Brain site-specific regulation of hedonic intake by orexin and DYN peptides: role of the PVN and obesity.

The orexin peptides promote hedonic intake and other reward behaviors through different brain sites. The opioid dynorphin peptides are co-released with orexin peptides but block their effects on reward in the ventral tegmental area (VTA). We previously showed that in the paraventricular hypothalamic nucleus (PVN), dynorphin and not orexin peptides enhance hedonic intake, suggesting they have brain-site-specific effects. Obesity alters the expression of orexin and dynorphin receptors, but whether their expression across different brain sites is important to hedonic intake is unclear. We hypothesized that hedonic intake is regulated by orexin and dynorphin peptides in PVN and that hedonic intake in obesity correlates with expression of their receptors. Here we show that in mice, injection of DYN-A1-13 (an opioid dynorphin peptide) in the PVN enhanced hedonic intake, whereas in the VTA, injection of OXA (orexin-A, an orexin peptide) enhanced hedonic intake. In PVN, OXA blunted the increase in hedonic intake caused by DYN-A1-13. In PVN, injection of norBNI (opioid receptor antagonist) reduced hedonic intake but a subsequent OXA injection failed to increase hedonic intake, suggesting that OXA activity in PVN is not influenced by endogenous opioid activity. In the PVN, DYN-A1-13 increased the intake of the less-preferred food in a two-food choice task. In obese mice fed a cafeteria diet, orexin 1 receptor mRNA across brain sites involved in hedonic intake correlated with fat preference but not caloric intake. Together, these data support that orexin and dynorphin peptides regulate hedonic intake in an opposing manner with brain-site-specific effects.

A sexually dimorphic hypothalamic response to chronic high-fat diet consumption.

In this review, we discuss the observations that, following chronic high-fat diet (HFD) exposure, male mice have higher levels of saturated fatty acids (FAs) and total sphingolipids, whereas lower amounts of polyunsaturated FAs in the central nervous system (CNS) than females. Furthermore, males, when compared with female mice, have higher levels of inflammatory markers in the hypothalamus following exposure to HFD. The increase in markers of inflammation in male mice is possibly due to the reductions in proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and estrogen receptor alpha (ERα), which is not recapitulated in female mice. Consistently, hypothalamic inflammation is induced both in male and female ERα total-body knockout mice when exposed to a HFD, thus confirming the key role of ERα in the regulation of HFD-induced hypothalamic inflammation. Finally, the HFD-induced depletion of hypothalamic ERα is associated with dysregulation in metabolic homeostasis, as evidenced by reductions in glucose tolerance and decrements in myocardial function.

Estrogen, astrocytes and the neuroendocrine control of metabolism.

Obesity, and its associated comorbidities such as type 2 diabetes, cardiovascular diseases, and certain cancers, represent major health challenges. Importantly, there is a sexual dimorphism with respect to the prevalence of obesity and its associated metabolic diseases, implicating a role for gonadal hormones. Specifically, estrogens have been demonstrated to regulate metabolism perhaps by acting as a leptin mimetic in the central nervous system (CNS). CNS estrogen receptors (ERs) include ER alpha (ERα) and ER beta (ERß), which are found in nuclear, cytoplasmic and membrane sites throughout the brain. Additionally, estrogens can bind to and activate a G protein-coupled estrogen receptor (GPER), which is a membrane-associated ER. ERs are expressed on neurons as well as glia, which are known to play a major role in providing nutrient supply for neurons and have recently received increasing attention for their potentially important involvement in the CNS regulation of systemic metabolism and energy balance. This brief overview summarizes data focusing on the potential role of astrocytic estrogen action as a key component of estrogenic modulation responsible for mediating the sexual dimorphism in body weight regulation and obesity.

Viral strategies for the evasion of immunogenic cell death.

Viral strategies for the evasion of immunogenic cell death (Symposium). J Intern Med 2010; 267: 526-542. Driven by co-evolutionary forces, viruses have refined a wide arsenal of strategies to interfere with the host defences. On one hand, viruses can block/retard programmed cell death in infected cells, thereby suppressing one of the most ancient mechanisms against viral dissemination. On the other hand, multiple viral factors can efficiently trigger the death of infected cells and uninfected cells from the immune system, which favours viral spreading and prevents/limits an active antiviral response, respectively. Moreover, several viruses are able to inhibit the molecular machinery that drives the translocation of calreticulin to the surface of dying cells. Thereby, viruses block the exposure of an engulfment signal that is required for the efficient uptake of dying cells by dendritic cells and for the induction of the immune response. In this review, we discuss a variety of mechanisms by which viruses interfere with the cell death machinery and, in particular, by which they subvert immunogenic cell death.

Spinal ependymomas and papilledema: report of 4 cases and review of the literature.

We report 4 cases of ependymoma of the filum terminale with associated intracranial hypertension syndrome. After analyzing the relevant published work, we consider the possible pathogenetic hypotheses for this rare association.

BH3 mimetics activate multiple pro-autophagic pathways.

The BH3 mimetic ABT737 induces autophagy by competitively disrupting the inhibitory interaction between the BH3 domain of Beclin 1 and the anti-apoptotic proteins Bcl-2 and Bcl-X(L), thereby stimulating the Beclin 1-dependent allosteric activation of the pro-autophagic lipid kinase VPS34. Here, we examined whether ABT737 stimulates other pro-autophagic signal-transduction pathways. ABT737 caused the activating phosphorylation of AMP-dependent kinase (AMPK) and of the AMPK substrate acetyl CoA carboxylase, the activating phosphorylation of several subunits of the inhibitor of NF-κB (IκB) kinase (IKK) and the hyperphosphorylation of the IKK substrate IκB, inhibition of the activity of mammalian target of rapamycin (mTOR) and consequent dephosphorylation of the mTOR substrate S6 kinase. In addition, ABT737 treatment dephosphorylates (and hence likewise inhibits) p53, glycogen synthase kinase-3 and Akt. All these effects were shared by ABT737 and another structurally unrelated BH3 mimetic, HA14-1. Functional experiments revealed that pharmacological or genetic inhibition of IKK, Sirtuin and the p53-depleting ubiquitin ligase MDM2 prevented ABT737-induced autophagy. These results point to unexpected and pleiotropic pro-autophagic effects of BH3 mimetics involving the modulation of multiple signalling pathways.

Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy.

Caloric restriction and autophagy-inducing pharmacological agents can prolong lifespan in model organisms including mice, flies, and nematodes. In this study, we show that transgenic expression of Sirtuin-1 induces autophagy in human cells in vitro and in Caenorhabditis elegans in vivo. The knockdown or knockout of Sirtuin-1 prevented the induction of autophagy by resveratrol and by nutrient deprivation in human cells as well as by dietary restriction in C. elegans. Conversely, Sirtuin-1 was not required for the induction of autophagy by rapamycin or p53 inhibition, neither in human cells nor in C. elegans. The knockdown or pharmacological inhibition of Sirtuin-1 enhanced the vulnerability of human cells to metabolic stress, unless they were stimulated to undergo autophagy by treatment with rapamycin or p53 inhibition. Along similar lines, resveratrol and dietary restriction only prolonged the lifespan of autophagy-proficient nematodes, whereas these beneficial effects on longevity were abolished by the knockdown of the essential autophagic modulator Beclin-1. We conclude that autophagy is universally required for the lifespan-prolonging effects of caloric restriction and pharmacological Sirtuin-1 activators.

Control of autophagy by oncogenes and tumor suppressor genes.

Multiple oncogenes (in particular phosphatidylinositol 3-kinase, PI3K; activated Akt1; antiapoptotic proteins from the Bcl-2 family) inhibit autophagy. Similarly, several tumor suppressor proteins (such as BH3-only proteins; death-associated protein kinase-1, DAPK1; the phosphatase that antagonizes PI3K, PTEN; tuberous sclerosic complex 1 and 2, TSC1 and TSC2; as well as LKB1/STK11) induce autophagy, meaning that their loss reduces autophagy. Beclin-1, which is required for autophagy induction acts as a haploinsufficient tumor suppressor protein, and other essential autophagy mediators (such as Atg4c, UVRAG and Bif-1) are bona fide oncosuppressors. One of the central tumor suppressor proteins, p53 exerts an ambiguous function in the regulation of autophagy. Within the nucleus, p53 can act as an autophagy-inducing transcription factor. Within the cytoplasm, p53 exerts a tonic autophagy-inhibitory function, and its degradation is actually required for the induction of autophagy. The role of autophagy in oncogenesis and anticancer therapy is contradictory. Chronic suppression of autophagy may stimulate oncogenesis. However, once a tumor is formed, autophagy inhibition may be a therapeutic goal for radiosensitization and chemosensitization. Altogether, the current state-of-the art suggests a complex relationship between cancer and deregulated autophagy that must be disentangled by further in-depth investigation.

The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1.

The inositol 1,4,5-trisphosphate receptor (IP(3)R) is a major regulator of apoptotic signaling. Through interactions with members of the Bcl-2 family of proteins, it drives calcium (Ca(2+)) transients from the endoplasmic reticulum (ER) to mitochondria, thereby establishing a functional and physical link between these organelles. Importantly, the IP(3)R also regulates autophagy, and in particular, its inhibition/depletion strongly induces macroautophagy. Here, we show that the IP(3)R antagonist xestospongin B induces autophagy by disrupting a molecular complex formed by the IP(3)R and Beclin 1, an interaction that is increased or inhibited by overexpression or knockdown of Bcl-2, respectively. An effect of Beclin 1 on Ca(2+) homeostasis was discarded as siRNA-mediated knockdown of Beclin 1 did not affect cytosolic or luminal ER Ca(2+) levels. Xestospongin B- or starvation-induced autophagy was inhibited by overexpression of the IP(3)R ligand-binding domain, which coimmunoprecipitated with Beclin 1. These results identify IP(3)R as a new regulator of the Beclin 1 complex that may bridge signals converging on the ER and initial phagophore formation.

Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death.

Following the screening of a battery of distinct small-interfering RNAs that target various components of the apoptotic machinery, we found that knockdown of the voltage-dependent anion channel 1 (VDAC1) was particularly efficient in preventing cell death induced by cisplatin (CDDP) in non-small cell lung cancer cells. Both the downregulation of VDAC1 and its chemical inhibition with 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid reduced the apoptosis-associated modifications induced by CDDP, including mitochondrial transmembrane potential dissipation and plasma membrane permeabilization. VDAC1 inhibition strongly reduced the CDDP-induced conformational activation of Bax, yet had no discernible effect on the activation of Bak, suggesting that VDAC1 acts downstream of Bak and upstream of Bax. Accordingly, knockdown of Bak abolished the activation of Bax, whereas Bax downregulation had no effect on Bak activation. In VDAC1-depleted cells, the failure of CDDP to activate Bax could be reversed by means of the Bcl-2/Bcl-X(L) antagonist ABT-737, which concomitantly restored CDDP cytotoxicity. Altogether, these results delineate a novel pathway for the induction of mitochondrial membrane permeabilization (MMP) in the course of CDDP-induced cell death that involves a hierarchical contribution of Bak, VDAC1 and Bax. Moreover, our data suggest that VDAC1 may act as a facultative regulator/effector of MMP, depending on the initial cytotoxic event.

Cerebral and cerebellar haemangioblastoma occurring in the same patient.

A middle-aged man who had undergone two previous operations on a cerebellar haemangioblastoma was found at CT follow-up thirteen years later to have a double supra-and infra-tentorial haemangioblastoma. The tumors were confirmed by vertebral angiography and removed by two-stage surgery. The importance of careful CT follow-up to detect the recurrence of multifocal haemangioblastoma is clear.

Pseudo-cystic dilatation of suprapineal recess. Case report.

We report an odd case of marked enlargement of suprapineal recess in a patient with triventricular hydrocephalus. Radiological diagnostic steps and etiological theories are discussed.

Treatment with cyclosporine A promotes axonal regeneration in rats submitted to transverse section of the spinal cord.

The abortive axonal regeneration in the central nervous system (CNS) of mammals has been attributed to a series of inhibitory factors. Previous reports suggest the development of autoimmune reactions following CNS lesion in mammals. In this study we investigated whether immunosuppressive treatment with cyclosporine A is able to facilitate axonal regeneration in rats submitted to complete transverse section of the spinal cord at the level of T7-T8. Treated animals received daily subcutaneous injections of cyclosporine A (2.5 mg/kg), while control rats were given a similar treatment with saline. Immunosuppression was begun immediately after spinal cord transection. Strong evidence of morphological axonal regeneration was observed 15 days after surgery in all cyclosporine A treated animals. Furthermore, treatment with cyclosporine A markedly reduced the seric immune reaction elicited by the lesion. The results of this study, although preliminary, provide further evidence for the development of autoimmune processes following lesion in the CNS, and suggest that blocking of the immune reaction facilitates axonal regeneration in the rat.

Treatment with cyclosporine A promotes axonal regeneration in rats submitted to transverse section of the spinal cord--II--Recovery of function.

Previous reports have suggested a correlation between autoimmunity and abortive axonal regeneration in mammalian CNS. In this study we investigated the effects of immunosuppressive treatment with Cyclosporine A (CyA) (2.5-5 mg/kg/day) on axonal regeneration after complete spinal transection in rats. Partial recovery of function was observed 30 days after surgery in rats treated with CyA, with the presence of incomplete spontaneous locomotion and a positive contact placing reaction. Restoration of somatosensory evoked potentials and positive retrograde fluorescent tracing were also observed. CyA reduced the autoimmune reaction which targeted components of the axons. These results provide further evidence of the role played by autoimmunity in blocking regeneration of fibre tracts in mammalian CNS.