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.

Impaired Endothelium-Dependent Hyperpolarization Underlies Endothelial Dysfunction during Early Metabolic Challenge: Increased ROS Generation and Possible Interference with NO Function.

Endothelial dysfunction is a hallmark of diabetic vasculopathies. Although hyperglycemia is believed to be the culprit causing endothelial damage, the mechanism underlying early endothelial insult in prediabetes remains obscure. We used a nonobese high-calorie (HC)-fed rat model with hyperinsulinemia, hypercholesterolemia, and delayed development of hyperglycemia to unravel this mechanism.

EMT Markers in Locally-Advanced Prostate Cancer: Predicting Recurrence?

Prostate cancer (PCa) is the second most frequent cause of cancer-related death in men worldwide. It is a heterogeneous disease at molecular and clinical levels which makes its prognosis and treatment outcome hard to predict. The epithelial-to-mesenchymal transition (EMT) marks a key step in the invasion and malignant progression of PCa.

The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease.

The mammalian HSP90 family of proteins is a cluster of highly conserved molecules that are involved in myriad cellular processes. Their distribution in various cellular compartments underlines their essential roles in cellular homeostasis. HSP90 and its co-chaperones orchestrate crucial physiological processes such as cell survival, cell cycle control, hormone signaling, and apoptosis.

Cross-talk between intestinal epithelial cells and immune cells in inflammatory bowel disease.

Inflammatory bowel disease (IBD) involves functional impairment of intestinal epithelial cells (IECs), concomitant with the infiltration of the lamina propria by inflammatory cells. We explored the reciprocal paracrine and direct interaction between human IECs and macrophages (MΦ) in a co-culture system that mimics some aspects of IBD. We investigated the expression of intercellular junctional proteins in cultured IECs under inflammatory conditions and in tissues from IBD patients.

Ziv-aflibercept in macular disease.

Background/aims: Aflibercept is an approved therapy for neovascular age-related macular degeneration (AMD) and diabetic macular oedema (DME). In vitro and in vivo studies did not detect toxicity to the retinal pigment epithelium cells using the approved cancer protein, ziv-aflibercept. Our purpose is to determine if ziv-aflibercept can be used in AMD and DME without ocular toxicity, to test the stability of ziv-aflibercept, and to do a cost analysis.

Context dependent reversion of tumor phenotype by connexin-43 expression in MDA-MB231 cells and MCF-7 cells: role of β-catenin/connexin43 association.

Connexins (Cx), gap junction (GJ) proteins, are regarded as tumor suppressors, and Cx43 expression is often down regulated in breast tumors. We assessed the effect of Cx43 over-expression in 2D and 3D cultures of two breast adenocarcinoma cell lines: MCF-7 and MDA-MB-231. While Cx43 over-expression decreased proliferation of 2D and 3D cultures of MCF-7 by 56% and 80% respectively, MDA-MB-231 growth was not altered in 2D cultures, but exhibited 35% reduction in 3D cultures.

Connexins: a junctional crossroad to breast cancer.

The mammary gland presents a valuable model for developmental studies, spanning the embryonic stage through menarche to menopause. The dynamic remodeling of this gland is orchestrated by cellular heterogeneity, integrating mammogenic, systemic and local cues. Gap junctional intercellular communication provides pivotal cross talk of mammary epithelial cells with the surrounding cells and their local microenvironment.

Gap junctions mediate STAT5-independent β-casein expression in CID-9 mammary epithelial cells.

Crosstalk between gap junction intracellular communication (GJIC), STAT5 and OCT-1 in gap junction (GJ)-dependent β-casein expression was investigated. CID-9 mammary cells plated with prolactin on non-adherent substratum (poly-HEMA) expressed β-casein independent of STAT5 only in the presence of the GJIC inducer, cAMP. Nuclear STAT5 levels were not detectable.

Differential expression of hippocampal connexins after acute hypoxia in the developing brain.

Acute hypoxia at postnatal day (P) 10 is an accepted model of human neonatal hypoxia which results, among other consequences, in increased hippocampal excitability. Hypoxic-ischemic injury, which mimics stroke, has been shown to result in changes in connexins (Cxs), however, changes in Cxs have not been studied in the P10 hypoxia model. The aim of this study was to investigate changes in the hippocampal expression of three different connexins at consecutive developmental stages after acute hypoxia at P10 (10min and 30min after reoxygenation, P11, P14, P17, P29, and P45) as compared to sham manipulated pups.

Connexins: a myriad of functions extending beyond assembly of gap junction channels.

Connexins constitute a large family of trans-membrane proteins that allow intercellular communication and the transfer of ions and small signaling molecules between cells. Recent studies have revealed complex translational and post-translational mechanisms that regulate connexin synthesis, maturation, membrane transport and degradation that in turn modulate gap junction intercellular communication. With the growing myriad of connexin interacting proteins, including cytoskeletal elements, junctional proteins, and enzymes, gap junctions are now perceived, not only as channels between neighboring cells, but as signaling complexes that regulate cell function and transformation.

Transient increase in cytokines and nerve growth factor in the rat dorsal root ganglia after nerve lesion and peripheral inflammation.

Inflammatory response occurs, in general, at the peripheral site of injury or irritation and in the corresponding spinal dorsal horn segments. In this study, we show transient increases in the protein concentrations of interleukins 1beta, 6, 8 and NGF in lumbar DRGs within hours after sciatic mononeuropathy in the rat. Comparable increases, with variation in temporal patterns, were observed after skin inflammation induced by intraplantar injection of endotoxin or complete Freund's adjuvant.

Heterocellular interaction enhances recruitment of alpha and beta-catenins and ZO-2 into functional gap-junction complexes and induces gap junction-dependant differentiation of mammary epithelial cells.

Gap junctions (GJ) are required for mammary epithelial differentiation. Using epithelial (SCp2) and myoepithelial-like (SCg6) mouse-derived mammary cells, the role of heterocellular interaction in assembly of GJ complexes and functional differentiation (beta-casein expression) was evaluated. Heterocellular interaction is critical for beta-casein expression, independent of exogenous basement membrane or cell anchoring substrata.

EAPB0203, a member of the imidazoquinoxaline family, inhibits growth and induces caspase-dependent apoptosis in T-cell lymphomas and HTLV-I-associated adult T-cell leukemia/lymphoma.

Imiquimod is an immune response modifier currently used as a topical treatment of genital warts, basal cell carcinoma, cutaneous metastasis of malignant melanoma, and vascular tumors. We developed more efficient killers from the same family of compounds that can induce apoptosis without the prominent pro-inflammatory response associated with imiquimod. Among these new products, tk;4EAPB0203, a member of the imidazo[1,2-a]quinoxalines, exhibits an important cytotoxic activity in vitro.

Gap junctional intercellular communication in hypoxia-ischemia-induced neuronal injury.

Brain hypoxia-ischemia is a relatively common and serious problem in neonates and in adults. Its consequences include long-term histological and behavioral changes and reduction in seizure threshold. Gap junction intercellular communication is pivotal in the spread of hypoxia-ischemia related injury and in mediating its long-term effects.

Xenogenic bone matrix extracts induce osteoblastic differentiation of human bone marrow-derived mesenchymal stem cells.

Colloss and Colloss-E are sterile acellular lyophilizates extracted from bovine and equine bone matrix, respectively. Animal and clinical studies have shown that these xenogenic bone matrix extracts (BMEs) are effective as bone graft substitutes. In this report, we investigated the effect of Colloss and Colloss-E on human adult in vitro-expanded bone marrow-derived mesenchymal stem cells (BMMSCs).

Ascorbic acid induces apoptosis in adult T-cell leukemia.

Background: Adult T-cell leukemia (ATL) is an acute malignancy of activated T-cells caused by the human T-cell lymphotrophic virus type-1 (HTLV-1).

Materials And Methods: The effects of non-cytotoxic concentrations of ascorbic acid (AA) were evaluated against HTLV-1 positive and negative cells. The effect of AA on apoptosis and proliferation was evaluated by cell cycle analysis.

Effects of a single dose of erythropoietin on subsequent seizure susceptibility in rats exposed to acute hypoxia at P10.

Purpose: To determine if posthypoxia treatment with erythropoietin (EPO) has protective effects against subsequent susceptibility to seizure related neuronal injury in rat pups subjected to acute hypoxia at P10.

Methods: Four groups of rats were manipulated at P10, as described below, then all received kainic acid (KA) (10 mg/kg i.p.

Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma.

HTLV-I associated adult T-cell leukemia (ATL) and HTLV-I-negative peripheral T-cell lymphomas are associated with poor prognosis. Using pharmacological concentrations of the proteasome inhibitor PS-341, we demonstrate inhibition of cell proliferation and induction of apoptosis in fresh ATL cells, HTLV-I transformed and HTLV-I-negative malignant T cells, while normal resting or activated T lymphocytes were resistant. Combination of PS-341 and doxorubicin or etoposide resulted in an additive growth inhibition.

New therapeutic approaches for adult T-cell leukaemia.

Adult T-cell leukaemia or lymphoma is an aggressive malignant disease of mature activated T cells caused by human T-cell lymphotropic virus type I. Patients with this disease have a very poor outlook because of intrinsic chemoresistance and severe immunosuppression. In acute adult T-cell leukaemia, clinical trials in Japan show that although non-targeted combinations of chemotherapy improve response, they do not have a significant effect on complete remission and survival.

Developmental expression patterns and regulation of connexins in the mouse mammary gland: expression of connexin30 in lactogenesis.

The mammary gland reaches a fully differentiated phenotype at lactation, a stage characterized by the abundant expression of beta-casein. We have investigated the expression and regulation of gap junction proteins (connexins, Cx) during the various developmental stages of mouse mammary gland. Immunohistochemical analysis, with specific antibodies, reveals that Cx26 and Cx32 are expressed and confined to the cell borders of luminal epithelial cells in all developmental stages of the gland.

Ceramide inhibits IL-2 production by preventing protein kinase C-dependent NF-kappaB activation: possible role in protein kinase Ctheta regulation.

The role of the sphingolipid ceramide in modulating the immune response has been controversial, in part because of conflicting data regarding its ability to regulate the transcription factor NF-kappaB. To help clarify this role, we investigated the effects of ceramide on IL-2, a central NF-kappaB target. We found that ceramide inhibited protein kinase C (PKC)-mediated activation of NF-kappaB.

Human T-cell lymphotropic virus type I-infected cells extravasate through the endothelial barrier by a local angiogenesis-like mechanism.

Extravasation of tumor cells through the endothelial barrier is a critical step in cancer metastasis. Human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL) is an aggressive disease characterized by visceral invasion. We show that ATL and HTLV-I-associated myelopathy patients exhibit high plasma levels of functional vascular endothelial growth factor and basic fibroblast growth factor.

Developmental regulation of gap junctions and their role in mammary epithelial cell differentiation.

Gap junctions play a critical role in the development and differentiation of many tissues. Formed by the joining of two connexons on opposing membranes of two cells, gap junctions permit passage of ions and small molecules. Six connexins (Cx) belonging to a family of closely related tetraspan transmembrane proteins form a connexon.

Regulation of nuclear factor-kappaB in intestinal epithelial cells in a cell model of inflammation.

Background: Interleukin-1 (IL-1), an inflammatory cytokine whose levels are elevated in inflamed mucosa, causes part of its effect on intestinal epithelial cells (IEC) through inducing ceramide production.

Aim: To study the role of nuclear factor-kappaB (NF-kappaB), a pro-inflammatory and anti-apoptotic factor, in IL-1-treated IEC.

Methods: NF-kappaB activity and levels of apoptotic proteins were assessed by electrophoretic mobility shift assay and RNA-protection assay, respectively.