Pathophysiology of Tumor Neovascularization

Neovascularization is essential to the process of development and differentiation of tissues in the vertebrate embryo, and is also involved in a wide variety of physiological and pathological conditions in adults, including wound repair, metabolic diseases, inflammation, cardiovascular disorders, and tumor progression. Thanks to cumulative studies on vasculature, new therapeutic approaches have been opened for us to some life-threatening diseases by controlling angiogenesis in the affected organs. In cancer therapy, for example, modulation of factors responsible for tumor angiogenesis may be beneficial in inhibiting of tumor progression. Several antiangiogenic approaches are currently under preclinical trial. However, the mechanisms of neovascularization in tumors are complicated and each tumor shows unique features in its vasculature, depending on tissue specificity, angiogenic micromilieu, grades and stages, host immunity, and so on. For better understanding and effective therapeutic approaches, it is important to clarify both the general mechanism of angiogenic events and the disease-specific mechanism of neovascularization. This review discusses the general features of angiogenesis under physiological and pathological conditions, mainly in tumor progression. In addition, recent topics such as contribution of the endothelial progenitor cells, tumor vasculogenic mimicry, markers for tumor-derived endothelial cells and pericytes, and angiogenic/angiostatic chemokines are summarized

Stress-Activated Protein Kinases in Spinal Cord Injury: Focus on Roles of p38

Spinal cord injury (SCI) consists of three phases—acute, secondary, and chronic damages—and limiting the development of secondary damage possibly improves functional recovery after SCI. A major component of the secondary phase of SCI is regarded as inflammation-triggered events: induction of cytokines, edema, microglial activation, apoptosis of cells including oligodendrocytes and neurons, demyelination, formation of the astrocytic scar, and so on. Two major stress-activated protein kinases (SAPKs)—c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK)—are activated in various types of cells in response to cellular stresses such as apoptotic stimuli and inflammatory waves. In animal models of SCI, inhibition of either JNK or p38 has been shown to promote neuroprotection-associated functional recovery. Here, we provide an overview on the roles of SAPKs in SCI and, in particular, the pathological role of p38 will be discussed as a promising target for therapeutic intervention in SCI

Endothelin B receptor-mediated encephalopathic events in mouse sepsis model

AbstractAimsWe evaluated whether pathophysiological events in the brain in sepsis are mediated by ET-1/ETB receptor axis.Main methodsWe prepared raw fecal fluid from soft stool of mice. Mice were randomly divided into three groups: pre-PBS+raw fecal fluid group (Sepsis, easy stool method (ESM) group); pre-BQ788+raw fecal fluid group (BQ group); and pre-BQ788+PBS group (PBS group). According to each experimental condition, PBS or BQ788 was intravenously injected into mice prior to intraperitoneal administration of fecal fluid or PBS. All groups of mice were sacrificed at 8h after administration, and then brain samples were prepared.Key findingsIn the ESM group, an increase of apoptotic neuroblasts was demonstrated in the subgranular zone of the hippocampal dentate gyrus, enhanced expression of c-FOS was observed in arginine-vasopressin-containing neurons in the hypothalamic paraventricular nucleus, and various cytokines involving TNF-α were upregulated in the brain, compared with those in the PBS group. In the region corresponding to their findings, the number of reactive microglia and vascular leakage was markedly increased. BQ788 inhibited the induction of c-FOS expression, neuroblast apoptosis, cytokine upregulation and reactive microglia without affecting vascular leakage.SignificanceWe demonstrated that BQ788 could protect the brain from the following sepsis-associated pathophysiological output: neural cell death, inflammatory response and the Hans Selye's environmental stress reaction