Ceramide in Cystic Fibrosis: A Potential New Target for Therapeutic Intervention

Patients with cystic fibrosis (CF) are afflicted with many symptoms but the greatest challenge is the fight against chronic bacterial infections, leading to decreased lung function and ultimately death. Our group has recently found reduced levels of ceramides in CF patients and mice. Ceramides are sphingolipids involved in the structure of cell membranes but also participate in the inflammatory response, in cell signalling through membrane microdomains (lipid rafts), and in apoptosis. These characteristics of ceramides make them strong candidates for therapeutic intervention in CF. As more studies have come to evaluate the role of ceramide in CF, conflicting results have been described. This paper discusses various views regarding the potential role of ceramide in CF, summarizes methods of ceramide detection and their role in the regulation of cellular and molecular processes

Genetics of Allergic Asthma and Current Perspectives on Therapeutic Management

Globally, more than 300 million people are asthmatics and this number has been estimated to become 400 million by 2025. Asthma is a chronic inflammatory condition, which, although has no cure, is treatable in most patients. The most common structural alterations in asthmatic airways include thickening of the epithelial and sub epithelial layers, increased airway smooth muscle mass, and angiogenesis. Several genetically controlled factors greatly influence the predisposition and severity of allergic asthma. Twin studies have attributed as much as 75% of asthma susceptibility to heredity. Particularly, genome-wide association studies (GWASs) have discovered several asthma and/or atopy susceptibility genes. Current treatment protocols for managing asthma involve the use of corticosteroids and β-agonists. Over the last 40 years, there has been a marked development-targeted therapy for asthma, such as anti-leukotrienes, anti-immunoglobulin (Ig)E, anti-tumor necrosis factor (TNF)-α, and anti-interleukins (ILs) (Th2 cytokines). To identify novel targets and to develop newer drug generations, better understanding of asthma molecular pathophysiology is required. Furthermore, the pharmacogenetic studies, focusing on better understanding of beneficial or/and adverse effects to anti-asthma drugs, will also facilitate the development of more effective and targeted treatments in specific subpopulations of patients suffering from asthma

New Frontiers in Cancer Chemotherapy — Targeting Cell Death Pathways

Cell death plays an important role in tumorigenesis, growth, and progression and affects the efficiency of chemotherapy to a great extent. Apoptosis is usually regarded as the principal mechanism of chemotherapy-induced cell death. However, the dysregulation of apoptosis occurs commonly in many cancers, which lowers the effectiveness of therapy and allows cells to survive. The mechanisms by which cells acquire this resistance to chemotherapy are not fully understood. Several studies uncovered alternative cell death pathways that are mechanistically distinct from apoptosis. These pathways, including autophagy and necrosis, represent potential targets for novel cancer treatment. By modulating the key regulatory molecules involved in the different types of cell death, more effective and less toxic chemotherapy might be developed. In this chapter, we describe the signaling pathways and the molecular events that are involved in these three major forms of programmed cell death. Additionally, we also discuss the emerging therapies targeting these cell death pathways as new strategies against cancer

Brg-1 mediates the constitutive and fenretinide-induced expression of SPARC in mammary carcinoma cells via its interaction with transcription factor Sp1

BACKGROUND: Secreted protein, acidic and rich in cysteine (SPARC) is a matricellular protein that mediates cell-matrix interactions. It has been shown, depending on the type of cancer, to possess either pro- or anti-tumorigenic properties. The transcriptional regulation of the SPARC gene expression has not been fully elucidated and the effects of anti-cancer drugs on this process have not been explored. RESULTS: In the present study, we demonstrated that chromatin remodeling factor Brg-1 is recruited to the proximal SPARC promoter region (-130/-56) through an interaction with transcription factor Sp1. We identified Brg-1 as a critical regulator for the constitutive expression levels of SPARC mRNA and protein in mammary carcinoma cell lines and for SPARC secretion into culture media. Furthermore, we found that Brg-1 cooperates with Sp1 to enhance SPARC promoter activity. Interestingly, fenretinide [N-4(hydroxyphenyl) retinamide, 4-HPR], a synthetic retinoid with anti-cancer properties, was found to up-regulate the transcription, expression and secretion of SPARC via induction of the Brg-1 in a dose-dependent manner. Finally, our results demonstrated that fenretinide-induced expression of SPARC contributes significantly to a decreased invasion of mammary carcinoma cells. CONCLUSIONS: Overall, our results reveal a novel cooperative role of Brg-1 and Sp1 in mediating the constitutive and fenretinide-induced expression of SPARC, and provide new insights for the understanding of the anti-cancer effects of fenretinide

Distinct Tryptophan Catabolism and Th17/Treg Balance in HIV Progressors and Elite Controllers

Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO) was previously linked to Th17/Treg differentiation and immune activation. Here we examined Trp catabolism and its impact on Th17/Treg balance in uninfected healthy subjects (HS) and a large cohort of HIV-infected patients with different clinical outcomes: ART-naïve, Successfully Treated (ST), and elite controllers (EC). In ART-naïve patients, increased IDO activity/expression, together with elevated levels of TNF-α and sCD40L, were associated with Treg expansion and an altered Th17/Treg balance. These alterations were normalized under ART. In contrast, Trp 2,3-dioxegenase (TDO) expression was dramatically lower in EC when compared to all other groups. Interestingly, EC displayed a distinctive Trp metabolism characterized by low Trp plasma levels similar to ART-naïve patients without accumulating immunosuppressive Kyn levels which was accompanied by a preserved Th17/Treg balance. These results suggest a distinctive Trp catabolism and Th17/Treg balance in HIV progressors and EC. Thus, IDO-induced immune-metabolism may be considered as a new inflammation-related marker for HIV-1 disease progression