pathways as a Potential Target for Glioblastoma Therapy?

Glioblastoma multiforme (GBM) is one of the most lethal forms of primary brain tumors. Glioblastoma stem cells (GSCs) play an undeniable role in tumor development by activating multiple signaling pathways such as Wnt/ß-catenin and PI3K/AKT/mTOR that facilitate brain tumor formation. CD133, a transmembrane glycoprotein, has been used to classify cancer stem cells (CSCs) in GBM. The therapeutic value of CD133 is a biomarker of the CSC in multiple cancers. It also leads to growth and recurrence of the tumor. More recent findings have confirmed the association of telomerase/TERT with Wnt/ß-catenin and the PI3K/AKT/mTOR signaling pathways. Advance studies have shown that crosstalk between CD133, Wnt/ß-catenin, and telomerase/TERT can facilitate GBM stemness and lead to therapeutic resistance. Mechanistic insight into signaling mechanisms downstream of surface biomarkers has been revolutionized by facilitating targeting of tumor-specific molecular deregulation. This review also addresses the importance of interplay between CD133, Wnt/ß-catenin and TERT signaling pathways in GSCs and outlines the future therapeutic goals for glioblastoma treatment.

Understanding Glioblastoma Biomarkers: Knocking a Mountain with a Hammer.

Gliomas are the most frequent and deadly form of human primary brain tumors. Among them, the most common and aggressive type is the high-grade glioblastoma multiforme (GBM), which rapidly grows and renders patients a very poor prognosis. Meanwhile, cancer stem cells (CSCs) have been determined in gliomas and play vital roles in driving tumor growth due to their competency in self-renewal and proliferation. Studies of gliomas have recognized CSCs via specific markers. This review comprehensively examines the current knowledge of the most significant CSCs markers in gliomas in general and in glioblastoma in particular and specifically focuses on their outlook and importance in gliomas CSCs research. We suggest that CSCs should be the superior therapeutic approach by directly targeting the markers. In addition, we highlight the association of these markers with each other in relation to their cascading pathways, and interactions with functional miRNAs, providing the role of the networks axes in glioblastoma signaling pathways.