Search results for "Signal Transduction"
showing 10 items of 2020 documents
Intrinsic fluorescence of the clinically approved multikinase inhibitor nintedanib reveals lysosomal sequestration as resistance mechanism in FGFR-dr…
2017
Background Studying the intracellular distribution of pharmacological agents, including anticancer compounds, is of central importance in biomedical research. It constitutes a prerequisite for a better understanding of the molecular mechanisms underlying drug action and resistance development. Hyperactivated fibroblast growth factor receptors (FGFRs) constitute a promising therapy target in several types of malignancies including lung cancer. The clinically approved small-molecule FGFR inhibitor nintedanib exerts strong cytotoxicity in FGFR-driven lung cancer cells. However, subcellular pharmacokinetics of this compound and its impact on therapeutic efficacy remain obscure. Methods 3-dimens…
Fluvastatin prevents glutamate-induced blood-brain-barrier disruption in vitro.
2008
Abstract Glutamate is an important excitatory amino acid in the central nervous system. Under pathological conditions glutamate levels dramatically increase. Aim of the present study was to examine whether the HMG-CoA inhibitor fluvastatin prevents glutamate-induced blood-brain-barrier (BBB) disruption. Measurements of transendothelial electrical resistance (TEER) were performed to analyze BBB integrity in an in vitro co-culture model of brain endothelial and glial cells. Myosin light chain (MLC) phosphorylation was detected by immunohistochemistry, or using the in-cell western technique. Intracellular Ca 2+ and reactive oxygen species (ROS) levels were analyzed using the fluorescence dyes …
A New Oxadiazole-Based Topsentin Derivative Modulates Cyclin-Dependent Kinase 1 Expression and Exerts Cytotoxic Effects on Pancreatic Cancer Cells
2021
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterized by drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emerged as promising pharmacological targets for the treatment of several solid and hematological tumors. Interestingly, cyclin-dependent kinase 1 (CDK1) is overexpressed in PDAC tissues and has been correlated to the aggressive nature of these tumors because of its key role in cell cycle progression and resistance to the induction of apoptosis. For these reasons, CDK1 is one of the main causes of chemoresistance, representing a promising pharmacological target. In this study, we report the synthesis of new 1,2,4…
The regulation of efferocytosis signaling pathways and adipose tissue homeostasis in physiological conditions and obesity: Current understanding and …
2022
Obesity is associated with changes in the resolution of acute inflammation that contribute to the clinical complications. The exact mechanisms underlying unresolved inflammation in obesity are not fully understood. Adipocyte death leads to pro-inflammatory adipose tissue macrophages, stimulating additional adipocyte apoptosis. Thus, a complex and tightly regulated process to inhibit inflammation and maintain homeostasis after adipocyte apoptosis is needed to maintain health. In normal condition, a specialized phagocytic process (efferocytosis) performs this function, clearing necrotic and apoptotic cells (ACs) and controlling inflammation. For efficient and continued efferocytosis, phagocyt…
Role of NF-kappaB in immune and inflammatory responses in the gut.
1998
NF-kappaB is a pleiotropic transcription factor with key functions in the intestinal immune system. NF-kappaB family members control transcriptional activity of various promoters of proinflammatory cytokines, cell surface receptors, transcription factors, and adhesion molecules that are involved in intestinal inflammation. The perpetuated activation of NF-kappaB in patients with active inflammatory bowel disease suggests that regulation of NF-kappaB activity is a very attractive target for therapeutic intervention. Such strategies include antioxidants, proteasome inhibitors, inhibition of NF-kappaB by adenoviral I kappaB alpha expression vectors, and antisense DNA targeting of NF-kappaB. Th…
Differential TNF-Signaling in Chronic Inflammatory Disorders
2004
TNF-alpha is a pleiotropic cytokine with strong proinflammatory and immunomodulatory properties. TNF-alpha plays a critical role in many acute or chronic inflammatory diseases and anti-TNF-strategies have proven to be clinically effective. Two TNF-specific cell surface receptors TNF-R1 and TNF-R2 have been identified and the function of these receptors and the downstream intracellular signal transduction pathways have been extensively studied in vitro. For a long time TNF-R1 was considered to be the predominant mediator of TNF-signaling, whereas TNF-R2 was ascribed only auxilliary function. However, there is increasing clinical and experimental evidence for an important independent role of …
Cytokines and Neurotrophins Interact in Normal and Diseased States
2006
Neurotrophins (NTs) such as nerve growth factor (NGF) as well as cytokines, for example, interleukin-6 (IL-6), are communicators between the nervous and immune systems. There is evidence for mutual interactions between NTs and cytokines. Strategies are being developed to elucidate the molecular mechanism/s of interactions and to understand how cytokines are involved in health and disease. Analysis of underlying signaling pathways in glial cells indicates that different transcription factors, such as NF-kappa B, cAMP-responsive-element binding protein (CREB), and activator protein 1 (AP-1), are involved in NT induction. IL-6 and NTs of the NGF family are coexpressed at sites of nerve injury.…
Anti-inflammatory Therapies for Cardiovascular Disease: Signaling Pathways and Mechanisms
2019
Cardiovascular diseases (CVD) are the clinical manifestation of atherosclerosis, a chronic inflammatory disease promoted by several risk factors such as dyslipidemia, type 2 diabetes mellitus, hypertension, and smoking. Acute CVD events are the result of an unresolved inflammatory chronic state that promotes the rupture of unstable plaque lesions. Of note, the existing intensive therapies modify risk factors but do not prevent life-threatening recurrent ischemic events in high-risk patients, who have a residual inflammatory risk displayed by increased C-reactive protein (CRP) levels. Better understanding of the role of innate and adaptive immunity in plaque development and rupture has led t…
Cross-talk between oxidative stress and pro-inflammatory cytokines in acute pancreatitis: a key role for protein phosphatases.
2009
Acute pancreatitis is an acute inflammatory process localized in the pancreatic gland that frequently involves peripancreatic tissues. It is still under investigation why an episode of acute pancreatitis remains mild affecting only the pancreas or progresses to a severe form leading to multiple organ failure and death. Proinflammatory cytokines and oxidative stress play a pivotal role in the early pathophysiological events of the disease. Cytokines such as interleukin 1beta and tumor necrosis factor alpha initiate and propagate almost all consequences of the systemic inflammatory response syndrome. On the other hand, depletion of pancreatic glutathione is an early hallmark of acute pancreat…
The inhibitor of differentiation-1 (Id1) enables lung cancer liver colonization through activation of an EMT program in tumor cells and establishment…
2017
Abstract: Id1 promotes carcinogenesis and metastasis, and predicts prognosis of non-small cell lung cancer (NSCLC)-adenocarcionoma patients. We hypothesized that Id1 may play a critical role in lung cancer colonization of the liver by affecting both tumor cells and the microenvironment. Depleted levels of Id1 in LLC (Lewis lung carcinoma cells, LLC shId1) significantly reduced cell proliferation and migration in vitro. Genetic loss of Id1 in the host tissue (Id1(-/-) mice) impaired liver colonization and increased survival of Id1 animals. Histologically, the presence of Idl in tumor cells of liver metastasis was responsible for liver colonization. Microarray analysis comparing liver tumor n…