Mineralocorticoid receptor activation restores medial perforant path LTP in diabetic rats.

In the hippocampus, glucocorticoids bind to two types of receptors: the mineralocorticoid receptor, which binds corticosterone with high affinity and is tonically occupied; and the glucocorticoid receptor, which is occupied during stress and at certain phases in the circadian cycle. Diabetes mellitus increases levels of glucocorticoids in both humans and animal models. To explore the contributions of hippocampal corticosteroid receptors to the diabetes-induced suppression of neuroplasticity, we manipulated these receptors in hippocampal slices from streptozocin-diabetic rats, a model of Type 1 diabetes mellitus.

Age and energy intake interact to modify cell stress pathways and stroke outcome.

Objective: Age and excessive energy intake/obesity are risk factors for cerebrovascular disease, but it is not known if and how these factors affect the extent of brain damage and outcome in ischemic stroke. We therefore determined the interactions of age and energy intake on the outcome of ischemic brain injury, and elucidated the underlying mechanisms.

Methods: We utilized a novel microchip-based immunoaffinity capillary electrophoresis technology to measure a panel of neurotrophic factors, cytokines, and cellular stress resistance proteins in brain tissue samples from young, middle-aged, and old mice that had been maintained on control or energy-restricted diets prior to middle cerebral artery occlusion and reperfusion.

Plumbagin, a novel Nrf2/ARE activator, protects against cerebral ischemia.

Many phytochemicals function as noxious agents that protect plants against insects and other damaging organisms. However, at subtoxic doses, the same phytochemicals may activate adaptive cellular stress response pathways that can protect cells against a variety of adverse conditions. We screened a panel of botanical pesticides using cultured human and rodent neuronal cell models, and identified plumbagin as a novel potent activator of the nuclear factor E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway.

The wheat germ cell-free protein synthesis system: a key tool for novel malaria vaccine candidate discovery.

Malaria kills more than a million people a year, causes malady in about three hundred million people and poses risk to approximately 40% of the world's population living in malarious countries. This disease is re-emerging mainly due to the development of drug-resistant parasites and insecticide-resistant mosquitoes. Therefore, we are now forced to resort to remedy through vaccination.

Wheat germ cell-free technology for accelerating the malaria vaccine research.

Background: Malaria causes about 300 million illnesses and 1 million deaths annually. The likeliest scenario is the aggravation of this disease due to the re-emergence of drug-resistant parasites and insecticide-resistant mosquitoes. One of the promising solutions to this disease are vaccines.

Alzheimer's disease and Notch signaling.

Cleavage of the amyloid precursor protein (APP) by gamma-secretase generates a neurotoxic amyloid beta-peptide (Abeta) that is thought to be associated with the neurodegeneration observed in Alzheimer's disease (AD) patients. Presenilin is the catalytic member of the gamma-secretase proteolytic complex and mutations in presenilins are the major cause of early-onset familial Alzheimer's disease. In addition to APP, gamma-secretase substrates include Notch1 homologues, Notch ligands Delta and Jagged, and additional type I membrane proteins, raising concerns about mechanism-based toxicities that might arise as a consequence of inhibiting gamma-secretase.

The ADMR receptor mediates the effects of adrenomedullin on pancreatic cancer cells and on cells of the tumor microenvironment.

Background: Adrenomedullin (AM) is highly expressed in pancreatic cancer and stimulates pancreatic cancer cells leading to increased tumor growth and metastasis. The current study examines the role of specific AM receptors on tumor and cells resembling the tumor microenvironment (human pancreatic stellate--HPSC, human umbilical vein-- HUVEC and mouse lung endothelial cells--MLEC).

Methods And Findings: AM receptors ADMR and CRLR were present in HPSC, HUVEC and MLECs while PDAC cells possessed only ADMR receptors as assessed by RT-PCR and western blotting.

Involvement of Fc receptors in disorders of the central nervous system.

Immunoglobulins are proteins with a highly variable antigen-binding domain and a constant region (Fc domain) that binds to a cell surface receptor (FcR). Activation of FcRs in immune cells (lymphocytes, macrophages, and mast cells) triggers effector responses including cytokine production, phagocytosis, and degranulation. In addition to their roles in normal responses to infection or tissue injury, and in immune-related diseases, FcRs are increasingly recognized for their involvement in neurological disorders.

Pivotal role for beta-1 integrin in neurovascular remodelling after ischemic stroke.

beta1 integrin is a cell surface molecule that is critical for endothelial cell adhesion, migration and survival during angiogenesis. In the present study we employed in vivo and in vitro models to elucidate the role of beta1 integrin in vascular remodelling and stroke outcomes. At 24 h after cerebral ischemia and reperfusion (I/R), the ischemic cortex (ipsilateral area) exhibited modest beta1 integrin immunoreactivity and a robust increase was observed at 72 h.

Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer.

A better understanding of drug resistance mechanisms is required to improve outcomes in patients with pancreatic cancer. Here, we characterized patterns of sensitivity and resistance to three conventional chemotherapeutic agents with divergent mechanisms of action [gemcitabine, 5-fluorouracil (5-FU), and cisplatin] in pancreatic cancer cells. Four (L3.

The homocysteine-inducible endoplasmic reticulum stress protein counteracts calcium store depletion and induction of CCAAT enhancer-binding protein homologous protein in a neurotoxin model of Parkinson disease.

The endoplasmic reticulum (ER) is a key organelle regulating intracellular Ca(2+) homeostasis. Oxidants and mitochondria-derived free radicals can target ER-based Ca(2+) regulatory proteins and cause uncontrolled Ca(2+) release that may contribute to protracted ER stress and apoptosis. Several ER stress proteins have been suggested to counteract the deregulation of ER Ca(2+) homeostasis and ER stress.

Temporal and spatial dynamics of cerebral immune cell accumulation in stroke.

Background And Purpose: Ischemic stroke leads to significant morbidity and mortality in the Western world. Early reperfusion strategies remain the treatment of choice but can initiate and augment an inflammatory response causing secondary brain damage. The understanding of postischemic inflammation is very limited.

Aspirin inhibits camptothecin-induced p21CIP1 levels and potentiates apoptosis in human breast cancer cells.

The ability of aspirin to trigger apoptosis in cancer cells is well known and is consistent with the clinical and epidemiological evidence on its chemopreventive effects in curtailing epithelial cancers, including breast cancer. We hypothesized that the anticancer effects of aspirin may involve acetylation of the tumor suppressor protein p53, a known regulator of apoptosis. In the present study, we determined if aspirin at the physiologically achievable concentration of 100 microM acetylates p53 and modulates the expression of p21CIP1, a protein involved in cell cycle arrest, and Bax, a pro-apoptotic protein.

Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation.

Toll-like receptors (TLRs) play important roles in innate immunity. Several TLR family members have recently been shown to be expressed by neurons and glial cells in the adult brain, and may mediate responses of these cells to injury and infection. To address the possibility that TLRs play a functional role in development of the nervous system, we analyzed the expression of TLRs during different stages of mouse brain development and assessed the role of TLRs in cell proliferation.

Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells.

Purpose: Nuclear factor kappaB (NFkappaB) activity may increase survival and protect cancer cells from chemotherapy. Therefore, NFkappaB activity may be prognostic, and inhibition of NFkappaB may be useful for pancreatic cancer therapy. To test these hypotheses, we examined NFkappaB activity and the effects of inhibiting NFkappaB in several pancreatic cancer cell lines with differing sensitivities to gemcitabine.

Neuropilin-2-mediated tumor growth and angiogenesis in pancreatic adenocarcinoma.

Purpose: Neuropilin-2 (NRP-2) is a coreceptor for vascular endothelial growth factor (VEGF) on endothelial cells. NRP-2 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) cells relative to nonmalignant ductal epithelium. This study determined the role of NRP-2 in PDAC cells.

Toll-like receptors in ischemia-reperfusion injury.

Ischemia-reperfusion (I/R) injuries are implicated in a large array of pathological conditions such as myocardial infarction, cerebral stroke, and hepatic, renal, and intestinal ischemia, as well as following cardiovascular and transplant surgeries. The hallmark of these pathologies is excessive inflammation. Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced inflammation and, more recently, injury-induced inflammation.

Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival.

Pancreatic cancer is a major oncological challenge due to its aggressive growth and metastasis. In the current study, we investigated the role of anterior gradient 2 (AGR2) in these processes. AGR2 mRNA, as assessed by quantitative real-time reverse transcription-PCR (Q-RT-PCR), was 14-fold higher in pancreatic cancer compared with normal and pancreatitis tissues.

Toll-like receptors in neurodegeneration.

The key roles of toll-like receptors (TLRs) as mediators of the detection and responses of immune cells to invading pathogens are well known. There are at least 13 mammalian TLRs which are integral membrane proteins with a leucine-rich extracellular domain and a cytoplasmic domain similar to that of the interleukin-1 receptor which initiates downstream signaling through kinases to activate transcription factors such as AP-1 and NFkappaB. TLRs are activated in glial cells (microglia, astrocytes and oligodendrocytes) and lymphocytes that infiltrate the nervous system in response to inflammation caused by infectious agents, tissue injury or autoimmune conditions.

Lifelong running reduces oxidative stress and degenerative changes in the testes of mice.

Regular exercise can counteract the adverse effects of aging on the musculoskeletal and cardiovascular systems. In males, the normal aging process is associated with reductions in testosterone production and impaired spermatogenesis, but the underlying mechanisms and their potential modification by exercise are unknown. Here, we report that lifelong regular exercise (running) protects the testes against the adverse effects of advancing age, and that this effect of running is associated with decreased amounts of oxidative damage to proteins, lipids, and DNA in spermatogenic and Leydig cells.

Neuroprotection in stroke by complement inhibition and immunoglobulin therapy.

Activation of the complement system occurs in a variety of neuroinflammatory diseases and neurodegenerative processes of the CNS. Studies in the last decade have demonstrated that essentially all of the activation components and receptors of the complement system are produced by astrocytes, microglia, and neurons. There is also rapidly growing evidence to indicate an active role of the complement system in cerebral ischemic injury.

Evidence that gamma-secretase mediates oxidative stress-induced beta-secretase expression in Alzheimer's disease.

Beta-secretase (BACE1), an enzyme responsible for the production of amyloid beta-peptide (Abeta), is increased by oxidative stress and is elevated in the brains of patients with sporadic Alzheimer's disease (AD). Here, we show that oxidative stress fails to induce BACE1 expression in presenilin-1 (gamma-secretase)-deficient cells and in normal cells treated with gamma-secretase inhibitors. Oxidative stress-induced beta-secretase activity and sAPPbeta levels were suppressed by gamma-secretase inhibitors.

Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal.

The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We recently found that neurons express several TLRs, and that the levels of TLR2 and TLR4 are increased in neurons in response to energy deprivation. Here we report that TLR4 expression increases in neurons when exposed to amyloid beta-peptide (Abeta1-42) or the lipid peroxidation product 4-hydroxynonenal (HNE).

RAGE and RAGE ligands in cancer.

The receptor for advanced glycation end-products (RAGE) is a multifunctional receptor with multiple ligands that is known to play a key role in several diseases, including diabetes, arthritis, and Alzheimer's disease. Recent evidence indicates that this receptor also has an important role in cancer. RAGE ligands, which include the S100/calgranulins and high-mobility group box 1 (HMGB1) ligands, are expressed and secreted by cancer cells and are associated with increased metastasis and poorer outcomes in a wide variety of tumors.