Nanotheranostic agents for neurodegenerative diseases

2020 ◽  
Vol 4 (6) ◽  
pp. 645-675
Author(s):  
Parasuraman Padmanabhan ◽  
Mathangi Palanivel ◽  
Ajay Kumar ◽  
Domokos Máthé ◽  
George K. Radda ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Neurodegenerative Diseases ◽  
Cell Types ◽  
Specific Cell ◽  
Ageing Population ◽  
Target Tissue ◽  
Therapeutic Approaches ◽  
Surface Receptors ◽  
Theranostic Agents ◽  
Preclinical Animal Models

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), affect the ageing population worldwide and while severely impairing the quality of life of millions, they also cause a massive economic burden to countries with progressively ageing populations. Parallel with the search for biomarkers for early detection and prediction, the pursuit for therapeutic approaches has become growingly intensive in recent years. Various prospective therapeutic approaches have been explored with an emphasis on early prevention and protection, including, but not limited to, gene therapy, stem cell therapy, immunotherapy and radiotherapy. Many pharmacological interventions have proved to be promising novel avenues, but successful applications are often hampered by the poor delivery of the therapeutics across the blood-brain-barrier (BBB). To overcome this challenge, nanoparticle (NP)-mediated drug delivery has been considered as a promising option, as NP-based drug delivery systems can be functionalized to target specific cell surface receptors and to achieve controlled and long-term release of therapeutics to the target tissue. The usefulness of NPs for loading and delivering of drugs has been extensively studied in the context of NDDs, and their biological efficacy has been demonstrated in numerous preclinical animal models. Efforts have also been made towards the development of NPs which can be used for targeting the BBB and various cell types in the brain. The main focus of this review is to briefly discuss the advantages of functionalized NPs as promising theranostic agents for the diagnosis and therapy of NDDs. We also summarize the results of diverse studies that specifically investigated the usage of different NPs for the treatment of NDDs, with a specific emphasis on AD and PD, and the associated pathophysiological changes. Finally, we offer perspectives on the existing challenges of using NPs as theranostic agents and possible futuristic approaches to improve them.

Extracellular nucleotides elevate [Ca2+]i in rat osteoblastic cells by interaction with two receptor subtypes

1992 ◽  
Vol 263 (5) ◽  
pp. C1040-C1048 ◽  
Author(s):  
W. J. Reimer ◽  
S. J. Dixon
Keyword(s):  
Cell Types ◽  
Extracellular Nucleotides ◽  
Osteoblastic Cells ◽  
Osteoblastic Cell ◽  
Receptor Subtypes ◽  
Specific Cell ◽  
Extracellular Medium ◽  
Osteoblastic Cell Line ◽  
Surface Receptors ◽  
Biological Responses

Extracellular nucleotides, through interaction with specific cell-surface receptors, mediate a variety of biological responses, including elevation of cytosolic free Ca2+ concentration ([Ca2+]i) in a number of cell types. The effects of nucleotides on [Ca2+]i in the rat osteoblastic cell line UMR-106 were studied by fluorescence spectrophotometry of indo-1-loaded cells. In response to ATP (100 microM), [Ca2+]i rose to peaks 228 +/- 16 nM (n = 59) above baseline (85 +/- 3 nM) before returning to near basal levels. Half-maximal elevation of [Ca2+]i was observed at an ATP concentration of 3 +/- 1 microM, consistent with a high-affinity interaction. The response arose primarily by release of Ca2+ from internal stores. UTP, ADP, and 2-methylthioadenosine 5'-triphosphate also induced Ca2+ transients, whereas adenosine, AMP, CTP, and TTP did not, demonstrating specificity. Responsiveness to adenosine 5'-O-(3-thiotriphosphate) and inhibition by Mg2+ of the response to ATP indicated that signaling was not dependent on nucleotide hydrolysis. Ca2+ responses to ADP, ATP, and UTP, added sequentially or simultaneously, were consistent with the presence of two distinct P2-purinoceptor subtypes, both linked to Ca2+ mobilization. ADP appeared to interact selectively with one receptor, whereas ATP and UTP interacted selectively with the other. After maximal stimulation with ATP, subsequent responses to ATP were abolished. However, removal of ATP from the extracellular medium rapidly restored responsiveness, suggesting that, with continued receptor occupation, there is time-dependent inactivation of the Ca2+ signaling pathway. Our findings indicate that extracellular nucleotides elevate [Ca2+]i in osteoblastic cells through interaction with two receptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Transporter-Targeted Nano-Sized Vehicles for Enhanced and Site-Specific Drug Delivery

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2837 ◽  
Author(s):  
Longfa Kou ◽  
Qing Yao ◽  
Hailin Zhang ◽  
Maoping Chu ◽  
Yangzom D. Bhutia ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Plasma Membrane ◽  
Blood Brain Barrier ◽  
Drug Delivery Systems ◽  
Cell Types ◽  
Delivery Systems ◽  
Target Cells ◽  
Specific Cell ◽  
Site Specific ◽  
Nano Drug Delivery

Nano-devices are recognized as increasingly attractive to deliver therapeutics to target cells. The specificity of this approach can be improved by modifying the surface of the delivery vehicles such that they are recognized by the target cells. In the past, cell-surface receptors were exploited for this purpose, but plasma membrane transporters also hold similar potential. Selective transporters are often highly expressed in biological barriers (e.g., intestinal barrier, blood–brain barrier, and blood–retinal barrier) in a site-specific manner, and play a key role in the vectorial transfer of nutrients. Similarly, selective transporters are also overexpressed in the plasma membrane of specific cell types under pathological states to meet the biological needs demanded by such conditions. Nano-drug delivery systems could be strategically modified to make them recognizable by these transporters to enhance the transfer of drugs across the biological barriers or to selectively expose specific cell types to therapeutic drugs. Here, we provide a comprehensive review and detailed evaluation of the recent advances in the field of transporter-targeted nano-drug delivery systems. We specifically focus on areas related to intestinal absorption, transfer across blood–brain barrier, tumor-cell selective targeting, ocular drug delivery, identification of the transporters appropriate for this purpose, and details of the rationale for the approach.

scholarly journals Characterization of the cytotoxic effect of extracellular ATP in J774 mouse macrophages

1992 ◽  
Vol 288 (3) ◽  
pp. 897-901 ◽  
Author(s):  
M Murgia ◽  
P Pizzo ◽  
T H Steinberg ◽  
F Di Virgilio
Keyword(s):  
Plasma Membrane ◽  
Membrane Permeability ◽  
Cell Types ◽  
Mouse Cell ◽  
Extracellular Atp ◽  
Cell Swelling ◽  
Specific Cell ◽  
Plasma Membrane Permeability ◽  
Experimental Conditions ◽  
Surface Receptors

Extracellular ATP (ATPo) is known to be cytotoxic to many cell types through a mechanism which is largely unknown. Very recently this nucleotide has been shown to cause cell death by apoptosis, probably by interacting with specific cell-surface receptors. In the present study we have investigated the mechanism of ATPo-dependent cytotoxicity in the macrophage-like mouse cell line J774. It has been previously reported that in this cell type ATPo activates trans-membrane Ca2+ and Na+ fluxes and a drastic increase in the plasma-membrane permeability to hydrophilic solutes smaller than 900 Da. These changes are followed by cell swelling and lysis. We show in the present study that, although this nucleotide triggers a rise in the cytoplasmic Ca2+ concentration, neither cell swelling nor lysis is Ca(2+)-dependent. Furthermore, cell lysis is not dependent on Na+ influx, as it is not prevented by iso-osmotic replacement of extracellular Na+ with choline or N-methylglucamine. On the contrary, ATPo-dependent cytotoxicity, but not the ATPo-dependent increase in plasma-membrane permeability, is completely abrogated in sucrose medium. Under our experimental conditions ATPo does not cause DNA fragmentation in J774 cells. We conclude from these findings that ATPo does not cause apoptosis of J774 macrophages and promotes a Ca(2+)- and Na(+)-independent colloido-osmotic lysis.

Role of microtubule-associated proteins in the control of microtubule assembly

1995 ◽  
Vol 75 (4) ◽  
pp. 835-864 ◽  
Author(s):  
R. B. Maccioni ◽  
V. Cambiazo
Keyword(s):  
Posttranslational Modifications ◽  
Mammalian Cells ◽  
Intracellular Transport ◽  
Cell Types ◽  
Regulatory Elements ◽  
Microtubule Assembly ◽  
Specific Cell ◽  
Surface Receptors ◽  
Microtubule Associated Proteins ◽  
Associated Proteins

In eukaryotic cells, microtubules, actin, and intermediate filaments interact to form the cytoskeletal network involved in determination of cell architecture, intracellular transport, modulation of surface receptors, mitosis, cell motility, and differentiation. Cytoskeletal organization and dynamics depend on protein self-associations and interactions with regulatory elements such as microtubule-associated proteins (MAPs). The MAP family includes large proteins like MAP-1A, MAP-1B, MAP-1C, MAP-2, and MAP-4 and smaller components like tau and MAP-2C. This review focuses on relevant aspects of MAP function, with emphasis on their roles in modulating cytoskeletal interactions. In this context, MAP expression mechanisms and posttranslational modifications are also discussed. Microtubule-associated proteins have a rather widespread distribution among cells, but certain MAPs have been identified in specific cell types. Within single neurons, MAP-2 is dendritic while tau is preferentially an axonal protein. Their expression is developmentally regulated. Even though MAPs share a capacity to interact with the COOH-terminal tubulin domain, stabilize microtubules, and link them with other cytoskeletal polymers, they exhibit structural differences. However, MAP-2, MAP-4, and tau have common repetitive microtubule-binding motifs. Microtubule-associated proteins not only control cytoskeletal integrity, but they also appear to interact with highly structural elements of cells. Molecular biological approaches permitted localization of new MAPs in cultured mammalian cells and invertebrate organisms and other microtubule-interacting proteins that exhibit transient interactions with microtubules. The structural/functional aspects of several new MAP-like proteins in centrosomes and the mitotic spindle, functionally implicated in cell cycle events, are also analyzed.

Genetic, epigenetic and biochemical regulation of succinate dehydrogenase function

2020 ◽  
Vol 401 (3) ◽  
pp. 319-330 ◽  
Author(s):  
Behrooz Moosavi ◽  
Xiao-lei Zhu ◽  
Wen-Chao Yang ◽  
Guang-Fu Yang
Keyword(s):  
Succinate Dehydrogenase ◽  
Metabolic Pathways ◽  
Tca Cycle ◽  
Cell Types ◽  
Specific Cell ◽  
Therapeutic Approaches ◽  
Energy Demands ◽  
Distinct Cell ◽  
Succinate:Quinone Oxidoreductase ◽  
Different Cell Types

AbstractSuccinate dehydrogenase (SDH), complex II or succinate:quinone oxidoreductase (SQR) is a crucial enzyme involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), the two primary metabolic pathways for generating ATP. Impaired function of SDH results in deleterious disorders from cancer to neurodegeneration. SDH function is tailored to meet the energy demands in different cell types. Thus, understanding how SDH function is regulated and how it operates in distinct cell types can support the development of therapeutic approaches against the diseases. In this article we discuss the molecular pathways which regulate SDH function and describe extra roles played by SDH in specific cell types.

Correlative transmission and high-resolution scanning electron microscopic studies on pituitary cells

1990 ◽  
Vol 48 (3) ◽  
pp. 20-21
Author(s):  
S. Tai
Keyword(s):  
Cell Types ◽  
Depth Of Field ◽  
Secretory Cells ◽  
Specific Cell ◽  
Pituitary Cells ◽  
Electron Microscopic ◽  
3 Dimensional ◽  
Microscopic Studies ◽  
Structure And Activity ◽  
Intracellular Structure

Extensive cytological and histological research, correlated with physiological experimental analysis, have been done on the anterior pituitaries of many different vertebrates which have provided the knowledge to create the concept that specific cell types synthesize, store and release their specific hormones. These hormones are stored in or associated with granules. Nevertheless, there are still many doubts - that need further studies, specially on the ultrastructure and physiology of these endocrine cells during the process of synthesis, transport and secretion, whereas some new methods may provide the information about the intracellular structure and activity in detail.In the present work, ultrastructural study of the hormone-secretory cells of chicken pituitaries have been done by using TEM as well as HR-SEM, to correlate the informations obtained from 2-dimensional TEM micrography with the 3-dimensional SEM topographic images, which have a continous surface with larger depth of field that - offers the adventage to interpretate some intracellular structures which were not possible to see using TEM.

Bridging the Gap of Drug Delivery in Colon Cancer: The Role of Chitosan and Pectin Based Nanocarriers System

2020 ◽  
Vol 17 (10) ◽  
pp. 911-924
Author(s):  
Rohitas Deshmukh
Keyword(s):  
Drug Delivery ◽  
Colon Cancer ◽  
Targeted Drug Delivery ◽  
Targeted Delivery ◽  
Therapeutic Agent ◽  
Therapeutic Agents ◽  
Delivery Systems ◽  
Target Tissue ◽  
Polymer Carriers

Colon cancer is one of the most prevalent diseases, and traditional chemotherapy has not been proven beneficial in its treatment. It ranks second in terms of mortality due to all cancers for all ages. Lack of selectivity and poor biodistribution are the biggest challenges in developing potential therapeutic agents for the treatment of colon cancer. Nanoparticles hold enormous prospects as an effective drug delivery system. The delivery systems employing the use of polymers, such as chitosan and pectin as carrier molecules, ensure the maximum absorption of the drug, reduce unwanted side effects and also offer protection to the therapeutic agent from quick clearance or degradation, thus allowing an increased amount of the drug to reach the target tissue or cells. In this systematic review of published literature, the author aimed to assess the role of chitosan and pectin as polymer-carriers in colon targeted delivery of drugs in colon cancer therapy. This review summarizes the various studies employing the use of chitosan and pectin in colon targeted drug delivery systems.

Epithelial Organotypic Cultures: A Viable Model to Address Mechanisms of Carcinogenesis by Epitheliotropic Viruses

2018 ◽  
Vol 18 (4) ◽  
pp. 246-255 ◽  
Author(s):  
Lara Termini ◽  
Enrique Boccardo
Keyword(s):  
Three Dimensional ◽  
Cell Types ◽  
Experimental Models ◽  
Biological Research ◽  
Specific Gene ◽  
Specific Cell ◽  
Organotypic Cultures ◽  
Skin Physiology

In vitro culture of primary or established cell lines is one of the leading techniques in many areas of basic biological research. The use of pure or highly enriched cultures of specific cell types obtained from different tissues and genetics backgrounds has greatly contributed to our current understanding of normal and pathological cellular processes. Cells in culture are easily propagated generating an almost endless source of material for experimentation. Besides, they can be manipulated to achieve gene silencing, gene overexpression and genome editing turning possible the dissection of specific gene functions and signaling pathways. However, monolayer and suspension cultures of cells do not reproduce the cell type diversity, cell-cell contacts, cell-matrix interactions and differentiation pathways typical of the three-dimensional environment of tissues and organs from where they were originated. Therefore, different experimental animal models have been developed and applied to address these and other complex issues in vivo. However, these systems are costly and time consuming. Most importantly the use of animals in scientific research poses moral and ethical concerns facing a steadily increasing opposition from different sectors of the society. Therefore, there is an urgent need for the development of alternative in vitro experimental models that accurately reproduce the events observed in vivo to reduce the use of animals. Organotypic cultures combine the flexibility of traditional culture systems with the possibility of culturing different cell types in a 3D environment that reproduces both the structure and the physiology of the parental organ. Here we present a summarized description of the use of epithelial organotypic for the study of skin physiology, human papillomavirus biology and associated tumorigenesis.

scholarly journals Nanocarriers, Progenitor Cells, Combinational Approaches, and New Insights on the Retinal Therapy

2021 ◽  
Vol 22 (4) ◽  
pp. 1776
Author(s):  
Elham Pishavar ◽  
Hongrong Luo ◽  
Johanna Bolander ◽  
Antony Atala ◽  
Seeram Ramakrishna
Keyword(s):  
Drug Delivery ◽  
Progenitor Cells ◽  
Transfection Efficiency ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Therapeutic Approaches ◽  
Age Related ◽  
Nanofibrous Scaffolds ◽  
The Stability

Progenitor cells derived from the retinal pigment epithelium (RPECs) have shown promise as therapeutic approaches to degenerative retinal disorders including diabetic retinopathy, age-related macular degeneration and Stargardt disease. However, the degeneration of Bruch’s membrane (BM), the natural substrate for the RPE, has been identified as one of the major limitations for utilizing RPECs. This degeneration leads to decreased support, survival and integration of the transplanted RPECs. It has been proposed that the generation of organized structures of nanofibers, in an attempt to mimic the natural retinal extracellular matrix (ECM) and its unique characteristics, could be utilized to overcome these limitations. Furthermore, nanoparticles could be incorporated to provide a platform for improved drug delivery and sustained release of molecules over several months to years. In addition, the incorporation of tissue-specific genes and stem cells into the nanostructures increased the stability and enhanced transfection efficiency of gene/drug to the posterior segment of the eye. This review discusses available drug delivery systems and combination therapies together with challenges associated with each approach. As the last step, we discuss the application of nanofibrous scaffolds for the implantation of RPE progenitor cells with the aim to enhance cell adhesion and support a functionally polarized RPE monolayer.

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