Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing.

Structural modifications of the antibacterial drug nitrofurantoin were envisioned, employing drug repurposing and biology-oriented drug synthesis, to serve as possible anticancer agents. Eleven compounds showed superior safety in non-cancerous human cells. Their antitumor efficacy was assessed on colorectal, breast, cervical, and liver cancer cells. Three compounds induced oxidative DNA damage in cancer cells with subsequent cellular apoptosis. They also upregulated the expression of Bax while downregulated that of Bcl-2 along with activating caspase 3/7. The DNA damage induced by these compounds, demonstrated by pATM nuclear shuttling, was comparable in both MCF7 and MDA-MB-231 (p53 mutant) cell lines. Mechanistic studies confirmed the dependence of these compounds on p53-mediated pathways as they suppressed the p53-MDM2 interaction. Indeed, exposure of radiosensitive prostatic cancer cells to low non-cytotoxic concentrations of compound 1 enhanced the cytotoxic response to radiation indicating a possible synergistic effect. In vivo antitumor activity was verified in an MCF7-xenograft animal model.

Pathophysiology of Coagulation and Emerging Roles for Extracellular Vesicles in Coagulation Cascades and Disorders.

The notion of blood coagulation dates back to the ancient Greek civilization. However, the emergence of innovative scientific discoveries that started in the seventeenth century formulated the fundamentals of blood coagulation. Our understanding of key coagulation processes continues to evolve, as novel homeostatic and pathophysiological aspects of hemostasis are revealed. Hemostasis is a dynamic physiological process, which stops bleeding at the site of injury while maintaining normal blood flow within the body. Intrinsic and extrinsic coagulation pathways culminate in the homeostatic cessation of blood loss, through the sequential activation of the coagulation factors. Recently, the cell-based theory, which combines these two pathways, along with newly discovered mechanisms, emerged to holistically describe intricate in vivo coagulation mechanisms. The complexity of these mechanisms becomes evident in coagulation diseases such as hemophilia, Von Willebrand disease, thrombophilia, and vitamin K deficiency, in which excessive bleeding, thrombosis, or unnecessary clotting, drive the development and progression of diseases. Accumulating evidence implicates cell-derived and platelet-derived extracellular vesicles (EVs), which comprise microvesicles (MVs), exosomes, and apoptotic bodies, in the modulation of the coagulation cascade in hemostasis and thrombosis. As these EVs are associated with intercellular communication, molecular recycling, and metastatic niche creation, emerging evidence explores EVs as valuable diagnostic and therapeutic approaches in thrombotic and prothrombotic diseases.

Hippocampal injury and learning deficits following non-convulsive status epilepticus in periadolescent rats.

The effects of non-convulsive status epilepticus (NCSE) on the developing brain remain largely elusive. Here we investigated potential hippocampal injury and learning deficits following one or two episodes of NCSE in periadolescent rats. Non-convulsive status epilepticus was induced with subconvulsive doses of intrahippocampal kainic acid (KA) under continuous EEG monitoring in postnatal day 43 (P43) rats. The RKA group (repeated KA) received intrahippocampal KA at P43 and P44, the SKA group (single KA injection) received KA at P43 and an intrahippocampal saline injection at P44. Controls were sham-treated with saline. The modified two-way active avoidance (MAAV) test was conducted between P45 and P52 to assess learning of context-cued and tone-signaled electrical foot-shock avoidance. Histological analyses were performed at P52 to assess hippocampal neuronal densities, as well as potential reactive astrocytosis and synaptic dysfunction with GFAP (glial fibrillary acidic protein) and synaptophysin (Syp) staining, respectively. Kainic acid injections resulted in electroclinical seizures characterized by behavioral arrest, oromotor automatisms and salivation, without tonic-clonic activity. Compared to controls, both the SKA and RKA groups had lower rates of tone-signaled shock avoidance (p < 0.05). In contextual testing, SKA rats were comparable to controls (p > 0.05), but the RKA group had learning deficits (p < 0.05). Hippocampal neuronal densities were comparable in all groups. Compared to controls, both the SKA and RKA groups had higher hippocampal GFAP levels (p < 0.05). The RKA group also had lower hippocampal Syp levels compared to the SKA and control groups (p < 0.05), which were comparable (p > 0.05). We show that hippocampal NCSE in periadolescent rats results in a seizure burden-dependent hippocampal injury accompanied by cognitive deficits. Our data suggest that the diagnosis and treatment of NCSE should be prompt.

Adipose Tissue Immunomodulation: A Novel Therapeutic Approach in Cardiovascular and Metabolic Diseases.

Adipose tissue is a critical regulator of systemic metabolism and bodily homeostasis as it secretes a myriad of adipokines, including inflammatory and anti-inflammatory cytokines. As the main storage pool of lipids, subcutaneous and visceral adipose tissues undergo marked hypertrophy and hyperplasia in response to nutritional excess leading to hypoxia, adipokine dysregulation, and subsequent low-grade inflammation that is characterized by increased infiltration and activation of innate and adaptive immune cells. The specific localization, physiology, susceptibility to inflammation and the heterogeneity of the inflammatory cell population of each adipose depot are unique and thus dictate the possible complications of adipose tissue chronic inflammation. Several lines of evidence link visceral and particularly perivascular, pericardial, and perirenal adipose tissue inflammation to the development of metabolic syndrome, insulin resistance, type 2 diabetes and cardiovascular diseases. In addition to the implication of the immune system in the regulation of adipose tissue function, adipose tissue immune components are pivotal in detrimental or otherwise favorable adipose tissue remodeling and thermogenesis. Adipose tissue resident and infiltrating immune cells undergo metabolic and morphological adaptation based on the systemic energy status and thus a better comprehension of the metabolic regulation of immune cells in adipose tissues is pivotal to address complications of chronic adipose tissue inflammation. In this review, we discuss the role of adipose innate and adaptive immune cells across various physiological and pathophysiological states that pertain to the development or progression of cardiovascular diseases associated with metabolic disorders. Understanding such mechanisms allows for the exploitation of the adipose tissue-immune system crosstalk, exploring how the adipose immune system might be targeted as a strategy to treat cardiovascular derangements associated with metabolic dysfunctions.

Arginine deprivation: a potential therapeutic for cancer cell metastasis? A review.

Arginine is a semi essential amino acid that is used in protein biosynthesis. It can be obtained from daily food intake or synthesized in the body through the urea cycle using l-citrulline as a substrate. Arginine has a versatile role in the body because it helps in cell division, wound healing, ammonia disposal, immune system, and hormone biosynthesis. It is noteworthy that l-arginine is the precursor for the biosynthesis of nitric oxide (NO) and polyamines. In the case of cancer cells, arginine de novo synthesis is not enough to compensate for their high nutritional needs, forcing them to rely on extracellular supply of arginine. In this review, we will go through the importance of arginine deprivation as a novel targeting therapy by discussing the different arginine deprivation agents and their mechanism of action. We will also focus on the factors that affect cell migration and on the influence of arginine on metastases through polyamine and NO.

The Role of Rho GTPases in Motility and Invasion of Glioblastoma Cells.

Astrocytomas are primary malignant brain tumors that originate from astrocytes. Grade IV astrocytoma or glioblastoma is a highly invasive tumor that occur within the brain parenchyma. The Rho family of small GTPases, which includes Rac1, Cdc42, and RhoA, is an important family whose members are key regulators of the invasion and migration of glioblastoma cells. In this review, we describe the role played by the Rho family of GTPases in the regulation of the invasion and migration of glioblastoma cells. Specifically, we focus on the role played by RhoA, Rac1, RhoG, and Cdc42 in cell migration through rearrangement of actin cytoskeleton, cell adhesion, and invasion. Finally, we highlight the importance of potentially targeting Rho GTPases in the treatment of glioblastoma.

Human Recombinant Arginase I [HuArgI (Co)-PEG5000]-Induced Arginine Depletion Inhibits Colorectal Cancer Cell Migration and Invasion.

PURPOSE: Colorectal cancer (CRC) is the third most common type of cancer worldwide, and it represents over half of all gastrointestinal cancer deaths. Knowing that cancer cells have a high proliferation rate, they require high amounts of amino acids, including arginine. In addition, several tumor types have been shown to downregulate ASS-1 expression, becoming auxotrophic for arginine. Therefore, Arginine deprivation is one of the promising therapeutic approaches to target cancer cells. This can be achieved through the use of a recombinant human arginase, HuArgI(Co)-PEG5000, an arginine degrading enzyme. METHODS: In this present study, the cytotoxic effect of HuArgI(Co)-PEG5000 on CRC cell lines (HT-29, Caco-2, Sw837) is examined though cytotoxicity assays. Wound healing assays, invasion assays, and adhesion assays were also performed to detect the effect on metastasis. RESULTS: Wound healing and invasion assays revealed a decrease in cell migration and invasion after treatment with arginase. Cells that were treated with arginase also showed a decrease in adhesion, which coincided with a decrease in RhoA activation, demonstrated though the use of a FRET biosensor to detect RhoA activation in a single cell assay, and a decrease in MMP-9 expression. Treating cells with both arginase and L-citrulline, which significantly restores intracellular arginine levels, reversed the effect of HuArgI(Co)-PEG5000 on cell viability, migration, and invasion. CONCLUSION: We can, therefore, conclude that colorectal cancer is partially auxotrophic to arginine and that arginine depletion is a potential selective inhibitory approach for motility and invasion in colon cancer cells.