Lipotoxicity,neuroinflammation, glial cells and oestrogenic compounds

The high concentrations of free fatty acids as a consequence of obesity and being overweight have become risk factors for the development of different diseases, including neurodegenerative ailments. Free fatty acids are strongly related to inflammatory events, causing cellular and tissue alterations in the brain, including cell death, deficits in neurogenesis and gliogenesis, and cognitive decline. It has been reported that people with a high body mass index have a higher risk of suffering from Alzheimer's disease. Hormones such as oestradiol not only have beneficial effects on brain tissue, but also exert some adverse effects on peripheral tissues, including the ovary and breast. For this reason, some studies have evaluated the protective effect of oestrogen receptor (ER) agonists with more specific tissue activities, such as the neuroactive steroid tibolone. Activation of ERs positively affects the expression of pro‐survival factors and cell signalling pathways, thus promoting cell survival. This review aims to discuss the relationship between lipotoxicity and the development of neurodegenerative diseases. We also elaborate on the cellular and molecular mechanisms involved in neuroprotection induced by oestrogens.     

Giant intracranial germinoma

Journal of Neuro-Oncology -     

Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation

Ryanodine receptors (RyR) amplify activity-dependent calcium influx via calcium-induced calcium release. Calcium signals trigger postsynaptic pathways in hippocampal neurons that underlie synaptic plasticity, learning, and memory. Recent evidence supports a role of the RyR2 and RyR3 isoforms in these processes. Along with calcium signals, brain-derived neurotrophic factor (BDNF) is a key signaling molecule for hippocampal synaptic plasticity and spatial memory. Upon binding to specific TrkB receptors, BDNF initiates complex signaling pathways that modify synaptic structure and function. Here, we show that BDNF-induced remodeling of hippocampal dendritic spines required functional RyR. Additionally, incubation with BDNF enhanced the expression of RyR2, RyR3, and PKMζ, an atypical protein kinase C isoform with key roles in hippocampal memory consolidation. Consistent with their increased RyR protein content, BDNF-treated neurons generated larger RyR-mediated calcium signals than controls. Selective inhibition of RyR-mediated calcium release with inhibitory ryanodine concentrations prevented the PKMζ, RyR2, and RyR3 protein content enhancement induced by BDNF. Intrahippocampal injection of BDNF or training rats in a spatial memory task enhanced PKMζ, RyR2, RyR3, and BDNF hippocampal protein content, while injection of ryanodine at concentrations that stimulate RyR-mediated calcium release improved spatial memory learning and enhanced memory consolidation. We propose that RyR-generated calcium signals are key features of the complex neuronal plasticity processes induced by BDNF, which include increased expression of RyR2, RyR3, and PKMζ and the spine remodeling required for spatial memory formation.     

Mechanisms involved in the effects of phenidone, diclofenac and ethacrynic acid in rat uterus in vitro.

1. The effects of phenidone (P, 10(-4)-10(-3) M), sodium diclofenac (D, 10(-5)-10(-4) M) and ethacrynic acid (E, 10(-5)-10(-4) M), proposed as inhibitors of eicosanoid synthesis, on the contractions of rat uterus induced by several agonists have been studied. 2. P, D and E inhibit the motility induced by oxytocin (4 mU/ml) (IC50: 4.62 x 10(-4), 2.55 x 10(-4) and 2.98 x 10(-5) M, respectively). 3. P (10(-3) M), D (10(-4) M) and E (10(-4) M) also inhibit the contraction induced by methacholine (10(-5) M), prostaglandin F2a (10(-6) M) and CaCl2 (6 mM), and relaxed, in a dose-dependent way, the tonic component of contraction to KCl (60 mM) (IC50: 5.81 x 10(-4), 6.67 x 10(-5) and 7.55 x 10(-5) M, respectively). 4. The CaCl2 (0.1-10 mM) reverted the relaxation of KCl contraction produced by P, but not by D or E. None of the inhibitions on CaCl2 (6 mM) are reverted by Bay K 8644. 5. D and E also relaxed the tonic contraction to vanadate (10(-4) M) in uterus incubated in calcium free solution P, enhances the vanadate-induced contractions.     

Effects of antiandrogens and progesterone on isolated rat uterus.

1. The effect of progesterone (P, 6 x 10(-6)-6 x 10(-5) M) and the antiandrogens cyproterone acetate (CPA, 10(-7)-10(-5) M), flutamide (F, 10(-6)-6 x 10(-5) M) and spironolactone (S, 10(-6)-6 x 10(-5) M) on the KCl-induced tonic contraction of the isolated rat uterus have been assayed. 2. The antiandrogens relaxed, in a dose-dependent way, the KCl-induced contraction (EC50, 2.804 +/- 0.506 x 10(-6); 1.671 +/- 0.308 x 10(-5); and 3.042 +/- 0.14 x 10(-5) M, respectively for CPA, S and F). P also relaxed the KCl-induced contraction (EC50, 2.436 +/- 0.524 x 10(-5) M). 3. CaCl2 (0.1-10 mM) counteracted the relaxing effect of CPA, S, F, and P, respectively, up to 100, 80.63, 60.66 and 90.57%. 4. The 17-OH-progesterone derivative CPA, but not S or F, reduces at small doses (6 x 10(-8) M), but not at higher concentrations (6 x 10(-7)-6 x 10(-6) M), the relaxing effect of progesterone.     

Utility of p57 protein(KIP2) in molar disease to determine its androgenetic origin

OBJECTIVE: To determine, qualitatively and semiquantitatively, the expression of p57 protein in different trophoblastic cell populations of hydatidiform mole and anembryonic pregnancy. STUDY DESIGN: We performed an observational study of the histopathologic and immunohistochemical findings of 48 cases of hydatidiform mole and 2 anembryonic pregnancies. The histologic samples stained with hematoxylin-eosin were reviewed blindly by 3 pathologists to establish a diagnosis and compare it to the previous one. Afterward, immunohistochemical staining was performed using a polyclonal antibody on paraffin-embedded, formalin-fixed tissue sections. The nuclear staining was assessed in 5 cell types: villous mesenchyme, cytotrophoblast, syncytiotrophoblast, intervillous trophoblast and decidua. RESULTS: The degree of agreement between the previous histologic diagnosis and the current one was excellent (kappa = 0.702). The sensitivity was 82.6% for complete and 84% for partial mole. On immunohistochemical analysis, the degree of agreement was low (kappa = 0.2). The sensitivity was 53.9% for complete mole and 59.1% for partial mole. The cell population with the least expression for p57 was the cytotrophoblast. The results for anembryonic pregnancies remained the same. CONCLUSION: Immunohistochemistry with p57 is a useful method to differentiate complete from partial mole, which is important to establish the prognosis of the patient.     

Outcome and Hepatic Hemodynamics in Liver Transplant Patients with Portal Vein Arterialization

Few cases of successful portal vein arterialization in orthotopic and auxiliary liver transplantation have been reported. AIM: To evaluate the effect of portal vein arterialization on hepatic hemodynamics and long-term clinical outcome in three patients undergoing liver transplantation. METHODS: Two patients with extensive splanchnic venous thrombosis received an orthotopic liver transplant and one with fulminant hepatic failure received an auxiliary heterotopic graft. Portal vein arterialization was performed in all cases. RESULTS: One patient died 4 months after transplant and two are still alive. Auxiliary liver graft was removed 3 months post-transplant when complete native liver regeneration was achieved. Immediate post-transplant liver function was excellent in all cases. Only one patient developed encephalopathy and variceal bleeding owing to prehepatic portal hypertension secondary to arterioportal fistula 14 months after transplant. He was successfully treated by embolization of the hepatic artery. Hepatic hemodynamic measurements demonstrated a normal pressure gradient between wedged and free hepatic venous pressures in all cases. Liver biopsy showed acceptable graft architecture in two cases and microsteatosis in one. CONCLUSIONS: Liver transplantation with portal vein arterialization is an acceptable salvage alternative when insufficient portal venous flow to the graft is present. The double arterial supply does not imply changes in hepatic hemodynamics, at least in the early months post-transplant.     

Liver Transplantation for Malignant Diseases: Selection andPattern of Recurrence

Liver transplantation (LT) for malignant tumors should be accepted if, with adequate case selection, long-term results are similar to those in patients transplanted for benign diseases. The aim of the present study was to reexamine selection criteria for LT in malignant diseases with particular emphasis on hepatocellular carcinoma (HCC) in cirrhosis. One hundred-three of 369 patients transplanted in our unit had HCC in cirrhosis (28%), 15 of which were incidental tumors, and 234 patients underwent LT for non-cholestatic cirrhosis. Pretransplant arterial chemoembolization(TACE) was performed in 36 cases (41%) of known HCC. Only early,well-delimited tumors in advanced cirrhosis with no extrahepatic disease were accepted for LT. Hepatocellular carcinoma characteristics included mean tumor size (3.1 cm), multiple (59%), bilobular involvement (31%), and vascular invasion (9.2%). Postoperative mortality was 4%. Median follow-up was 67.5 months. Tumor recurrence rate was 14.5%, 33% (5/15) in incidental tumors and 11.4% (10/88) in known HCC and by tumor stage (pTNM): 7.7% (1/13) in stage I, 16.7%(5/30) in stage II, 15% (3/20) in stage III, and 17% (6/35) in stage IV. Mean time for recurrence was 20.6 months. Tumoral vascular invasion, tumor differentiation, and satellite tumors were significant factors for tumor recurrence in univariate analysis, whereas tumor vascular invasion was the only significant factor for tumor recurrence in multivariate analysis. Actuarial survival rates at 1, 3, and 5 years were 81%, 66%, 58%, respectively, in patients with HCC and were similar to those of cirrhotic patients 76%, 67%, 63%, respectively.In conclusion, patients with early HCC in cirrhosis are good candidates for LT; results are similar when compared with those of cirrhotic patients without tumor. Liver transplantation for other malignancies is admitted only in fibrolamellar hepatoma, hepatoblastoma, epithelioid hemangioendothelioma without extrahepatic disease, and in metastases from carcinoid tumors.