Current Molecular Medicine - Volume 15, Issue 1, 2015

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in adults and its prevalence is rising around the world. This pathology is characterized by accumulation of liver fat, which exceeds 5% of liver weight in absence of alcohol consumption, viral infection or other hepatic etiology. Since NAFLD has been associated with obesity, insulin resistance, diabetes or alteration of lipid profiles, it is considered as the liver manifestation of metabolic syndrome. Pathogenic mechanisms of NAFLD have not been clearly elucidated, but different events such as lipid accumulation, insulin resistance, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction and inflammation are involved. Modifications in lifestyle constitute the first line for the management of NAFLD. Nutritional interventions include low fat and carbohydrate diet with higher polyunsaturated fatty acids ingestion. Moreover, supplementation with antioxidant and cytoprotective agents could be useful to decrease oxidative stress, inflammation and fibrosis. Physical activity enables to reduce the expression of lipogenic genes, fat accumulation, or insulin resistance and improves cardiorespiratory fitness. Benefits have been found following both aerobic exercise and resistance training, and remain even after exercise cessation. However, more studies are required to analyze the molecular and cellular mechanisms involved in nutritional and physical intervention, and to define the volume of activity required and its association with weight loss. In this paper, we offer an updated overview of the mechanisms implicated in the progression of NAFLD, and analyze the beneficial effects of nutritional interventions and physical exercise in the prevention and treatment of this condition.

The Klotho protein deficiency is known to participate in premature aging. As an aging suppressor, Klotho is an important molecule in aging processes and its overexpression results in longevity. Due to many reasons, the insulin/insulin-like growth factor-1 (IGF-1) has been considered as a key pathway in aging research. The Klotho gene is closely related to this pathway. The Klotho gene encodes a transmembrane protein that after cleavage is also found as a secreted protein. Importantly, its overexpression suppresses insulin/IGF-1 signaling and thus extends the lifespan. In addition, Klotho participates in the regulation of several other intracellular signaling pathways, including regulation of FGF23 signaling, cAMP, PKC, transforming growth factor-β (TGF-β), p53/p21, and Wnt signaling. The aim of this review is to summarize current literature that shows the involvement of Klotho in the regulation of several intracellular pathways. The results of our review clearly indicate that Klotho participates in several intracellular signaling pathways, and by regulating them, Klotho is involved in aging and longevity.

The endoplasmic reticulum(ER) is crucial for protein and lipid synthesis, folding and cellular homeostasis. Function impairment of ER would induce ER stress, which might play an important role in many different pathological states. Small heat shock proteins (sHsps) are known to be widely expressed throughout many tissues. SHsps are found to regulate many different pathological and pathophysiological processes and they are supposed to be potential therapeutic targets. Recent studies indicate that multiple sHsps localize to the mammalian and plant ER and sHsps confer protection against ER stress in multiple cellular processes. The mechanisms responsible for the cytoprotective effects of sHsps are related to maintaining ER homeostasis. Improved understanding of sHsps-related cytoprotective action on ER and successful strategies which could specifically target components of ER stress signalling responses amelioration of their toxic effects by sHsps is of great importance in the development of therapeutic approach for the disorders induced by dysfunction of ER.

HSPB5 or αB-crystallin (αBC) is a major protein of the vertebrate eye lens belonging to the small heat-shock protein family of proteins that respond to various stressful conditions. αBC also is found outside the lens in various non-ocular tissues and acts as a molecular chaperone by preventing aggregation of proteins, inhibits apoptosis and inflammation, and maintains cytoskeletal architecture. The αBC protein is phosphorylated on three serine residues S59, S45, and S19, and several functions of αBC are modulated by phosphorylation. Numerous studies have revealed the upregulation of αBC in pathological conditions such as neurodegenerative diseases, cancers, diabetes, retinal diseases, cataracts, ischemia/repurfusion, aging, and others. However, it is unknown whether the up-regulation of αBC is causative or protective for these pathological conditions. Although αBC has been shown to provide a protective effect in neurodegenerative diseases, inflammation, diabetes, and retinal diseases, other studies have described a deleterious role of αBC in cancers and pulmonary fibrosis. The therapeutic potential of αBC alone or in combination with αA-crystallin has been reported. Acetylated αBC peptides have been shown to be more potent than native αBC for chaperone as well as therapeutic activities using both in vitro and in vivo models. Further, for efficient delivery of α BC into cells, carrier molecules such as polylacticcoglycolic acid, polycaprolactone and cell penetration peptides have been used. In this review, we have summarized current data from emerging and exciting studies of the therapeutic strategies of α BC and α BC peptides and the efficient delivery strategies of these proteins in various disease models, including neurodegenerative diseases, retinal diseases, platelet aggregation, inflammation, and ischemia.

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system, local mediator in the gut and vasoactive agent in the blood. Serotonin exerts its multiple, sometimes opposing actions through interaction with a multiplicity of receptors coupled to various signalling pathways. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumoral cells. Serotonin exhibits a growth stimulatory effect in aggressive cancers and carcinoids more often through 5- HT1 and 5-HT2 receptors. In contrast, low doses of serotonin can inhibit tumour growth via the decrease of blood supply to the tumour, suggesting that the role of serotonin on tumour growth is concentration-dependent. Data are also available on serotonin involvement in cancer cell migration, metastatic processes and as a mediator of angiogenesis. Moreover, the progression of some tumours is accompanied by a dysregulation of the pattern of serotonin receptor expressions. Serum serotonin level was found to be suitable for prognosis evaluation of urothelial carcinoma in the urinary bladder, adenocarcinoma of the prostate and renal cell carcinoma. In some cases, antagonists of serotonin receptors, inhibitors of selective serotonin transporter and of serotonin synthesis have been successfully used to prevent cancer cell growth. This review revaluates serotonin involvement in several types of cancer and at different stages of their progression.

Immune tolerance can be induced by numerous methods. This review article aims to draw lines of similarity and contrast between two unique models of immune tolerance, namely Anterior Chamber Associated Immune Deviation (ACAID) and Nickel-induced oral tolerance. ACAID is an immune tolerance model that leads to the generation of CD4+ T regulatory cells and CD8+ T regulatory cells in the periphery after the injection of an antigen into the anterior chamber of the eye. Nickel-induced oral tolerance is another immune tolerance model that is induced by the contact allergen Nickel and leads to the generation of Nickel-specific CD4+ CD25+ T regulatory cells after oral exposure. The goal of comparing different models of immune tolerance is to identify which mechanisms are universal and which mechanisms are model-specific. The knowledge of such mechanisms would allow scientists and clinicians to better intervene in different immune deregulation scenarios.

Medulloblastoma is the most common malignant childhood brain tumor and is associated with a poor outcome. There is an urgent need to develop novel targeted therapeutic approaches for medulloblastoma, which will arise from an enhanced understanding of the disease at the molecular level. Medulloblastoma has been recognized to be a heterogeneous disease, and no recurrent cancer gene mutations have been found, although many of the mutations described so far affect key intracellular signaling pathways, such as sonic hedgehog (SHH) and Wnt/β-catenin. The PI3K/AKT/mTOR (PAM) signaling pathway controls key cellular responses, such as cell growth and proliferation, survival, migration and metabolism. Over the last decades, it has been recognized that this intracellular signaling pathway is frequently activated by genetic and epigenetic alterations in malignant brain tumors, including medulloblastoma. Clinical trials have started to evaluate the safety and efficacy of agents targeting this pathway in malignant brain tumors. Due to the complexity of the PAM signaling pathway, there remain significant difficulties in the development of novel therapeutic approaches. The future challenges in developing effective treatments for cancer patients include the development of predictive biomarkers and combinatorial approaches to effectively target multiple signal transduction pathways. In this review article, we will summarize the current knowledge about the role of PAM signaling in medulloblastoma and discuss the strategies that are currently being evaluated with targeted agents against this pathway.

Glucocorticoids (GCs) exert their effects through regulation of gene expression after activation in the cytoplasm of the glucocorticoid receptor (GR) encoded by NR3C1 gene. A negative feedback mechanism resulting in GR autoregulation has been demonstrated through the binding of the activated receptor to intragenic sequences called GRE-like elements, contained in GR gene. The long noncoding RNA growth arrest–specific transcript 5 (GAS5) interacts with the activated GR suppressing its transcriptional activity. The aim of this study was to evaluate the possible role of GAS5 and NR3C1 gene expression in the antiproliferative effect of methylprednisolone in peripheral blood mononuclear cells and to correlate the expression with individual sensitivity to GCs. Subjects being poor responders to GCs presented higher levels of GAS5 and NR3C1 in comparison with good responders. We suggest that abnormal levels of GAS5 may alter GC effectiveness, probably interfering with the mechanism of GR autoregulation.

Wip1 is a serine/threonine protein phosphatase which plays a critical role in neutrophil development and maturation. In the present study, we used a neutrophildependent model of intestinal ischemia/reperfusion (I/R) injury to identify the role of Wip1 in neutrophil function under the condition of oxidative stress and inflammation. Wip1- deficient mice displayed more severe intestinal I/R injury with increased infiltration of neutrophils and higher expression of chemokines like CXCL-1, CXCL-2 and CCL-2, as well as inflammatory cytokine like TNF-α and IL-17. Studies in Wip1KOa→WT full hematopoietic chimera mice showed that Wip1 intrinsically regulated the function of immune cells after intestinal I/R injury. Through adoptive transfer of neutrophils from WT mice or mice with deficiency of IL-17, IL-17/Wip1 or Wip1, we demonstrated that Wip1KO neutrophils produced more IL-17 and eventually led to more severe intestinal I/R injury. Thus, our findings identify Wip1 as an intrinsic negative regulator of neutrophil inflammation in intestinal I/R injury process.