BackgroundMechanisms underlying the attenuation of body weight gain and insulin resistance in response to high fat diet (HFD) by the curry compound curcumin need to be further explored. Although the attenuation of the inflammatory pathway is an accepted mechanism, a recent study suggested that curcumin stimulates Wnt signaling pathway and hence suppresses adipogenic differentiation. This is in contrast with the known repressive effect of curcumin on Wnt signaling in other cell lineages.Methodology and Principal FindingsWe conducted the examination on low fat diet, or HFD fed C57BL/6J mice with or without curcumin intervention for 28 weeks. Curcumin significantly attenuated the effect of HFD on glucose disposal, body weight/fat gain, as well as the development of insulin resistance. No stimulatory effect on Wnt activation was observed in the mature fat tissue. In addition, curcumin did not stimulate Wnt signaling in vitro in primary rat adipocytes. Furthermore, curcumin inhibited lipogenic gene expression in the liver and blocked the effects of HFD on macrophage infiltration and the inflammatory pathway in the adipose tissue.Conclusions and SignificanceWe conclude that the beneficial effect of curcumin during HFD consumption is mediated by attenuating lipogenic gene expression in the liver and the inflammatory response in the adipose tissue, in the absence of stimulation of Wnt signaling in mature adipocytes.

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S ubarachnoid hemorrhage (SAH) affects ≈10 in 100 000 people/y.1 Although SAH accounts for only 5% to 10% of all strokes, it is particularly devastating: half of all SAH patients die within 1 month and half of those who survive will require life-long assistance for daily living (ie, ≈75% of patients die or are seriously debilitated).2,3 The poor clinical outcome can be attributed to the biphasic course of the disease, characterized by an initial hemorrhagic stroke that is frequently followed by delayed cerebral ischemia (DCI) within 4 to 12 days. 4,5 The latter is a primary therapeutic concern when treating SAH, because DCI causes at least half of the morbidity and mortality in SAH. 2The transition from the hemorrhagic insult to secondary ischemia is driven by prominent changes in cerebrovascular reactivity, which compromises cerebral autoregulation 6,7 and evokes angiographic vasospasm (ie, radiographically identifiable arterial narrowing in the proximal cerebrovascular circulation).2,8 Conceptually, both events originate from augmentedBackground and Purpose-Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed by delayed cerebrovascular constriction and ischemia. Current therapeutic strategies nonselectively curtail exacerbated cerebrovascular constriction, which necessarily disrupts the essential and protective process of cerebral blood flow autoregulation. This study identifies a smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in a murine model of experimental SAH: it links tumor necrosis factor-α (TNFα), the cystic fibrosis transmembrane conductance regulator, and sphingosine-1-phosphate signaling. Methods-Mouse olfactory cerebral resistance arteries were isolated, cannulated, and pressurized for in vitro vascular reactivity assessments. Cerebral blood flow was measured by speckle flowmetry and magnetic resonance imaging. Standard Western blot, immunohistochemical techniques, and neurobehavioral assessments were also used. Results-We demonstrate that targeting TNFα and sphingosine-1-phosphate signaling in vivo has potential therapeutic application in SAH. Both interventions (1) eliminate the SAH-induced myogenic tone enhancement, but otherwise leave vascular reactivity intact; (2) ameliorate SAH-induced neuronal degeneration and apoptosis; and (3) improve neurobehavioral performance in mice with SAH. Furthermore, TNFα sequestration with etanercept normalizes cerebral perfusion in SAH. Conclusions-Vascular smooth muscle cell TNFα and sphingosine-1-phosphate signaling significantly enhance cerebral artery tone in SAH; anti-TNFα and anti-sphingosine-1-phosphate treatment may significantly improve clinical outcome.

Background-Heart failure is associated with neurological deficits, including cognitive dysfunction. However, the molecular mechanisms underlying reduced cerebral blood flow in the early stages of heart failure, particularly when blood pressure is minimally affected, are not known. Methods and Results-Using a myocardial infarction model in mice, we demonstrate a tumor necrosis factor-␣ (TNF␣)-dependent enhancement of posterior cerebral artery tone that reduces cerebral blood flow before any overt changes in brain structure and function. TNF␣ expression is increased in mouse posterior cerebral artery smooth muscle cells at 6 weeks after myocardial infarction. Coordinately, isolated posterior cerebral arteries display augmented myogenic tone, which can be fully reversed in vitro by the competitive TNF␣ antagonist etanercept. TNF␣ mediates its effect via a sphingosine-1-phosphate (S1P)-dependent mechanism, requiring sphingosine kinase 1 and the S1P 2 receptor. In vivo, sphingosine kinase 1 deletion prevents and etanercept (2-week treatment initiated 6 weeks after myocardial infarction) reverses the reduction of cerebral blood flow, without improving cardiac function. Conclusions-Cerebral artery vasoconstriction and decreased cerebral blood flow occur early in an animal model of heart failure; these perturbations are reversed by interrupting TNF␣/S1P signaling. This signaling pathway may represent a potential therapeutic target to improve cognitive function in heart failure.

Aims/hypothesis We investigated whether oltipraz, a nuclear respiratory factor 2 alpha subunit (NRF2) activator, improves insulin sensitivity and prevents the development of obesity in mice. Methods C57BL/6J mice were fed with a low-fat diet (10% of energy as fat), a high-fat diet (HFD) (45% of energy as fat) or a HFD with oltipraz for 28 weeks. The effects of oltipraz on body weight, fat content, glucose disposal, insulin signalling, metabolic profiles and endogenous NRF2 functional status in the three groups of mice were investigated. Results Oltipraz prevented or significantly attenuated the effect of HFD on glucose disposal, body weight and fat gain. Impairment of protein kinase B/Akt phosphorylation in this HFD-fed mouse model in response to intraperitoneal insulin injection was observed in adipose tissue, but not in the muscles, accompanied by inhibition of AMP-activated protein kinase signalling and activation of p70S6 kinase, as well as reduced GLUT4 content. These defects were Z. Yu and W. Shao contributed equally to this study. Diabetologia (2011) 54:922-934 DOI 10.1007/s00125-010-2001 attenuated by oltipraz administration. Nuclear content of NRF2 in adipose tissue was reduced by HFD feeding, associated with increased Keap1 mRNA expression and reduced production of haem oxygenase-1 and superoxide dismutase, increased protein oxidation, decreased plasma reduced:oxidised glutathione ratio and the appearance of macrophage marker F4/80. These defects were also restored by oltipraz. Finally, oltipraz attenuated HFD-induced inducible nitric oxide synthase overproduction. Conclusions/interpretation Impairment of the endogenous redox system is important in the development of obesity and insulin resistance in chronic HFD feeding. NRF2 activation represents a potential novel approach in the treatment and prevention of obesity and diabetes. Electronic supplementary material

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Metastatic brain cancers, in particular cancers with multiple lesions, are one of the most difficult malignancies to treat owing to their location and aggressiveness. Chemotherapy for brain metastases offers some hope. However, its efficacy is severely limited as most chemotherapeutic agents are incapable of crossing the blood-brain barrier (BBB) efficiently. Thus, a multifunctional nanotheranostic system based on poly(methacrylic acid)-polysorbate 80-grafted-starch was designed herein for the delivery of BBB-impermeable imaging and therapeutic agents to brain metastases of breast cancer. In vivo magnetic resonance imaging and confocal fluorescence microscopy were used to confirm extravasation of gadolinium and dye-loaded nanoparticles from intact brain microvessels in healthy mice. The targetability of doxorubicin (Dox)-loaded nanoparticles to intracranially established brain metastases of breast cancer was evaluated using whole body and ex vivo fluorescence imaging of the brain. Coexistence of nanoparticles and Dox in brain metastatic lesions was further confirmed by histological and microscopic examination of dissected brain tissue. Immuno-histochemical staining for caspase-3 and terminal-deoxynucleotidyl transferase dUTP nick end labeling for DNA fragmentation in tumor-bearing brain sections revealed that Dox-loaded nanoparticles selectively induced cancer cell apoptosis 24 h post-injection, while sparing normal brain cells from harm. Such effects were not observed in the mice treated with free Dox. Treatment with Dox-loaded nanoparticles significantly inhibited brain tumor growth compared to free Dox at the same dose as assessed by in vivo bioluminescence imaging of the brain metastases. These findings suggest that the multifunctional nanoparticles are promising for the treatment of brain metastases.

A key contributor to the progression of nearly all forms of CKD is fibrosis, a largely irreversible process that drives further kidney injury. Despite its importance, clinicians currently have no means of noninvasively assessing renal scar, and thus have historically relied on percutaneous renal biopsy to assess fibrotic burden. Although helpful in the initial diagnostic assessment, renal biopsy remains an imperfect test for fibrosis measurement, limited not only by its invasiveness, but also, because of the small amounts of tissue analyzed, its susceptibility to sampling bias. These concerns have limited not only the prognostic utility of biopsy analysis and its ability to guide therapeutic decisions, but also the clinical translation of experimental antifibrotic agents. Recent advances in imaging technology have raised the exciting possibility of magnetic resonance imaging (MRI)-based renal scar analysis, by capitalizing on the differing physical features of fibrotic and nonfibrotic tissue. In this review, we describe two key fibrosis-induced pathologic changes (capillary loss and kidney stiffening) that can be imaged by MRI techniques, and the potential for these new MRI-based technologies to noninvasively image renal scar.