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Today, 12 Ιουλίου 2016, 4:05:55 μμ
Nanocarriers Made from Non-Ionic Surfactants or Natural Polymers for Pulmonary Drug Delivery
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Background: Treatment by the pulmonary route can be used for drugs that act locally in the lungs (e.g. lung cancer) or non-invasive administration of drugs that act systemically (e.g. diabetes). The potential of using drug delivery systems (DDS) formed from non-ionic surfactants or natural products for pulmonary drug delivery are reviewed. </p><p> Methods: The effectiveness of each DDS depends on it ability to not only entrap the relevant drug and alter its bio distribution, but also its ability to withstand the physical stresses during nebulization and for the nebuliser to produce aerosol particles with the size for deposition in the appropriate part of the lungs. Different methods must be used to prepare nanoparticles (NP) using non-ionic surfactants, or biocompatible polymers from natural proteins or sugars, and the aqueous solubility of the drug also influences the manufacture method. </p><p> Results: NP produced using non-ionic surfactants, proteins such as collagen, albumin or gluten, and polysaccharides such as chitosan, hyaluronate, cellulose, carrageenans, alginate or starch has successfully delivered different types of drugs given by the pulmonary route. Drug entrapment efficiency depends on the DDS constituents and the manufacture method used. Large scale manufacture of DDS from natural products is technically challenging but changing from batch manufacture to continuous manufacturing processes has addressed some of these issues, and inclusion of a spray drying step has been beneficial in some cases. </p><p> Conclusion: DDS for lung delivery can be produced using natural products but identifying a cost effective manufacture method may be challenging and the impact of using different type of nebulisers on the physiochemical characteristics of the aerosolised formulation should be an essential part of formulation development. This would ensure that some of the development work e.g. stability studies do not have to be repeated as they will identify if a carrier to protect the DDS from the physical trauma caused by nebulisation. </p><p>
Natural Alpha-Glucosidase Inhibitors: Therapeutic Implication and Structure- Activity Relation Ship
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Background: Alpha-glucosidase is the key enzyme involved in catalyzing the carbohydrate alpha-glucosidase through hydrolysis. It is implicated in several metabolic pathways, including carbohydrate digestion in the intestine, and glycoprotein and glycolipid processing. Alpha-glucosidase inhibitors are currently being investigated for their therapeutic effect against some diseases such as diabetes, cancer, hepatitis B and human immunodeficiency virus (HIV). </p> <p> Objective: The aim of this review is to clarify the effect of alpha-glucosidase inhibitors in the treatment of some diseases, and to evaluate the structure-activity relationship of about 270 inhibitors isolated from about 60 plants. </p> <p> Methods: We reviewed 121 articles published between 1965 and 2013 (PubMed and Sciencedirect). All the molecules structures were provided in ChemDraw software. </p> <p> Results and Conclusions: In this work we elucidated the therapeutic effect of alpha-glucosidase inhibitors against some diseases and we concluded that alpha-glucosidase flavonoid inhibitors (representing 22% of the reviewed inhibitors) have common components that are responsible of their inhibitory activity. The general structure of these inhibitors is composed of three rings. It seems that the hydroxyl groups in each ring have an important role in the α-glucosidase inhibitory activity.
Nature and Nurture in the Early-Life Origins of Metabolic Syndrome
Today, 12 Ιουλίου 2016, 4:05:56 μμ
The combination of genetic background together with food excess and lack of exercise has become the cornerstone of metabolic disorders associated to lifestyle. The scenario is furthermore reinforced by their interaction with other environmental factors (stress, sleeping patterns, education, culture, rural versus urban locations, and xenobiotics, among others) inducing epigenetic changes in the exposed individuals. The immediate consequence is the development of further alterations like obesity and metabolic syndrome, and other adverse health conditions (type-2 diabetes, cardiovascular diseases, cancer, reproductive, immune and neurological disorders). Thus, having in mind the impact of the metabolic syndrome on the worldwide public health, the present review affords the relative roles and the interrelationships of nature (genetic predisposition to metabolic syndrome) and nurture (lifestyle and environmental effects causing epigenetic changes), on the establishment of the metabolic disorders in women; disorders that may evolve to metabolic syndrome prior or during pregnancy and may be transmitted to their descendants.
Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Aberrant expression and activation of receptor tyrosine kinases (RTK) is a frequent feature of tumor cells that may underlie tumor aggressiveness. Among RTK, Axl, a member of the Tyro3-Axl-Mer family, represents a potential therapeutic target in different tumor types given its over-expression which leads to activation of oncogenic signaling promoting cell proliferation and survival, as well as migration and invasion. Axl can promote aggressiveness of various cell types through PI3K/Akt and/or MAPK/ERK, and its expression can be transcriptionally regulated by multiple factors. Deregulated Axl expression and activation have been shown to be implicated in reduced sensitivity of tumor cells to target-specific and conventional antitumor agents, but the precise mechanism underlying these phenomena are still poorly understood. Several small molecules acting as Axl inhibitors have been reported, and some of them are undergoing clinical investigation. In this review, we describe Axl biological functions, its expression in cancer and in drug-resistant tumor cells and the development of inhibitors tailored to this receptor tyrosine kinase.
Dendritic Cells in Colorectal Cancer and a Potential for their Use in Therapeutic Approaches
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Multiple pathogenic mechanisms contribute to the development of colorectal cancer. This tumor is characterized by high chemoresistance and low immunogenicity due to the effective mechanisms of immunosuppression. Dendritic cells (DCs) play a key role in recognition of tumor antigens and induction of T-cell-primed anticancer response. However, in cancer microenvironment, the function of tumor-infiltrating DCs becomes impaired and switched from the immunostimulation to the immunosuppression. Colorectal cancer cells express anti-inflammatory cytokines such as IL-10 and TGF-β that could affect DC phenotype and support tumor escape from the immune surveillance. As a result, tumor-associated DCs display numerous defects in antigen-presenting capacity and have an altered pattern of expression of immune costimulatory molecules towards the immunoregulatory phenotype. Indeed, understanding of mechanisms, such as how tumor could impair activity of DCs, would help in the development of new DC-based vaccines against colorectal cancer.
Application of Mesenchymal Stem Cells in the Targeted Gene Therapy for Gastric Cancer
Today, 12 Ιουλίου 2016, 4:05:56 μμ
The incidence of gastric cancer is third most prevalent among all malignant tumors in China. The conventional therapies for advanced gastric cancer are futile. Targeted gene therapy has become a promising alternative approach. Mesenchymal stem cells (MSCs) can be used as potential cellular vehicles for cancer therapy in vivo. This review will summarize the published data about the application of MSC-based targeted therapy for gastric cancer, and discuss some of the challenges associated with this method.
Intervertebral Disc Engineering through Exploiting Mesenchymal Stem Cells: Progress and Perspective
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Intervertebral disc degeneration is a common spinal disorder and may manifest with low back pain or sciatica. The degeneration is characterized by the loss of extracellular matrix integrity and dehydration in the nucleus pulposus. This compromises the viscoelastic property and compressive strength of the disc and therefore the capacity to withstand axial load, eventually causing the disc to collapse or leading to disc bulging or herniation due to abnormal strains on the surrounding annulus. Mesenchymal stem/stromal cells (MSCs) are attractive cell sources for engineering or repair of the disc tissues with respect to their ease of availability and capacity to expand in vitro. Moreover, recent investigations have proposed a potential of MSCs to differentiate into disc-like cells. This review discusses the approaches and concerns for engineering intervertebral disc through manipulating MSCs, with a highlight on the relevance of disc progenitor discovery. Ultimately, stem cell-based engineering of intervertebral disc may facilitate the preservation of motion segment function and address degenerative disc disease in future without spinal fusion.
Development of Anti-CD20 Antigen-Targeting Therapies for B-cell Lymphoproliferative Malignancies - The State of the Art
Today, 12 Ιουλίου 2016, 4:05:56 μμ
For decades, the available anticancer therapies were mostly based on nonspecific cytotoxic regimens. These cytostatic combinations, while effective in some subpopulations of patients, are often limited by extensive toxicity and/or development of tumor resistance. Although standard chemotherapy still remains a common therapeutic tool in the fight with cancer, immunotherapy increasingly revolutionizes treatment strategy for several hematologic malignancies. For a subset of patients with B-cell lymphoproliferative disease, the introduction of subsequently developed classes of anti-CD20 monoclonal antibodies (mAbs) has resulted in improved overall response rates and, to some extent, patient overall survival. Rituximab, the most thoroughly-explored chimeric mouse anti-human anti-CD20 mAb, has been widely and successfully introduced to oncohematology, but also to other fields of medicine, such as transfusiology or rheumatology. Currently, several new generation anti-CD20 mAbs are undergoing different stages of preclinical and clinical studies of assessment to further improve the outcome and overcome mechanisms of resistance. The nature of the direct mechanisms responsible for the anticancer properties of different classes of anti-CD20 mAbs is still not fully understood. This is reflected in different approaches during the investigation of novel anti-CD20 agents. So far, three classes of anti- CD20 mAb have been described. In this review, we focus on CD20 antigen-targeting therapies both currently available and undergoing preclinical or clinical investigation for B-cell lymphoproliferative malignancies.
Label-Free Cell Phenotypic Assays for Assessing Drug Polypharmacology
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Background: Most drugs exert their biological and physiological effects via binding to protein targets. Although drugs are traditionally optimized against a single protein, most marketed drugs exhibit clinically relevant polypharmacology – the activity of drugs at multiple targets. The wide-spread presence of polypharmacology makes it challenging to assess the mechanisms of action of multi-target drugs. Methods: This paper first reviews approaches for discovering multi-targets of drug molecules, then discusses key characteristics of label-free cell phenotypic assays, and finally focuses on how to use these assays to assess drug polypharmacology. Results: labelfree cell phenotypic assays have ability to provide a holistic view of drug action in living cells with wide phenotype/ target/pathway coverage, and permit effective deconvolution of the action of multi-target drugs at the whole cell level. Conclusion: Label-free cell phenotypic assays hold great potential in assessing drug polypharmacology.
Potential Clinical Use of Differentiated Cells From Embryonic or Mesencyhmal Stem Cells in Orthopaedic Problems
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Stem cells are classified by their tissue source. Embryonic stem cells that are derived from the inner cell mass of blastocyst stage embryos are highly proliferative in their undifferentiated state. A multipotent type of mesenchymal stem cells is isolated from various types of tissues such as bone marrow, fat tissue etc. The dynamics of embryonic and adult stem cell cycles are profoundly dissimilar from the culture of stem cells. After improving the culture conditions and differentiation potentials, differentiated stem cells are the first cells to be preferred in modern regenerative medicine and tissue engineering. This review article focuses on the cell-based therapy of orthopedic problems. We explore the challenges associated with bone repair and regeneration using embryonic or mesenchymal stem cells that are in undifferentiated or/and differentiated condition. This paper also discusses optimizing the best cell type, differentiation condition and using them on bone tissue engineering for future investigations.
Exploring a Novel Target Treatment on Breast Cancer: Aloe-emodin Mediated Photodynamic Therapy Induced Cell Apoptosis and Inhibited Cell Metastasis
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Photodynamic therapy (PDT) as a clinical cancer therapy, is a mild therapy, which involves application of photosensitizers (PSs) located in target cells and then irradiated by corresponding wavelength. The activation of PSs generates radical oxygen species (ROS) to exert a selective cytotoxic activity for the target cells. Aloe-emodin (AE) has been found to be an anti-tumor agent in many studies, and has also been demonstrated as a photosensitizer, in the recent years. In order to study the mechanisms of aloe-emodin as a photosensitizer, we investigated the mechanisms of photo-cytotoxicity induced by aloe-emodin in breast cancer MCF-7 cells in the present study. Analysis of cell proliferation evidenced that there was a drastic depression after photodynamic treatment with a series of aloe-emodin concentrations and light doses. We observed changes in apoptosis and demonstrated that the mechanisms of apoptosis were involved in mitochondrial and endoplasmic reticulum death pathways. The capacity of adhesion, migration and invasion of breast cells was measured using WST8 and transwell assay and demonstrated that AE-PDT significantly inhibited adhesion, migration and invasion of MCF-7cells. The expression of MMP2, MMP9, VEGF and Nrf2 demonstrated that the metastasis was related to oxidative stress. Analysis of changes in cytoskeleton components (F-actin) evidenced cytoskeleton disorganization after treatment with AE-PDT. Taken together, the present results indicated that PDT with aloe-emodin effectively suppressed cancer development in MCF-7cells, suggesting the potential of AE as a new photosensitizer in PDT which can provide a new modility for treating cancer.
Synthesis and Biological Evaluation of Macamides Derivatives as Potent Inhibitors of Breast Cancer Cell MCF-7
Today, 12 Ιουλίου 2016, 4:05:56 μμ
A series of macamides (1-4) and their synthetic analogs (5-14) were synthesized and evaluated for in vitro inhibitory activities against breast cancer cell MCF-7. The results of bioactive assay showed that two of the macamides (compound 1 and 4) and one synthetic analog (compound 5) displayed comparable inhibitory activities against MCF-7 cell line, with IC<sub>50</sub> values of 29.6, 36.2 and 27.2 µM, respectively.
Betulinic Acid Kills Colon Cancer Stem Cells
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Cancer stem cells (CSCs) are considered to be the origin of cancer and it is suggested that they are resistant to chemotherapy. Current therapies fail to eradicate CSCs and therefore selecting a resistant cell subset that is able to facilitate tumor recurrences. Betulinic acid (BetA) is a broad acting natural compound, shown to induce cell death via the inhibition of the stearoyl-CoA- desaturase (SCD- 1). This enzyme converts saturated fatty acids into unsaturated fatty acids and is over-expressed in tumor cells. Here we show that BetA induces rapid cell death in all colon CSCs tested and is able to affect the CSCs directly as shown, via the loss of clonogenic capacity. Similar results were observed with inhibition of SCD-1, suggesting that SCD-1 activity is indeed a vulnerable link in colon CSCs and can be considered an ideal target for therapy in colon cancer.
Biomaterial and Stem Cell Interactions: Histological Biocompatibility
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Advancements in biomaterials and stem cell technology have lead current medical technology to tissue engineering and regenerative medicine. Human engineered cartilage, bone, fascia, tendon, nerve and skin tissues have been used for the treatment of tissue injuries and degenerative diseases in combination with embryonic, fetal or adult stem and progenitor cells. Mesenchymal stem cells are one of the most extensively studied adult stem cell population and are widely utilized in cell therapies. Regeneration and 3-dimensional reconstruction of specialized connective tissues by combining differently originated micro and nanoscaled, natural or synthetic scaffolds with stem or progenitor cells are highly expected to guarantee patients to maintain acceptable life quality. In this review we discuss the important issues in biomaterial and stem cell interactions based on histological biocompatibility, updating recent basic research in this field and addressing possible future perspectives.
Mesenchymal Stem Cells and Nano-Bioceramics for Bone Regeneration
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Orthopedic disorders and trauma usually result in bone loss. Bone grafts are widely used to replace this tissue. Bone grafts excluding autografts unfortunately have disadvantages like evoking immune response, contamination and rejection. Autografts are of limited sources and optimum biomaterials that can replace bone have been searched for several decades. Bioceramics, which have the similar inorganic structure of natural bone, are widely used to regenerate bone or coat metallic implants. As people continuously look for a higher life quality, there are developments in technology almost everyday to meet their expectations. Nanotechnology is one of such technologies and it attracts everyone’s attention in biomaterial science. Nano scale biomaterials have many advantages like larger surface area and higher biocompatibility and these properties make them more preferable than micro scale. Also, stem cells are used for bone regeneration besides nano-bioceramics due to their differentiation characteristics. This review covers current research on nano-bioceramics and mesenchymal stem cells and their role in bone regeneration.
Isolation, Purification and Characterization of a Novel Steroidal Saponin Cholestanol Glucoside from Lasiodiplodia theobromae that Induces Apoptosis in A549 Cells
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Search for novel anticancer lead molecules continues to be a major focus of cancer research due to the limitations of existing drugs such as lack of tumor selectivity, narrow therapeutic index and multidrug resistance of cancer types. Natural molecules often possess better pharmacokinetic traits compared to synthetic molecules as they continually evolve by natural selection process to interact with biological macromolecules. Microbial metabolites constitute nearly half of the pharmaceuticals in market today. Endophytic fungi, owing to its rich chemical diversity, are viewed as attractive sources of novel bioactive compounds. In the present study, we report the purification and characterization of a novel steroidal saponin, cholestanol glucoside (CG) from Saraca asoca endophytic fungus Lasiodiplodia theobromae. The compound was assessed for its cytotoxic potentialities in six human cancer cell lines, A549, PC3, HepG2, U251, MCF7 and OVCAR3. CG exhibited significant cytotoxicities towards A549, PC3 and HepG2 among which A549 cells were most vulnerable to CG treatment. However, CG treatment exhibited negligible cytotoxicity in non malignant human lung fibroblast cell line (WI-38). Induction of cell death by CG treatment in A549 cells was further investigated. CG induced the generation of reactive oxygen species (ROS) and mitochondrial membrane permeability loss followed by apoptotic cell death. Mitochondrial membrane depolarization and apoptotic cell death in CG treated A549 cells were completely blocked in presence of an antioxidant, N-acetyl cysteine (NAC). Hence it could be concluded that CG initiates apoptosis in cancer cells by augmenting the basal oxidative stress and that the generation of intracellular ROS is crucial for the induction of apoptosis.
A Review on Novel Breast Cancer Therapies: Photodynamic Therapy and Plant Derived Agent Induced Cell Death Mechanisms
Today, 12 Ιουλίου 2016, 4:05:56 μμ
This review article presents an extensive examination of risk factors for breast cancer, treatment strategies with special attention to photodynamic therapy and natural product based treatments. Breast cancer remains the most commonly occurring cancer in women worldwide and the detection, treatment, and prevention are prominent concerns in public health. Background information on current developments in treatment helps to update the approach towards risk assessment. Breast cancer risk is linked to many factors such as hereditary, reproductive and lifestyle factors. Minimally invasive Photodynamic therapy (PDT) can be used in the management of various cancers; it uses a light sensitive drug (a photosensitizer, PS) and a light of visible wavelength, to destroy targeted cancer cells. State of the art analyses has been carried out to investigate advancement in the search for the cure and control of cancer progression using natural products. Traditional medicinal plants have been used as lead compounds for drug discovery in modern medicine. Both PDT and plant derived drugs induce cell death via different mechanisms including apoptosis, necrosis, autophagy, cell cycle regulation and even the regulation of various cell signalling pathways.
An Overview of Chromatin-Regulating Proteins in Cells
Today, 12 Ιουλίου 2016, 4:05:56 μμ
In eukaryotic cells, gene expressions on chromosome DNA are orchestrated by a dynamic chromosome structure state that is largely controlled by chromatin-regulating proteins, which regulate chromatin structures, release DNA from the nucleosome, and activate or suppress gene expression by modifying nucleosome histones or mobilizing DNA-histone structure. The two classes of chromatinregulating proteins are 1) enzymes that modify histones through methylation, acetylation, phosphorylation, adenosine diphosphate–ribosylation, glycosylation, sumoylation, or ubiquitylation and 2) enzymes that remodel DNA-histone structure with energy from ATP hydrolysis. Chromatin-regulating proteins, which modulate DNA-histone interaction, change chromatin conformation, and increase or decrease the binding of functional DNA-regulating protein complexes, have major functions in nuclear processes, including gene transcription and DNA replication, repair, and recombination. This review provides a general overview of chromatin-regulating proteins, including their classification, molecular functions, and interactions with the nucleosome in eukaryotic cells.
Stem Cells in Skeletal Tissue Engineering: Technologies and Models
Today, 12 Ιουλίου 2016, 4:05:56 μμ
This review surveys the use of pluripotent and multipotent stem cells in skeletal tissue engineering. Specific emphasis is focused on evaluating the function and activities of these cells in the context of development in vivo, and how technologies and methods of stem cell-based tissue engineering for stem cells must draw inspiration from developmental biology. Information on the embryonic origin and in vivo differentiation of skeletal tissues is first reviewed, to shed light on the persistence and activities of adult stem cells that remain in skeletal tissues after embryogenesis. Next, the development and differentiation of pluripotent stem cells is discussed, and some of their advantages and disadvantages in the context of tissue engineering are presented. The final section highlights current use of multipotent adult mesenchymal stem cells, reviewing their origin, differentiation capacity, and potential applications to tissue engineering.
Establishment of Cell-Based Neuroglobin Promoter Reporter Assay for Neuroprotective Compounds Screening
Today, 12 Ιουλίου 2016, 4:05:56 μμ
Neuroglobin (Ngb) has been demonstrated to be neuroprotective against stroke and neurodegenerative diseases, thus upregulating Ngb might be a novel approach for neuroprotection. In this study we aimed to establish cell-based Ngb reporter systems for screening neuroprotective compounds targeting Ngb upregulation. We developed both mouse and human stable Ngb reporter systems containing a luciferase reporter gene directed by mouse and human Ngb promoter, respectively. To validate these reporter systems, we used them to screen a pool of natural plant compounds. RT-PCR was used to verify the Ngb-upregulating effects of selected compounds, and neurotoxicity assay was used to test their neuroprotection effects in primary cultured neurons. We identified polydatin, genistein, daidzein, biochanin A and formononetin that can upregulate both mouse and human Ngb promoter activity. RT-PCR confirmed that polydatin, genistein and formononetin significantly increased Ngb mRNA expression in primary neurons. Furthermore, formononetin significantly decreased oxygen-glucose deprivation (OGD)-induced neurotoxicity. Moreover, inhibition of cAMP response element-binding protein (CREB) showed that CREB is required for formononetin-induced Ngb upregulation. These results suggest that these Ngb reporter systems are suitable for neuroprotective compound screening, which will be used to screen larger compound libraries for more potent neuroprotectants. This preliminary study will facilitate the development of Ngb-targeted therapeutics for stroke and neurodegenerative diseases.
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