The role of morbid obesity in the promotion of metabolic disruptions and non-alcoholic steatohepatitis by Helicobacter Pylori

Helicobacter pylory (HP) infection has been associated to an increased rate of type 2 diabetes (T2D) and liver disease through its effect on insulin resistance and systemic inflammation. However, results are inconstant and no studies exist in morbidly obese patients, in which both insulin resistance and inflammation coexist

Vanin-1 Pantetheinase Drives Smooth Muscle Cell Activation in Post-Arterial Injury Neointimal Hyperplasia

The pantetheinase vanin-1 generates cysteamine, which inhibits reduced glutathione (GSH) synthesis. Vanin-1 promotes inflammation and tissue injury partly by inducing oxidative stress, and partly by peroxisome proliferator-activated receptor gamma (PPARγ) expression. Vascular smooth muscle cells (SMCs) contribute to neointimal hyperplasia in response to injury, by multiple mechanisms including modulation of oxidative stress and PPARγ. Therefore, we tested the hypothesis that vanin-1 drives SMC activation and neointimal hyperplasia. We studied reactive oxygen species (ROS) generation and functional responses to platelet-derived growth factor (PDGF) and the pro-oxidant diamide in cultured mouse aortic SMCs, and also assessed neointima formation after carotid artery ligation in vanin-1 deficiency. Vnn1−/− SMCs demonstrated decreased oxidative stress, proliferation, migration, and matrix metalloproteinase 9 (MMP-9) activity in response to PDGF and/or diamide, with the effects on proliferation linked, in these studies, to both increased GSH levels and PPARγ expression. Vnn1−/− mice displayed markedly decreased neointima formation in response to carotid artery ligation, including decreased intima:media ratio and cross-sectional area of the neointima. We conclude that vanin-1, via dual modulation of GSH and PPARγ, critically regulates the activation of cultured SMCs and development of neointimal hyperplasia in response to carotid artery ligation. Vanin-1 is a novel potential therapeutic target for neointimal hyperplasia following revascularization

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis.

Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease

Heterodimers of photoreceptor-specific nuclear receptor (PNR/NR2E3) and peroxisome proliferator-activated receptor (PPARγ) are disrupted by retinal disease-associated mutations

Photoreceptor-specific nuclear receptor (PNR/NR2E3) and Tailless homolog (TLX/NR2E1) are human orthologs of the NR2E group, a subgroup of phylogenetically related members of the Nuclear Receptor (NR) superfamily of transcription factors. We assessed the ability of these NRs to form heterodimers with other members of the human NRs representing all major subgroups. The TLX ligand binding domain (LBD) did not appear to form homodimers or interact directly with any other NR tested. The PNR LBD was able to form homodimers, but also exhibited robust interactions with the LBDs of PPARγ/NR1C3 and TRβ/NR1A2. The binding of PNR to PPARγ was specific for this paralog, as no interaction was observed with the LBDs of PPARαNR1C1 or PPARδNR1C2. In support of these findings, PPARγ and PNR were found to be co-expressed in human retinal tissue extracts and could be co-immunoprecipitated as a native complex. Selected sequence variants in the PNR LBD associated with human retinopathies, or a mutation in the dimerization region of PPARγ LBD associated with familial partial lipodystrophy type 3, were found to disrupt PNR/PPARγ complex formation. Wild type PNR, but not a PNR309G mutant, was able to repress PPARγ-mediated transcription in reporter assays. In summary our results reveal novel heterodimer interactions in the NR superfamily, suggesting previously unknown functional interactions of PNR with PPARγ and TRβ that have potential importance in retinal development and disease

Increased renal papillary density in kidney stone formers detectable by CT scan is a potential marker of stone risk, but is unrelated to underlying hypercalciuria

Several previous studies have reported an increase in Hounsfield unit density of the renal papillae in patients with nephrolithiasis compared with controls. Kidney stone formers (KSF) were found to have higher papillary and cortical density in both kidneys, irrespective of which side had calculi, and it was proposed that this might be related to the presence of underlying hypercalciuria. The current study was designed: (1) to determine whether recurrent KSF do have higher papillary density compared with healthy controls; (2) to test an association between higher renal papillary density and the presence of hypercalciuria in KSF. This retrospective case-matched controlled study was carried out at the Royal Free Hospital, London, UK. We investigated 111 patients, 57 of whom were KSF and 54 healthy controls. The CT attenuation values were measured within a 0.2 cm2 area of the renal papilla in the upper, middle, and lower segments of each kidney, and were compared between KSF and non-stone formers, and between KSF with and without hypercalciuria. There were no significant differences in age and sex between groups. Papillary density was significantly higher in KSF by both crude and adjusted analyses (p < 0.001). However, there was no association between higher papillary density and hypercalciuria in KSF. The papillary density measured by CT is a useful, non-invasive tool to differentiate between KSF and healthy controls. The absence of any correlation between papillary density and hypercalciuria suggests that the presence of clinically significant underlying renal stone disease, rather than urinary metabolic abnormalities, correlates with radiologically detectable increased papillary density

Palliative sedation in controlling the refractort symptoms in oncologic patients. A bioethical approach

Palliative care asserts the importance of life, considering that the human beings have the right to be cared and respected until the last moment of their lives. In oncologic patients, physical symptoms in general, and pain, in particular, are enhanced by psychological, social, cultural and spiritual issues. Along with progression of the disease, symptoms may become overwhelming and refractory to usual therapeutic approaches, despite the efforts, sometimes even aggressive, to identify a tolerable therapy which does not compromise the consciousness and relieves pain. One of the solutions may be palliative sedation, which means the voluntary administration of the opioids and non-opioids drugs in adequate doses and concentrations in order to lower the consciousness as much as necessary to ameliorate one or more symptoms which are refractory to other therapies. Palliative sedation, since the proposition of its practice in the healthcare of the terminal patient, with unbearable pain, generated numerous dilemmas and debates which are still ongoing. In this paper the authors approach the issue of the palliative sedation both from medical and ethical perspectives, highlighting the importance of placing the patient in the center of the decision-making process regarding the medical treatment and its guidance according to the risks and benefits for the patient