Pancreatic cancer is the fourth most common cancer to cause death due to advanced stage at diagnosis and poor response to current treatment. Autophagy is the lysosome-mediated degradation pathway which plays a critical role in cellular defense, quality control, and energy metabolism. Targeting autophagy is now an exciting field for translational cancer research, as autophagy dysfunction is among the hallmarks of cancer. Pancreatic tumors have elevated autophagy under basal conditions when compared with other epithelial cancers. This review describes our current understanding of the interaction between autophagy and pancreatic cancer development, including risk factors (e.g., pancreatitis, smoking, and alcohol use), tumor microenvironment (e.g., hypoxia and stromal cells), and molecular biology (e.g., K-Ras and p53) of pancreatic cancer. The importance of the HMGB1-RAGE pathway in regulation of autophagy and pancreatic cancer is also presented. Finally, we describe current studies involving autophagy inhibition using either pharmacological inhibitors (e.g., chloroquine) or RNA interference of essential autophagy genes that regulate chemotherapy sensitivity in pancreatic cancer. Summarily, autophagy plays multiple roles in the regulation of pancreatic cancer pathogenesis and treatment, although the exact mechanisms remain unknown.

In this study we analyze MR-negative malignant lesions of the breast. A total of 204 patients with palpable and/or mammographic lesions were studied. The MR technique consisted of the turbo FLASH and MP-RAGE subtraction techniques. All patients underwent surgical biopsy and/or mastectomy and all specimens were examined by the correlative radiologic-histologic mapping technique. A total of 208 lesions were evaluated; 145 turned out to be malignant and 63 proved to be benign. Six malignant lesions were misinterpreted as benign on MR imaging; thus, suspicious contrast enhancement was present in 96 % of the lesions detected by mammography, US, or clinical examination. Especially 4 of the 17 ductal carcinoma in situ (DCIS) lesions were misinterpreted (23.5 %). Despite optimal technique, 6 malignant lesions were not identified by MR imaging. The highest prevalence of these MR occult lesions was in the group of DCIS. Although MR imaging has an important role in the evaluation of breast lesions and, primarily, in ruling out malignancy, one should be aware of the fact that false-negative MR findings do occur.

Inflammatory damage plays an important role in cerebral ischemic pathogenesis. HMGB1-induced NF-kappaB activation pathway has been gaining recognition as a key contributor to the proinflammatory response. Tanshinone II A (Tan II A) has been proved to elicit a series of biologic effects through its antiinflammatory property. But the mechanism underlying is poorly understood. This study evaluated the Tan II A's protective role in cerebral ischemia and its potential mechanism. Male Sprague-Dawley rats were subjected to pMCAO. Experiment 1 was used to evaluate the longitudinal expression of HMGB1, RAGE and TLR4 and NF-kappaB in the cerebral ischemia. Experiment 2 was used to detect Tan II A's neuroprotection. At 24 h after pMCAO, neurologic deficit, brain water content and infarct size were measured. Immunohistochemistry, RT-PCR, Western blot and confocal microscope were used to analyze the expression of HMGB1, RAGE, TLR4 and NF-kappaB. Experiment 3 was used to detect Tan II A's influence on BBB. The expressions of HMGB1, TLR4, RAGE and NF-kappaB were up-regulated in ischemic brain. Compared with pMCAO group, the expressions of these factors significantly decreased in Tan II A-H group, the neurologic deficit, infarct volume and brain water content were alleviated (P<0.05) and claudin-5 was predominantly expressed in brain capillaries. Tan II A protected the brain from damage caused by pMCAO; this effect may be through down-regulation of HMGB1, RAGE and TLR4, NF-kappaB and up-regulation claudin-5 expression.

BACKGROUND

Mechanisms of cardiovascular injuries from exposure to gas and particulate air pollutants are unknown.

OBJECTIVE

We sought to determine whether episodic exposure of rats to ozone or diesel exhaust particles (DEP) causes differential cardiovascular impairments that are exacerbated by ozone plus DEP.

RESULTS

Male Wistar Kyoto rats (10-12 weeks of age) were exposed to air, ozone (0.4 ppm), DEP (2.1 mg/m(3)), or ozone (0.38 ppm) + DEP (2.2 mg/m(3)) for 5 hr/day, 1 day/week for 16 weeks, or to air, ozone (0.51 or 1.0 ppm), or DEP (1.9 mg/m(3)) for 5 hr/day for 2 days. At the end of each exposure period, we examined pulmonary and cardiovascular biomarkers of injury. In the 16-week study, we observed mild pulmonary pathology in the ozone, DEP, and ozone + DEP exposure groups, a slight decrease in circulating lymphocytes in the ozone and DEP groups, and decreased platelets in the DEP group. After 16 weeks of exposure, mRNA biomarkers of oxidative stress (hemeoxygenase-1), thrombosis (tissue factor, plasminogen activator inhibitor-1, tissue plasminogen activator, and von Willebrand factor), vasoconstriction (endothelin-1, endothelin receptors A and B, endothelial NO synthase) and proteolysis [matrix metalloprotease (MMP)-2, MMP-3, and tissue inhibitor of matrix metalloprotease-2] were increased by DEP and/or ozone in the aorta, but not in the heart. Aortic LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) mRNA and protein increased after ozone exposure, and LOX-1 protein increased after exposure to ozone + DEP. RAGE (receptor for advanced glycation end products) mRNA increased in the ozone + DEP group. Exposure to ozone or DEP depleted cardiac mitochondrial phospholipid fatty acids (DEP>> ozone). The combined effect of ozone and DEP exposure was less pronounced than exposure to either pollutant alone. Exposure to ozone or DEP for 2 days (acute) caused mild changes in the aorta.

CONCLUSIONS

In animals exposed to ozone or DEP alone for 16 weeks, we observed elevated biomarkers of vascular impairments in the aorta, with the loss of phospholipid fatty acids in myocardial mitochondria. We conclude that there is a possible role of oxidized lipids and protein through LOX-1 and/or RAGE signaling.

BACKGROUND

Visual assessment rating scales for medial temporal lobe (MTL) atrophy have been used by neuroradiologists in clinical practice to aid the diagnosis of Alzheimer's disease (AD). Recently multivariate classification methods for magnetic resonance imaging (MRI) data have been suggested as alternative tools. If computerized methods are to be implemented in clinical practice they need to be as good as, or better than experienced neuroradiologists and carefully validated. The aims of this study were: (1) To compare the ability of MTL atrophy visual assessment rating scales, a multivariate MRI classification method and manually measured hippocampal volumes to distinguish between subjects with AD and healthy elderly controls (CTL). (2) To assess how well the three techniques perform when predicting future conversion from mild cognitive impairment (MCI) to AD.

METHODS

High resolution sagittal 3D T1w MP-RAGE datasets were acquired from 75 AD patients, 101 subjects with MCI and 81 CTL from the multi-centre AddNeuroMed study. An automated analysis method was used to generate regional volume and regional cortical thickness measures, providing 57 variables for multivariate analysis (orthogonal partial least squares to latent structures using seven-fold cross-validation). Manual hippocampal measurements were also determined for each subject. Visual rating assessment of MTL atrophy was performed by an experienced neuroradiologist according to the approach of Scheltens et al.

RESULTS

We found prediction accuracies for distinguishing between AD and CTL of 83% for multivariate classification, 81% for the visual rating assessments and 89% for manual measurements of total hippocampal volume. The three different techniques showed similar accuracy in predicting conversion from MCI to AD at one year follow-up.

CONCLUSIONS

Visual rating assessment of the MTL gave similar prediction accuracy to multivariate classification and manual hippocampal volumes. This suggests a potential future role for computerized methods as a complement to clinical assessment of AD.

Nearly 12% of children and 6% of adults in Canada have been diagnosed with asthma. Although in most patients symptoms are controlled by inhaled steroids, a subpopulation (approximately 10%) characterized by excessive airway neutrophilia, is refractory to treatment; these patients exhibit severe disease, and account for more than 50% of asthma health care costs. These numbers underscore the need to better understand the biology of severe asthma and identify pro-asthma mediators released by cells, such as neutrophils, that are unresponsive to common steroid therapy. This review focuses on a unique protein complex consisting of S100A8 and S100A9. These subunits belong to the large Ca2+-binding S100 protein family and are some of the most abundant proteins in neutrophils and macrophages. S100A8/A9 is a damage-associated molecular pattern (DAMP) protein complex released in abundance in rheumatoid arthritis, inflammatory bowel disease, and cancer, but there are no definitive studies on its role in inflammation and obstructive airways disease. Two receptors for S100A8/A9, the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4), are expressed in lung. TLR4 is linked with innate immunity that programs local airway inflammation, and RAGE participates in mediating fibroproliferative remodeling in idiopathic pulmonary fibrosis. S100A8/A9 can induce cell proliferation, or apoptosis, inflammation, collagen synthesis, and cell migration. We hypothesize that this capacity suggests S100A8/A9 could underpin chronic airway inflammation and airway remodeling in asthma by inducing effector responses of resident and infiltrating airway cells. This review highlights some key issues related to this hypothesis and provides a template for future research.

The receptor for advanced glycation end products (RAGE) is produced either as a transmembrane or soluble form (sRAGE). Substantial evidence supports a role for RAGE and its ligands in disease. sRAGE is reported to be a competitive, negative regulator of membrane RAGE activation, inhibiting ligand binding. However, some reports indicate that sRAGE is associated with inflammatory disease. We sought to define the biological function of sRAGE on inflammatory cell recruitment, survival, and differentiation in vivo and in vitro. To test the in vivo impact of sRAGE, the recombinant protein was intratracheally administered to mice, which demonstrated monocyte- and neutrophil-mediated lung inflammation. We also observed that sRAGE induced human monocyte and neutrophil migration in vitro. Human monocytes treated with sRAGE produced proinflammatory cytokines and chemokines. Our data demonstrated that sRAGE directly bound human monocytes and monocyte-derived macrophages. Binding of sRAGE to monocytes promoted their survival and differentiation to macrophages. Furthermore, sRAGE binding to cells increased during maturation, which was similar in freshly isolated mouse monocytes compared with mature tissue macrophages. Because sRAGE activated cell survival and differentiation, we examined intracellular pathways that were activated by sRAGE. In primary human monocytes and macrophages, sRAGE treatment activated Akt, Erk, and NF-kappaB, and their activation appeared to be critical for cell survival and differentiation. Our data suggest a novel role for sRAGE in monocyte- and neutrophil-mediated inflammation and mononuclear phagocyte survival and differentiation.

OBJECTIVE

Amphoterin is considered as a regulator for the ability of invasion and migration in tumor cells and embryonic neurons through binding to receptor for advanced glycation end products (RAGE), a multiligand cell surface molecule of the immunoglobulin superfamily. As matrix metalloproteinase-9 (MMP-9, gelatinase B) has been reported to play a critical role in tumor progression and metastasis, we have examined the relation of RAGE and MMP in human pancreatic cancer.

METHODS

Three representative human pancreatic carcinoma cells were rendered for the study which show different metastatic potential, PANC-1 and MIA PaCa-2 as the cells with high ability, BxPC-3 as with low. The expression of RAGE was examined by RT-PCR. The expression of MMP-9 protein was examined by Western blotting.

RESULTS

RAGE was strongly expressed in MIA PaCa-2 and PANC-1 that have high metastatic ability. On the contrary, RAGE was expressed little in BxPC-3 that has low ability. Similarly, expression of MMP-9 showed almost the same tendency. RAGE and MMP-9 are expressed concordant with the metastatic ability of the human pancreatic cancer cells.

CONCLUSIONS

Control of these molecules could be a key to regulating the metastatic ability of pancreatic cancer and this may be exploited in targeted therapy of this cancer.

Development of colon cancer is a multistep process that is regulated by intrinsic and extrinsic cellular signals. Extrinsic factors include molecular patterns that are derived from either pathogens (PAMPs) or cellular damage (DAMPs). These molecules can promote tumourigenesis by activation of the innate immune system, but the individual contribution of ligands and their receptors remains elusive. The receptor for advanced glycation end products (Rage) is a pattern recognition receptor that binds multiple ligands derived from a damaged cell environment such as Hmgb1 and S100 protein. Here we show that Rage signalling has a critical role in sporadic development of intestinal adenomas, as Apc(Min/+) Rage(-/-) mice are protected against tumourigenesis.

Interactions between advanced glycation endproducts (AGE) and the receptor for AGE (RAGE) have been implicated in the development of diabetic vascular complications. RAGE has two N-glycosylation sites in and near the AGE-binding domain, and G82S mutation in the second N-glycosylation motif was recently reported in human. In this study, we examined whether de-N-glycosylation or G82S of RAGE affect its ability to bind AGE and cellular response to AGE. Recombinant wild-type, de-N-glycosylation and G82S RAGE proteins were produced in COS-7 cells, purified and assayed for ligand-binding abilities. De-N-glycosylation at N81 and G82S mutation decreased Kd for glycolaldehyde-derived AGE to three orders of magnitude lower levels compared with wild-type. AGE-induced upregulation of VEGF mRNA was significantly augmented in endothelial cell-derived ECV304 cells expressing de-N-glycosylated and G82S RAGE when compared with wild-type expressor. Exposure to low glucose resulted in the appearance of RAGE proteins of deglycosylated size in wild-type RAGE-expressing cells and significantly enhanced glycolaldehyde-derived AGE-induced VEGF mRNA expression. De-N-glycosylation or G82S mutation of RAGE increases affinity for AGE ligands, and may sensitize cells or conditions with it to AGE.

The extracellular functions of S100 proteins have attracted more attention in recent years. S100 proteins are a group of calcium-binding proteins which exhibit cell- and tissue-specific expression, and different expression levels of members from this family have been observed in various pathological conditions. The reported extracellular functions of S100 proteins include the ability to enhance neurite outgrowth, involvement in inflammation, and motility of tumour cells. In our previous study, we reported translocation of S100A13 in response to the elevated intracellular calcium levels induced by angiotensin II. In order to investigate potential effects of extracellular S100A13, recombinant S100A13 was used here to stimulate human endothelial cells. Addition of extracellular S100A13 to the cells resulted in both endogenous protein translocation and protein uptake from the extracellular space. To test specificity of this effect, addition of various other S100 proteins was also performed. Interestingly, translocation of specific S100 proteins was only observed when the cells were stimulated with the same extracellular S100 protein. Since the receptor for advanced glycation end products (RAGE) is a putative cell surface receptor for S100 proteins and is involved in various signal transduction pathways, we next investigated the interaction between the receptor and extracellular S100 proteins. We show here that NF-kappaB which is a downstream regulator in RAGE-mediated transduction pathways can be activated by addition of extracellular S100 proteins, and translocation of S100 proteins was inhibited by soluble RAGE. These experiments suggest a common cell surface receptor for S100 proteins on endothelial cells even though intracellular translocation induced by extracellular S100 proteins is specific.

BACKGROUND

Increasing evidence suggests that an inflammatory reaction contributes to the secondary brain injury that plays a critical role in the clinical outcome of patients with traumatic brain injury (TBI). Recently, high-mobility group box 1 (HMGB1) has been identified as a key cytokine in the inflammatory reaction and may represent a new target for the treatment of TBI. However, the expression of HMGB1 during this injury process has not yet been studied.

METHODS

In this study, the levels of both HMGB1 and receptor for advanced glycation end products (RAGE) in the rat brain were analyzed by Western blot at different time points after TBI. Immunohistochemistry was also performed to examine the expression pattern of HMGB1 and RAGE in both the rat and the human brain after TBI.

RESULTS

In the rat brain, HMGB1 levels significantly declined below the basal level at 6 hours after TBI and then gradually returned to the basal level 2 days later. RAGE expression increased 6 hours after TBI and reached its peak after 1 day; this level then slowly decreased but remained higher than the sham-injury group until 6 days after TBI. In both rat and human brains, HMGB1 either disappeared or was translocated from the nucleus to the cytoplasm at early stages after TBI and then was localized to the cytoplasm of phagocytic microglia at later stages. RAGE expression increased in the region surrounding the contused area after TBI in both rat and human brains. At later stages, RAGE was mainly expressed in microglia.

CONCLUSIONS

HMGB1 is involved in both early and later stages after TBI. Targeting HMGB1 signaling may be a promising therapeutic approach for the treatment of TBI.

Receptor for advanced glycation end products (RAGE) has been shown to be involved in adiposity as well as atherosclerosis even in nondiabetic conditions. In this study, we examined mechanisms underlying how RAGE regulates adiposity and insulin sensitivity. RAGE overexpression in 3T3-L1 preadipocytes using adenoviral gene transfer accelerated adipocyte hypertrophy, whereas inhibitions of RAGE by small interfering RNA significantly decrease adipocyte hypertrophy. Furthermore, double knockdown of high mobility group box-1 and S100b, both of which are RAGE ligands endogenously expressed in 3T3-L1 cells, also canceled RAGE-medicated adipocyte hypertrophy, implicating a fundamental role of ligands-RAGE ligation. Adipocyte hypertrophy induced by RAGE overexpression is associated with suppression of glucose transporter type 4 and adiponectin mRNA expression, attenuated insulin-stimulated glucose uptake, and insulin-stimulated signaling. Toll-like receptor (Tlr)2 mRNA, but not Tlr4 mRNA, is rapidly upregulated by RAGE overexpression, and inhibition of Tlr2 almost completely abrogates RAGE-mediated adipocyte hypertrophy. Finally, RAGE(-/-) mice exhibited significantly less body weight, epididymal fat weight, epididymal adipocyte size, higher serum adiponectin levels, and higher insulin sensitivity than wild-type mice. RAGE deficiency is associated with early suppression of Tlr2 mRNA expression in adipose tissues. Thus, RAGE appears to be involved in mouse adipocyte hypertrophy and insulin sensitivity, whereas Tlr2 regulation may partly play a role.

Violence and aggression are major causes of death and injury, thus constituting primary public health problems throughout much of the world costing billions of dollars to society. The present review relates our understanding of the neurobiology of aggression and rage to pharmacological treatment strategies that have been utilized and those which may be applied in the future. Knowledge of the neural mechanisms governing aggression and rage is derived from studies in cat and rodents. The primary brain structures involved in the expression of rage behavior include the hypothalamus and midbrain periaqueductal gray. Limbic structures, which include amygdala, hippocampal formation, septal area, prefrontal cortex and anterior cingulate gyrus serve important modulating functions. Excitatory neurotransmitters that potentiate rage behavior include excitatory amino acids, substance P, catecholamines, cholecystokinin, vasopressin, and serotonin that act through 5-HT(2) receptors. Inhibitory neurotransmitters include GABA, enkephalins, and serotonin that act through 5-HT(1) receptors. Recent studies have demonstrated that brain cytokines, including IL-1beta and IL-2, powerfully modulate rage behavior. IL-1-beta exerts its actions by acting through 5-HT(2) receptors, while IL-2 acts through GABAA or NK(1) receptors. Pharmacological treatment strategies utilized for control of violent behavior have met with varying degrees of success. The most common approach has been to apply serotonergic compounds. Others included the application of antipsychotic, GABAergic (anti-epileptic) and dopaminergic drugs. Present and futures studies on the neurobiology of aggression may provide the basis for new and novel treatment strategies for the control of aggression and violence as well as the continuation of existing pharmacological approaches.

In the AD brain, there are elevated amounts of soluble and insoluble Abeta peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble Abeta to soluble RAGE inhibits further aggregation of Abeta peptides, while membrane bound RAGE-Abeta interactions elicit activation of the NF-kappaB transcription factor promoting sustained chronic neuroinflammation. Atomic force microscopy observations demonstrated that the N-terminal domain of RAGE, by interacting with Abeta, is a powerful inhibitor of Abeta polymerization even at prolonged periods of incubation. Hence, the potential RAGE-Abeta structural interactions were further explored utilizing a series of computational chemistry algorithms. Our modeling suggests that a soluble dimeric RAGE assembly creates a positively charged well into which the negative charges of the N-terminal domain of dimeric Abeta dock.

Aging is the most important single risk factor for developing Alzheimer disease. We measured amyloid-beta peptide (Abeta) levels in rat cerebral cortex and hippocampus during normal aging of Brown-Norway/Fischer rats. Amyloid-beta accumulation was associated with expression of the Abeta influx transporter, the receptor for advanced glycation end-products (RAGEs) at the blood-brain barrier. Rats at selected ages from 3 to 36 months were analyzed by 1) immunohistochemistry for amyloid deposition and quantitative microvessel surface area RAGE expression, 2) ELISA for cortical Abeta40 and Abeta42 concentrations, and 3) Western blotting of microvessel proteins for RAGE expression. Immunohistochemistry showed increasing accumulation of brain Abeta with aging. By ELISA analysis, both Abeta40 and Abeta42 concentrations in cortical homogenates rose sharply from 9 to 12 months. The Abeta42 continued to rise up to age 30 months, whereas Abeta40 stabilized after 12 months. The expression of RAGE initially decreased between 3 and 12 months but then increased between 12 and 34 months by immunohistochemistry. On immunoblotting, RAGE decreased up to 9 months and then progressively increased up to 36 months. These data indicate an association between amyloid and microvessel RAGE during aging. An increase in capillary RAGE expression seems to play a role in the later Abeta accumulation but not in the initial increase.

BACKGROUND

The Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS) trial demonstrated that early aggressive statin therapy in patients with ACS significantly reduces plaque volume (PV). Advanced glycation end products (AGEs) and the receptors of AGEs (RAGE) may lead to angiopathy in diabetes mellitus (DM) and may affect on the development of coronary PV. The present sub-study of JAPAN-ACS investigates the association between AGEs and RAGE, and PV.

METHODS

Intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) was undertaken, followed by the initiation of statin treatment (either 4 mg/day of pitavastatin or 20 mg/day of atorvastatin), in patients with ACS. In the 208 JAPAN-ACS subjects, PV using IVUS in non-culprit segment>> 5 mm proximal or distal to the culprit lesion and, serum levels of AGEs and soluble RAGE (sRAGE) were measured at baseline and 8-12 months after PCI.

RESULTS

At baseline, no differences in the levels of either AGEs or sRAGE were found between patients with DM and those without DM. The levels of AGEs decreased significantly with statin therapy from 8.6 ± 2.2 to 8.0 ± 2.1 U/ml (p < 0.001), whereas the levels of sRAGE did not change. There were no significant correlations between changes in PV and the changes in levels of AGEs as well as sRAGE. However, high baseline AGEs levels were significantly associated with plaque progression (odds ratio, 1.21; 95% confidence interval, 1.01 - 1.48; p = 0.044) even after adjusting for DM in multivariate logistic regression models.

CONCLUSIONS

High baseline AGEs levels were associated with plaque progression in the JAPAN-ACS trial. This relationship was independent of DM. These findings suggest AGEs may be related to long-term glucose control and other oxidative stresses in ACS.

BACKGROUND

NCT00242944.

Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) generate ROS, and therefore this study evaluated the effects of RAGE deletion, decreasing AGE accumulation, or lowering dietary AGE content on oxidative parameters in diabetic nephropathy (DN). Control and diabetic male wild-type and RAGE-deficient (RAGE-/-) mice were fed high- or low-AGE diets, with two groups given the inhibitor of AGE accumulation, alagebrium chloride, and followed for 24 wk. Diabetic RAGE-/- mice were protected against albuminuria, hyperfiltration, glomerulosclerosis, decreased renal mitochondrial ATP production, and excess generation of both mitochondrial and cytosolic superoxide. Whereas glomerulosclerosis, tubulointerstitial expansion, and hyperfiltration were improved in diabetic mice treated with alagebrium, there was no effect on urinary albumin excretion. Both diabetic RAGE-/- and alagebrium-treated mice had an attenuation of renal RAGE expression and decreased renal and urinary AGE (carboxymethyllysine) levels. Low-AGE diets did not confer renoprotection, lower the AGE burden or renal RAGE expression, or improve cytosolic or mitochondrial superoxide generation. Renal uncoupling protein-2 gene expression and mitochondrial membrane potential were attenuated by all therapeutic interventions in diabetic mice. In the present study, diverse approaches to block the AGE-RAGE axis had disparate effects on DN, which has potential clinical implications for the way this axis should be targeted in humans.

Acute kidney injury (AKI) is a severe complication of sepsis. High-mobility group box (HMGB)-1 was implicated as a late mediator of lethal systemic inflammation in sepsis. Since glutamine (GLN) was shown to have anti-inflammatory and antioxidant properties, we hypothesized that GLN administration may downregulate an HMGB-1-mediated pathway and thus ameliorate sepsis-induced AKI. Mice were randomly assigned to a normal group (NC), a septic saline group (SS), or a septic GLN group (SG). Sepsis was induced by cecal ligation and puncture (CLP). The SS group was injected with saline, and the SG group was given 0.75 g GLN/kg body wt once via a tail vein 1 h after CLP. Mice were killed 2, 6, and 24 h after CLP, and blood and kidneys of the animals were harvested for further analysis. The results showed that sepsis resulted in higher mRNA and/or protein expressions of kidney HMGB-1, toll-like receptor (TLR) 4, myeloid differentiation primary-response protein (MyD) 88, and receptor of advanced glycation end products (RAGE) compared with normal mice. Septic mice with GLN administration exhibited decreased HMGB-1, TLR4, RAGE, and phosphorylated NF-κB p65 protein expressions and reduced nitrotyrosine levels in kidney tissues. The histological findings showed that damage to the kidneys was less severe, and survival improved in the SG group. These results indicated that a single dose of GLN administered after the initiation of sepsis plays a prophylactic role in downregulating the expressions of HMGB-1-related mediators and decreasing oxidative stress in the kidneys, which may consequently have ameliorated AKI induced by sepsis.

Large randomized studies have established that early intensive glycemic control reduces the risk of diabetic complications, both micro and macrovascular. However, epidemiological and prospective data support a long-term influence of early metabolic control on clinical outcomes. This phenomenon has recently been defined as "metabolic memory." Potential mechanisms for propagating this "memory" may be the production of reactive species unrelated to the presence of hyperglycemia, depending on the previous production of AGEs which can maintain RAGE over-expression, on the level of glycation of mitochondrial proteins and on the amount of mtDNA produced, all conditions able to induce an altered gene expression which may be persistent even when glycemia is normalized. Clinically, the emergence of this "metabolic memory" suggests the need for a very early aggressive treatment aiming to "normalize" the metabolic control and the addition of agents which reduce cellular reactive species and glycation in addition to normalizing glucose levels in diabetic patients in order to minimize long-term diabetic complications.

The blood-brain barrier (BBB) is involved in the pathogenesis of Alzheimer's disease (AD). BBB is a highly selective semipermeable structural and chemical barrier which ensures a stable internal environment of the brain and prevents foreign objects invading the brain tissue. BBB dysfunction induces the failure of Aβ transport from brain to the peripheral circulation across the BBB. Especially, decreased levels of LRP-1 (low density lipoprotein receptor-related protein 1) and increased levels of RAGE (receptor for advanced glycation endproducts) at the BBB can cause the failure of Aβ transport. The pathogenesis of AD is related to the BBB structural components, including pericytes, astrocytes, vascular endothelial cells, and tight junctions. BBB dysfunction will trigger neuroinflammation and oxidative stress, then enhance the activity of β-secretase and γ-secretase, and finally promote Aβ generation. A progressive accumulation of Aβ in brain and BBB dysfunction may become a feedback loop that gives rise to cognitive impairment and the onset of dementia. The correlation between BBB dysfunction and tau pathology has been well-reported. Therefore, regulating BBB function may be a new therapeutic target for treating AD.

Autophagy is a dynamic process for degradation of cytosolic components such as dysfunctional organelles and proteins and a means for generating metabolic substrates during periods of starvation. Mitochondrial autophagy ("mitophagy") is a selective form of autophagy, which is important in maintaining mitochondrial homeostasis. High mobility group box 1 (HMGB1) plays important intranuclear, cytosolic and extracellular roles in the regulation of autophagy. Cytoplasmic HMGB1 is a novel Beclin 1-binding protein active in autophagy. Extracellular HMGB1 induces autophagy, and this role is dependent on its redox state and receptor (Receptor for Advanced Glycation End products, RAGE) expression. Nuclear HMGB1 modulates the expression of heat shock protein β-1 (HSPB1/HSP27). As a cytoskeleton regulator, HSPB1 is critical for dynamic intracellular trafficking during autophagy and mitophagy. Loss of either HMGB1 or HSPB1 results in a phenotypically similar deficiency in mitophagy typified by mitochondrial fragmentation with decreased aerobic respiration and adenosine triphosphate (ATP) production. These findings reveal a novel pathway coupling autophagy and cellular energy metabolism.

Vascular calcification is an unfavorable event in the natural history of atherosclerosis that predicts cardiovascular morbidity and mortality. However, increasing evidence suggests that different calcification patterns are associated with different or even opposite histopathological and clinical features, reflecting the dual relationship between inflammation and calcification. In fact, initial calcium deposition in response to pro-inflammatory stimuli results in the formation of spotty or granular calcification ("microcalcification"), which induces further inflammation. This vicious cycle favors plaque rupture, unless an adaptive response prevails, with blunting of inflammation and survival of vascular smooth muscle cells (VSMCs). VSMCs promote fibrosis and also undergo osteogenic transdifferentiation, with formation of homogeneous or sheet-like calcification ("macrocalcification"), that stabilizes the plaque by serving as a barrier towards inflammation. Unfortunately, little is known about the molecular mechanisms regulating this adaptive response. The advanced glycation/lipoxidation endproducts (AGEs/ALEs) have been shown to promote vascular calcification and atherosclerosis. Recent evidence suggests that two AGE/ALE receptors, RAGE and galectin-3, modulate in divergent ways, not only inflammation, but also vascular osteogenesis, by favoring "microcalcification" and "macrocalcification", respectively. Galectin-3 seems essential for VSMC transdifferentiation into osteoblast-like cells via direct modulation of the WNT-β-catenin signaling, thus driving formation of "macrocalcification", whereas RAGE favors deposition of "microcalcification" by promoting and perpetuating inflammation and by counteracting the osteoblastogenic effect of galectin-3. Further studies are required to understand the molecular mechanisms regulating transition from "microcalcification" to "macrocalcification", thus allowing to design therapeutic strategies which favor this adaptive process, in order to limit the adverse effects of established atherosclerotic calcification.

OBJECTIVE

The diagnosis of dural sinus thrombosis is often difficult because of its variable and nonspecific clinical presentation and the overlapping signal intensities of thrombosis and venous flow on conventional MR images and MR venograms. We compared 3D contrast-enhanced magnetization-prepared rapid gradient-echo (MP-RAGE) sequences with 2D time-of-flight (TOF) MR venography, digital subtraction angiography (DSA), and conventional spin-echo (SE) MR imaging for the assessment of normal and abnormal dural sinuses.

METHODS

In a phantom study, a plastic tube with pulsating flow was used to simulate the intracranial dural sinus. With 3D MP-RAGE, a variety of flow velocities, contrast material concentrations, and angulations between the phantom flow tube and the plane of acquisition were tested to measure their relationship to signal-to-noise ratio (SNR). In a clinical study, 35 patients, including 18 with suspected dural sinus thrombosis, were studied with both MR imaging and DSA. Receiver operating characteristic (ROC) analysis was performed in a blinded fashion using DSA as the reference standard.

RESULTS

With the phantom, the SNR of flow increased with increasing contrast concentration, but was not affected by the angle between the tube and scan slab. There was no relationship between SNR and velocity when the contrast concentration was 1.0 mmol/L or greater. In the clinical study, dural sinus thrombosis as well as the normal anatomy of the dural sinuses were seen better with 3D contrast-enhanced MP-RAGE than with 2D-TOF MR venography. Three-dimensional contrast-enhanced MP-RAGE showed the highest diagnostic confidence on ROC curves in the diagnosis of thrombosis.

CONCLUSIONS

Three-dimensional contrast-enhanced MP-RAGE is superior to 2D-TOF MR venography and conventional SE MR imaging in the depiction of normal venous structures and the diagnosis of dural sinus thrombosis, and is a potential alternative to DSA.