Unveiling the Neurodegenerative Alterations through Oral Stem Cells.

Parkinson's disease (PD) is a neurodegenerative condition characterized by the progressive and selective loss of dopaminergic (DAergic) neurons in the midbrain. The replacement of neuromelanin (NM)-containing DAergic neurons in the substantia nigra and the enhancement of NM concentration could offer a promising and safe approach to treating PD symptoms. The objective of this study was to investigate and compare the potential of human periapical-cysts mesenchymal stem cells (hPCy-MSCs) and dental pulp stem cells (DPSCs) to differentiate into DAergic NM-producing neurons and to generate functional 3-dimensional (3D) midbrain-like organoids in vitro.

Resveratrol Treatment in Human -Mutant Fibroblasts Modulates cAMP and Calcium Homeostasis Regulating the Expression of Mitochondria-Associated Membranes Resident Proteins.

Parkin plays an important role in ensuring efficient mitochondrial function and calcium homeostasis. -mutant human fibroblasts, with defective oxidative phosphorylation activity, showed high basal cAMP level likely ascribed to increased activity/expression of soluble adenylyl cyclase and/or low expression/activity of the phosphodiesterase isoform 4 and to a higher Ca level. Overall, these findings support the existence, in -mutant fibroblasts, of an abnormal Ca and cAMP homeostasis in mitochondria.

Behind the Scene: Exploiting MC1R in Skin Cancer Risk and Prevention.

Melanoma and non-melanoma skin cancers (NMSCs) are the most frequent cancers of the skin in white populations. An increased risk in the development of skin cancers has been associated with the combination of several environmental factors (i.e.

Clinical course of choroidal neovascular membrane in West Nile virus chorioretinitis: a case report.

Background: This report describes the clinical course of choroidal neovascular membrane (CNV) in West Nile virus-associated chorioretinitis.

Case Presentation: A 28-year-old Italian woman was referred to our institution because of reduced visual acuity in the left eye dating back 4 months. A diagnosis of retinal vasculitis in the right eye and chorioretinitis with CNV in the left eye was made.

Mitochondria, Oxidative Stress, cAMP Signalling and Apoptosis: A Crossroads in Lymphocytes of Multiple Sclerosis, a Possible Role of Nutraceutics.

Multiple sclerosis (MS) is a complex inflammatory and neurodegenerative chronic disease that involves the immune and central nervous systems (CNS). The pathogenesis involves the loss of blood-brain barrier integrity, resulting in the invasion of lymphocytes into the CNS with consequent tissue damage. The MS etiology is probably a combination of immunological, genetic, and environmental factors.

Effect of Cladribine on Neuronal Apoptosis: New Insight of In Vitro Study in Multiple Sclerosis Therapy.

Background: Cladribine (2-CdA) can cross the blood-brain barrier, resulting in inhibition of DNA synthesis and repair and disruption of cellular proliferation in actively dividing lymphocytes. No data on effect on neurons are available.

Aim: To study "in vitro" 2-CdA apoptotic effects on neurons in healthy donor and multiple sclerosis patient lymphocytes.

Tomatine Displays Antitumor Potential in In Vitro Models of Metastatic Melanoma.

There is a growing interest in the cytotoxic effects of bioactive glycoalkaloids, such as α-tomatine on tumor cells. Here, for the first time, we determine the antitumor potential of tomatine, a mixture of α-tomatine and dehydrotomatine, in metastatic melanoma (MM) cell lines harboring different BRAF and MC1R variants. We performed cytotoxicity experiments and annexin-V/propidium iodide staining to assess the apoptotic/necrotic status of the cells.

PBMC of Multiple Sclerosis Patients Show Deregulation of OPA1 Processing Associated with Increased ROS and PHB2 Protein Levels.

Multiple sclerosis (MS) is an autoimmune disease in which activated lymphocytes affect the central nervous system. Increase of reactive oxygen species (ROS), impairment of mitochondria-mediated apoptosis and mitochondrial alterations have been reported in peripheral lymphocytes of MS patients. Mitochondria-mediated apoptosis is regulated by several mechanisms and proteins.

Mitochondrial Dynamics of Proximal Tubular Epithelial Cells in Nephropathic Cystinosis.

Nephropathic cystinosis is a rare lysosomal storage disorder caused by mutations in gene leading to Fanconi syndrome. Independent studies reported defective clearance of damaged mitochondria and mitochondrial fragmentation in cystinosis. Proteins involved in the mitochondrial dynamics and the mitochondrial ultrastructure were analyzed in -/- cells treated with cysteamine, the only drug currently used in the therapy for cystinosis but ineffective to treat Fanconi syndrome.

PGC-1β Induces Susceptibility To Acetaminophen-Driven Acute Liver Failure.

Acetaminophen (APAP) is a worldwide commonly used painkiller drug. However, high doses of APAP can lead to acute hepatic failure and, in some cases, death. Previous studies indicated that different factors, including life-style and metabolic diseases, could predispose to the risk of APAP-induced liver failure.

Decreased amount of vimentin N-terminal truncated proteolytic products in parkin-mutant skin fibroblasts.

Vimentin, a member of cytoskeleton intermediate filaments proteins, plays a critical role in cell structure and dynamics. The present proteomic study reveals reduced amount of six different lengths, N-terminal truncated proteolytic products of vimentin, in the primary skin fibroblasts from two unrelated PD patients, as compared to control fibroblasts. The decreased amount of N-terminal truncated forms of vimentin in parkin-mutant fibroblasts, could contribute to impairment of cellular function, potentially contributing to the pathogenesis of Parkinson disease.

Human Ovarian Cancer Tissue Exhibits Increase of Mitochondrial Biogenesis and Cristae Remodeling.

Ovarian cancer (OC) is the most lethal gynecologic cancer characterized by an elevated apoptosis resistance that, potentially, leads to chemo-resistance in the recurrent disease. Mitochondrial oxidative phosphorylation was found altered in OC, and mitochondria were proposed as a target for therapy. Molecular evidence suggests that the deregulation of mitochondrial biogenesis, morphology, dynamics, and apoptosis is involved in carcinogenesis.

Synergistic Effect of Mitochondrial and Lysosomal Dysfunction in Parkinson's Disease.

Crosstalk between lysosomes and mitochondria plays a central role in Parkinson's Disease (PD). Lysosomal function may be influenced by mitochondrial quality control, dynamics and/or respiration, but whether dysfunction of endocytic or autophagic pathway is associated with mitochondrial impairment determining accumulation of defective mitochondria, is not yet understood. Here, we performed live imaging, western blotting analysis, sequencing of mitochondrial DNA (mtDNA) and senescence-associated beta-galactosidase activity assay on primary fibroblasts from a young patient affected by PD, her mother and a healthy control to analyze the occurrence of mtDNA mutations, lysosomal abundance, acidification and function, mitochondrial biogenesis activation and senescence.

Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in -Mutant Fibroblasts.

Almost half of autosomal recessive early-onset parkinsonism has been associated with mutations in , coding for parkin, which plays an important role in mitochondria function and calcium homeostasis. Cyclic adenosine monophosphate (cAMP) is a major second messenger regulating mitochondrial metabolism, and it is strictly interlocked with calcium homeostasis. -mutant (Pt) fibroblasts, exhibiting defective mitochondrial respiratory/OxPhos activity, showed a significant higher value of basal intracellular level of cAMP, as compared with normal fibroblasts (CTRL).

Translational control mechanisms in cutaneous malignant melanoma: the role of eIF2α.

Background: Melanoma cells develop adaptive responses in order to cope with particular conditions of tumor microenvironment, characterized by stress conditions and deregulated proliferation. Recently, the interplay between the stress response and the gene expression programs leading to metastatic spread has been reported.

Methods: We evaluated levels and localization of eIF2α/peIF2α in V600BRAF and wtBRAF metastatic melanoma cell lines by means of western blot and confocal microscopy analyses.

Resveratrol Modulation of Protein Expression in -Mutant Human Skin Fibroblasts: A Proteomic Approach.

In this study, we investigated by two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) analysis the effects of resveratrol treatment on skin primary fibroblasts from a healthy subject and from a -mutant early onset Parkinson's disease patient. Parkin, an E3 ubiquitin ligase, is the most frequently mutated gene in hereditary Parkinson's disease. Functional alteration of parkin leads to impairment of the ubiquitin-proteasome system, resulting in the accumulation of misfolded or aggregated proteins accountable for the neurodegenerative process.

New insight into the role of metabolic reprogramming in melanoma cells harboring BRAF mutations.

This study explores the BRAF-MITF-PGC-1α axis and compares metabolic and functional changes occurring in primary and metastatic BRAF melanoma cell lines. BRAF mutations in homo/heterozygosis were found to be correlated to high levels of pERK, to downregulate PGC-1α/β, MITF and tyrosinase activity, resulting in a reduced melanin synthesis as compared to BRAFwt melanoma cells. In this scenario, BRAF switches on a metabolic reprogramming in melanoma, leading to a decreased OXPHOS activity and increased glycolytic ATP, lactate, HIF-1α and MCT4 levels.

Detrimental effects of melanocortin-1 receptor (MC1R) variants on the clinical outcomes of BRAF V600 metastatic melanoma patients treated with BRAF inhibitors.

Melanocortin-1 receptor (MC1R) plays a key role in skin pigmentation, and its variants are linked with a higher melanoma risk. The influence of MC1R variants on the outcomes of patients with metastatic melanoma (MM) treated with BRAF inhibitors (BRAFi) is unknown. We studied the MC1R status in a cohort of 53 consecutive BRAF-mutated patients with MM treated with BRAFi.

Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015.

MELANOMA BRIDGE 2015 KEYNOTE SPEAKER PRESENTATIONS Molecular and immuno-advances K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A.

Altered protein expression pattern in skin fibroblasts from parkin-mutant early-onset Parkinson's disease patients.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder caused primarily by selective degeneration of the dopaminergic neurons in substantia nigra. In this work the proteomes extracted from primary fibroblasts of two unrelated, hereditary cases of PD patients, with different parkin mutations, were compared with the proteomes extracted from commercial adult normal human dermal fibroblasts (NHDF) and primary fibroblasts from the healthy mother of one of the two patients. The results show that the fibroblasts from the two different cases of parkin-mutant patients display analogous alterations in the expression level of proteins involved in different cellular functions, like cytoskeleton structure-dynamics, calcium homeostasis, oxidative stress response, protein and RNA processing.

Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy.

Background: The poor response to chemotherapy and the brief response to vemurafenib in metastatic melanoma patients, make the identification of new therapeutic approaches an urgent need. Interestingly the increased expression and activity of the Aurora kinase B during melanoma progression suggests it as a promising therapeutic target.

Methods: The efficacy of the Aurora B kinase inhibitor barasertib-HQPA was evaluated in BRAF mutated cells, sensitive and made resistant to vemurafenib after chronic exposure to the drug, and in BRAF wild type cells.

Cytoskeletal Alterations and Biomechanical Properties of parkin-Mutant Human Primary Fibroblasts.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Genes which have been implicated in autosomal-recessive PD include PARK2 which codes for parkin, an E3 ubiquitin ligase that participates in a variety of cellular activities. In this study, we compared parkin-mutant primary fibroblasts, from a patient with parkin compound heterozygous mutations, to healthy control cells.

Effect of resveratrol on mitochondrial function: implications in parkin-associated familiar Parkinson's disease.

Mitochondrial dysfunction and oxidative stress occur in Parkinson's disease (PD), but the molecular mechanisms controlling these events are not completely understood. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator known as master regulator of mitochondrial functions and oxidative metabolism. Recent studies, including one from our group, have highlighted altered PGC-1α activity and transcriptional deregulation of its target genes in PD pathogenesis suggesting it as a new potential therapeutic target.