Cell communication by tunneling nanotubes: Implications in disease and therapeutic applications

Intercellular communication is essential for the development and maintenance of multicellular organisms. Tunneling nanotubes (TNTs) are a recently recognized means of long and short distance communication between a wide variety of cell types. TNTs are transient filamentous membrane protrusions that connect cytoplasm of neighboring or distant cells. Cytoskeleton fiber-mediated transport of various cargoes occurs through these tubules. These cargoes range from small ions to whole organelles. TNTs have been shown to contribute not only to embryonic development and maintenance of homeostasis, but also to the spread of infectious particles and resistance to therapies. These functions in the development and progression of cancer and infectious disease have sparked increasing scrutiny of TNTs, as their contribution to disease progression lends them a promising therapeutic target. Herein, we summarize the current knowledge of TNT structure and formation as well as the role of TNTs in pathology, focusing on viral, prion, and malignant disease. We then discuss the therapeutic possibilities of TNTs in light of their varied functions. Despite recent progress in the growing field of TNT research, more studies are needed to precisely understand the role of TNTs in pathological conditions and to develop novel therapeutic strategies.     

HPLC method for the determination of carboplatin and paclitaxel with cremophorEL in an amphiphilic polymer matrix

Simple and rapid reversed phase HPLC methods for individual as well as simultaneous analysis of paclitaxel and carboplatin with cremophorEL (CrEL) in an amphiphilic polymer matrix were developed. Different analytical performance parameters such as linearity, accuracy, precision, specificity, limit of detection (LOD) and limit of quantification (LOQ) were determined according to ICH guidelines. All the analytical methods were developed by reverse phase HPLC on C-18 column with a mobile phase comprising of water-acetonitrile run on isocratic mode for the analysis of carboplatin and gradient mode for individual analysis of paclitaxel and for simultaneous analysis of the two drugs at a flow rate of 1 ml/min at 227 nm. The proposed methods for independent analysis of the drugs elute out carboplatin in 4.3 min and paclitaxel in 10.5 min while in simultaneous analysis carboplatin shows R(t) at 4 min and paclitaxel at 18 min with a continuous run for 17 more minutes to elute out CrEL. These methods were found to be specific as none of the components of the media, i.e. polymer, CrEL and buffer interfered with the drug peaks. The linearity of the calibration curves for each analyte in the desired concentration range was found to be good (r(2)>0.9995). The methods were accurate and precise with recoveries ranging from 98 to 101% for each drug and relative standard deviation (%RSD) <2%. Peaks corresponding to each of the drug showed positive value for the minimum peak purity index over the entire range of integrated chromatographic peak thus indicating the purity of the peaks. Stability analysis of the two drugs revealed that the drugs remain stable during the period of study.     

A hierarchical approach employing metabolic and gene expression profiles to identify the pathways that confer cytotoxicity in HepG2 cells

Background  

Free fatty acids (FFA) and tumor necrosis factor alpha (TNF-α) have been implicated in the pathogenesis of many obesity-related metabolic disorders. When human hepatoblastoma cells (HepG2) were exposed to different types of FFA and TNF-α, saturated fatty acid was found to be cytotoxic and its toxicity was exacerbated by TNF-α. In order to identify the processes associated with the toxicity of saturated FFA and TNF-α, the metabolic and gene expression profiles were measured to characterize the cellular states. A computational model was developed to integrate these disparate data to reveal the underlying pathways and mechanisms involved in saturated fatty acid toxicity.     

Id1 restrains p21 expression to control endothelial progenitor cell formation

Loss of Id1 in the bone marrow (BM) severely impairs tumor angiogenesis resulting in significant inhibition of tumor growth. This phenotype has been associated with the absence of circulating endothelial progenitor cells (EPCs) in the peripheral blood of Id1 mutant mice. However, the manner in which Id1 loss in the BM controls EPC generation or mobilization is largely unknown. Using genetically modified mouse models we demonstrate here that the generation of EPCs in the BM depends on the ability of Id1 to restrain the expression of its target gene p21. Through a series of cellular and functional studies we show that the increased myeloid commitment of BM stem cells and the absence of EPCs in Id1 knockout mice are associated with elevated p21 expression. Genetic ablation of p21 rescues the EPC population in the Id1 null animals, re-establishing functional BM-derived angiogenesis and restoring normal tumor growth. These results demonstrate that the restraint of p21 expression by Id1 is one key element of its activity in facilitating the generation of EPCs in the BM and highlight the critical role these cells play in tumor angiogenesis.     

Polymeric black tea polyphenols modulate the localization and activity of 12-O-tetradecanoylphorbol-13-acetate-mediated kinases in mouse skin: Mechanisms of their anti-tumor-promoting action

Polymeric black tea polyphenols (PBPs) have been shown to possess anti-tumor-promoting effects in two-stage skin carcinogenesis. However, their mechanisms of action are not fully elucidated. In this study, mechanisms of PBP-mediated antipromoting effects were investigated in a mouse model employing the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Compared to controls, a single topical application of TPA to mouse skin increased the translocation of protein kinase C (PKC) from cytosol to membrane. Pretreatment with PBPs 1-3 decreased TPA-induced translocation of PKC isozymes (α, β, η, γ, ε) from cytosol to membrane, whereas PBPs 4 and 5 were less effective. The levels of PKCs δ and ζ in cytosol/membrane were similar in all the treatment groups. Complementary confocal microscopic evaluation showed a decrease in TPA-induced PKCα fluorescence in PBP-3-pretreated membranes, whereas pretreatment with PBP-5 did not show a similar decrease. Based on the experiments with specific enzyme inhibitors and phosphospecific antibodies, both PBP-3 and PBP-5 were observed to decrease TPA-induced level and/or activity of phosphatidylinositol 3-kinase (PI3K) and AKT1 (pS473). An additional ability of PBP-3 to inhibit site-specific phosphorylation of PKCα at all three positions responsible for its activation [PKCα (pT497), PKC PAN (βII pS660), PKCα/βII (pT638/641)] and AKT1 at the Thr308 position, along with a decrease in TPA-induced PDK1 protein level, correlated with the inhibition of translocation of PKC, which may impart relatively stronger chemoprotective activity to PBP-3 than to PBP-5. Altogether, PBP-mediated decrease in TPA-induced PKC phosphorylation correlated well with decreased TPA-induced NF-κB phosphorylation and downstream target proteins associated with proliferation, apoptosis, and inflammation in mouse skin. Results suggest that the antipromoting effects of PBPs are due to modulation of TPA-induced PI3K-mediated signal transduction.     

Management of a post-radiotherapy xerostomic patient--a case report

doi: 10.1111/j.1741‐2358.2011.00519.x Management of a post‐radiotherapy xerostomic patient – a case report Objective: The objective of the study was to fabricate complete denture with palatal reservoir filled with artificial saliva for a post radiotherapy edentulous patient. Background: Xerostomia is a subjective complaint rather than a disease. It is caused by irradiation, medication, Sjogren's syndrome & neurological factors such as stress. Radiotherapeutic treatment of head and neck cancer patients often causes long term dysfunction involving their salivary function, swallowing capabilities & taste. All three of these domains are affected by radiation‐ induced damage to the salivary glands. This in turn results in poor retention of complete denture, frequent trauma to alveolar ridge & other oral infections. All these events drastically affects quality of life of ageing patients. Material and Method: A complete denture in heat cure acrylic resin was fabricated in which a palatal reservoir was made on the palatal side. Results: Problems arising due to xerostomia were reduced to a great extent. Conclusion: Prosthodontic management of Xerostomic patient include several techniques. This paper presents a case report of post radiotherapy edentulous patient in which complete denture with palatal reservoir filled with artificial saliva was fabricated.     

Geriatric dentistry--meet the need

Geriatric dentistry or gerodontics is the delivery of dental care to older adults involving the diagnosis, prevention, and treatment of problems associated with normal ageing and age-related diseases as part of an inter-disciplinary team with other health care professionals. Geriatric health is an ignored and under-explored area worldwide. Oral health reflects overall well being for the elderly population. Conversely, elderly patients are more predisposed to oral conditions due to age-related systemic diseases and functional changes. The major barriers to practising geriatric dentistry are the lack of trained faculty members, a crowded curriculum and monetary concerns. For successful treatment, the practitioner must adopt a humanitarian approach and develop a better understanding of the feelings and attitudes of the elderly. Prevention and early intervention strategies must be formulated to reduce the risk of oral diseases in this population. In future, dental professionals must have a proper understanding of the magnitude of the services to be provided to the elderly. This could only be realised through an education programme in geriatric dentistry, which should be started without further delay. This article hence sets out the objectives, needs, present scenario, strategies and types of dental treatment required by the elderly population.