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Yesterday, 18 Ιουλίου 2016, 8:17:55 πμ
Peripheral Immune Signatures in Alzheimer Disease
Yesterday, 18 Ιουλίου 2016, 8:17:59 πμ
According to the current paradigm, the main cause of AD is the accumulation of neurotoxic amyloid beta (Aβ) peptide aggregates resulting from the cleavage of the amyloid precursor protein into peptides of different length, with the 42 amino acid long Aβ42 being the most toxic form. Aβ can aggregate and form plaques in the brain. It further promotes the hyperphosphorylation of the tau protein which forms characteristic neurofibrillary tangles and thereby loses its important role in axonal transport and contributes to neurodegeneration. Therefore, treatments have targeted Aβ, but clinical trials of immunotherapies caused severe side effects and showed that Aβ clearance alone did not result in any cognitive improvement. This leads to the question: what else promotes AD pathology? Here, we review data on systemic inflammation and the possible roles that the immune system might play in AD. Microglia and astrocytes are activated and secrete inflammatory cytokines and chemokines. Via a disturbed blood-brain barrier, peripheral immune cells are activated and recruited towards inflamed brain lesions and amyloid plaques, but due to the chronic nature of the amyloid burden and their reduced function, these cells are not able to control inflammation and the associated detrimental immune responses. In addition, age-related inflammation and chronic infection with herpes viruses might contribute to the systemic inflammation and exacerbate attempts to restore the balance of inflammation.
Synthesis and Applications of Glyconanoparticles
Yesterday, 18 Ιουλίου 2016, 8:17:59 πμ
Glyconanoparticles are the subject of numerous literatures and are emerging for applications in biomedicine, glycoscience, and material science due to their unique properties. They are hybrid materials each of which contains a nanoparticle core surrounded by a carbohydrate shell. The core can be metallic, magnetic, and/or photoluminescent, while the shell may be composed of mono-, di-, oligo- and/or poly-saccharides. Sugars are attached to the surface of the nanoparticles through covalent or non-covalent interaction. Here, we give a brief summary of the synthetic methodologies adopted in the preparation of different types of glyconanoparticles, which can be utilized in various applications including catalysis, drug delivery, vaccine, imaging and study of carbohydrate-lectin interactions.
Preclinical Models of Multiple Sclerosis: Advantages and Limitations Towards Better Therapies
Yesterday, 18 Ιουλίου 2016, 8:17:59 πμ
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) with an unknown etiology. MS complex pathophysiology—characterized by CNS inflammation, demyelination and axonal injury—has made its modeling in experimental systems particularly problematic. Moreover, the evidence that MS does not naturally occur in other species has further complicated MS preclinical studies. Through the years, several MS in vivo models have been developed. Experimental autoimmune encephalomyelitis (EAE) represents the most widely used MS experimental model and relies upon the autoimmune paradigm to explore MS neuropathology. Although EAE has been instrumental in understanding the molecular events which take place upon neuroinflammation, not all MS hallmarks can be efficiently shaped within this conceptual frameshift. Thus, alternative models of CNS demyelination have been characterized, either based on viral infection or neurotoxin administration. However imperfect, these models have greatly improved our knowledge of the immune system's function in health and disease. On the other side, their intrinsic distance from MS has often led to misinterpreting and overestimating the data gleaned from these experimental systems. In this review, each model will be discussed in the light of its potentiality to mimic MS and translate the most promising therapies to patients. In addition, we will address how new genomic technologies can help improve the existing models.
Natural Polymeric Nanoparticles for Brain-Targeting: Implications on Drug and Gene Delivery
Yesterday, 18 Ιουλίου 2016, 8:17:59 πμ
There is a broad range of biological, chemical and physical hurdles for drugs to reach the brain. Nanoparticulate drug delivery systems hold tremendous potential for diagnosis and treatment of brain disorders, including the capacity of crossing the blood–brain barrier and accessing to the brain after systemic administration. Thus, nanoparticles enable the delivery of a great variety of drugs including anticancer drugs, analgesics, anti- Alzheimer's drugs, protease inhibitors, and several macromolecules into the brain. Moreover, nanoparticles may importantly reduce the drug's toxicity and adverse effects due to an alteration of the body distribution. A very critical and important requirement for nanoparticulate brain delivery is that the employed nanoparticles are biocompatible and, moreover, rapidly biodegradable. Therefore, nanocarriers fabricated from natural polymers including polysaccharides and proteins are particularly interesting. Meeting requirements such as low cytotoxicity, abundant surface functional groups, high drug binding capacity and significant uptake into the targeted cells, natural polymer-based nanocarriers represent promising candidates for efficient drug and gene delivery to the brain. The current review highlights the latest advances achieved in developing drug-loaded polysaccharide and protein nanocarriers for brain delivery. The nanoparticles are discussed with respect to their formulation aspects, advantages, limitations, as well as the major outcomes of the in vitro and in vivo investigations. Modification of the nanoparticle surface with specific brain targeting ligands or by coating with certain surfactants for enhanced brain delivery is also reviewed. In addition, the mechanisms of the nanoparticle-mediated drug transport across the BBB are also discussed in this review.
Decreased Expression of Sox-1 in Cerebellum of Rat with Generalized Seizures Induced by Kindling Model
Πέμπτη, 14 Ιουλίου 2016, 8:53:26 πμ
The single feature of all malformations in cortical development is the clinical association with epilepsy. It has been proven that Sox-1 expression is essential during neurodevelopment and it is reported that Sox-1 knockout mice present spontaneous generalized seizures. Particularly in cerebellum, Sox-1 plays a key role in the Bergmann´s glia (BG) function, which allows the correct function of the Purkinje cells (PC). The targets of PC are the dentate and interpositus nuclei, which form the main cerebellar efferents involved in the physiopathology of epilepsy. Here we present the Sox-1 expression in cerebellum of rats during electric amygdala-kindling. We obtained seizures and once they had 3, 15 and 45 electric stimuli, the animals were sacrificed; the cerebellum was processed for inmunohistochemistry and Western blot analysis was performed to determine Sox-1 expression. Liquid chromatography was performed to examine gammaaminobutyric acid (GABA) and glutamate concentration. According to the literature, a progressive increase was observed in the electrographic and behavioral parameters. We found that Sox-1 expression in 15 and 45-stimuli groups had a statistically significant decrease as compared with controls, while the 3-stimuli group was similar to the control group. The concentration of glutamate was increased in rats with 45 stimuli. We can conclude that Sox-1 expression decreases as the number of seizures increases, and this is probably due to an altered glutamate regulation by a dysfunctional BG. In this way, we can suggest this mechanism as a one possible explanation of how the cerebellum participates in the pathophysiology of epilepsy.
Anti-arthritic Effect and Underlying Mechanism of Ginsenoside Metabolite Compound K
Πέμπτη, 14 Ιουλίου 2016, 8:53:26 πμ
Ginsenoside metabolite compound K (CK) is a degradation product of panaxadiol (Rb1, Rb2, Rc) in the intestine by bacteria and is the major form of ginsenoside absorbed in the body. Recently, the anti-arthritic effect of CK has been confirmed in adjuvant-induced arthritis rats and collagen- induced arthritis mice and also in in vitro experiments. CK can regulate the function of cells which are involved in rheumatoid arthritis including immune cells, endothelial cells and fibroblast synoviocytes resulting in the anti-arthritic effect. The mechanisms of these effects may be mediated by different signaling pathways including glucocorticoid receptors, Toll-like receptors, ion channels, NF-κB and MAPKs.
What is the Current Role of Immunotherapy for Colon Cancer?
Πέμπτη, 14 Ιουλίου 2016, 8:53:26 πμ
Colon cancer is a leading cause of cancer related mortality. Until very recently the only existing options that medical oncologists had to treat metastatic colon cancer were a combination of chemotherapy, anti-EGFR and anti-angiogenic agents. We currently have the first proof that immune therapies could be an effective approach to battle colorectal cancers that carry a mismatch repair machinery deficient phenotype. It is expected that as our knowledge of the different mechanisms of immune-resistance grows, this therapeutic modality might soon be applicable to all patients. However, due to the continuous increase in the cost of oncological drugs, some treatment overheads may soon become prohibitive for many. In this review we will examine the current evidence related to this topic with the objective to provide the reader with concise but practical information about the potential role of immunotherapy in CRC.
Serum Levels of Progranulin Do Not Reflect Cerebrospinal Fluid Levels in Neurodegenerative Disease
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Altered progranulin levels play a major role in neurodegenerative diseases, like Alzheimer’s dementia (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), even in the absence of GRN mutations. Increasing progranulin levels could hereby provide a novel treatment strategy. However, knowledge on progranulin regulation in neurodegenerative diseases remains limited. We here demonstrate that cerebrospinal fluid progranulin levels do not correlate with its serum levels in AD, FTD and ALS, indicating a differential regulation of its central and peripheral levels in neurodegeneration. Blood progranulin levels thus do not reliably predict central nervous progranulin levels and their response to future progranulin-increasing therapeutics.
Vaccination to Alzheimer Disease. Is it a Promising Tool or a Blind Way?
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Alzheimer disease (AD) is an irreversible neurodegenerative disorder associated with cognitive dysfunction. The disease incidence has growing tendency worldwide with strong impact on healthcare funds. The fact that there is no effective therapy makes the disorder more serious. Currently, AD manifestation can be suppressed by having impact on enzyme acetylcholinesterase: donepezil, rivastigmine, and galantamine or ionotropic glutamate NMDA receptor ( memanitine). Contrary to the drugs effecting symptomatically, vaccination against amyloid plaques or neurofibrillary tangles and their precursors amyloid beta and hyperphosphorylated tau are expected to be more suitable. Huge numbers of works have been done on the issue. Unfortunately, the promising vaccines like the AN 1792 were halted during clinical trials because of adverse effects like meningoencephalitis. Monoclonal antibody specific to amyloid plaques, Bapineuzumab, was closest to the practical performance but the clinical trials were also stopped. The review summarizes facts about AD, opportunities in AD vaccination, and obstacles that limit the vaccination including reasons why the recent trials have fallen.
A Perspective on Rational Designs of a Hemagglutinin Based Universal Influenza Vaccine
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Background: The influenza virus is one of the most critical threats to public health with major economic impact. Though annual influenza vaccination is currently the most effective prevention strategy against flu epidemics and pandemics, the mutational evolution of the influenza virus tends to reduce the effectiveness of strain-specific vaccines. Methods: For past decades, a broad spectrum of potentially universal influenza vaccines has been thoroughly investigated to suppress different strains and subtypes of influenza virus concomitantly. Universal influenza vaccines were attempted to be designed to target conserved regions of surface receptors to provide the necessary preventive strategy against new influenza outbreaks. Conclusion: Notably, the influenza hemagglutinin (HA) receptor has evolutionary conserved domains that can serve as basis for the rational design of a universal influenza vaccine. In this review, we examine recent studies on HA-based universal influenza vaccines and address their molecular mechanism.
Evidence for Mitochondrial UPR Gene Activation in Familial and Sporadic Alzheimer’s Disease
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Mitochondrial perturbations such as oxidative stress, increased fission/fusion dysfunction, and mitophagy are consistent features of Alzheimer’s disease (AD), yet the mechanisms that initiate these perturbations are unclear. One potential source for mitochondrial defects could be an imbalance in mitochondrial proteostasis. In this regard, studies indicate that a specialized mitochondrial unfolded protein response (mtUPR) is activated upon the aberrant accumulation of damaged or unfolded proteins in the mitochondrial matrix, resulting in the up-regulation of key genes involved in mitochondrial stabilization. To test whether mtUPR activation occurs in AD, we performed real-time quantitative PCR on postmortem frontal cortex samples from subjects classified as sporadic AD, familial AD linked to presenilin-1 mutations, or cognitively intact controls. Compared to controls, sporadic AD subjects exhibited a significant ~40-60% increase in expression levels of select genes activated by the mtUPR, including mitochondrial chaperones dnaja3, hspd1, and hspe1, mitochondrial proteases clpp and yme1l1, and txn2, a mitochondrial-specific oxidoreductase. Furthermore, levels of all six mtUPR genes were significantly up-regulated by ~70-90% in familial AD compared to controls, and these expression levels were significantly higher compared to sporadic AD. The increase in hspd1 (Hsp60) was validated by western blotting. These data support the concept that both sporadic and familial AD are characterized by mtUPR gene activation. Understanding the physiological consequences of this response may provide subcellular mechanistic clues to selective neuronal vulnerability or endogenous compensatory mechanisms during the progression of AD.
Characterization of Seven New Polystyrene Plates Binding Peptides from a Phage-Displayed Random 12-Peptide Library
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
A random 12-peptide library was screened against Erysipelothrix rhusiopthiae and porcine circovirus 2 recombinant Cap protein and the selected peptides were used for detecting the corresponding pathogens quickly and effectively. To our surprise, seven peptides, P1 (WHWNAP WWNGVY), P2 (FHWTWQFPYTST), P3 (GAMHLPWHMGTL), P4 (HWNIWWQHHPSP), P5 (HFFKWHTRTNDQ), P6 (HFFRWHPSAHLG) and P7 (HFAYWWNGVRGP) with the characteristics of polystyrene plate (PS) binding target-unrelated peptides (TUPs), were selected from the library. It has been found that P2 and P4 shared common motif of plastic binding peptide, moreover, P2, P3, P5 and P7 have been isolated repeatedly in other research groups using different targets. Then, the seven peptide phage clones were identified as the PS binding TUP phages by phage-ELISA and elution titration, particularly, P1 and P2 showed strong PS binding affinity which can not be inhibited by usual blocking buffers. In addition, all of the phages were not propagation-related TUP, but P3 showed the similar propagation rate with M13KE (vector phage). We also found that the seven PS-TUPs are rich in W, H, F, P and G, particularly, both W and H are contained in all PS-TUPs. It deduced that they may play a potential role in peptide binding to plastic. Although it is difficult to eliminate the TUP phages in phage display completely, these PS-TUPs can be used to exclude the false positive peptides rapidly and effectively and help us to obtain truly interesting peptides more accurately.
A Case of Hepatotoxicity Induced by Adulterated “Tiger King”, a Chinese Herbal Medicine Containing Sildenafil
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Detection of Phosphodiesterase Type 5 (PDE-5) inhibitors and their analogues in “100% natural” or “herbal” supplements have been described in numerous reports. However, few reports have been published in relation to actual harm caused by counterfeit erectile dysfunction herbal supplements. We describe a case of a 65-year old male admitted to a tertiary hospital with acute liver toxicity, possibly induced by adulterated “Chinese herbal” supplement “Tiger King” for sexual enhancement. Chemical analysis of the tablets discovered the presence of therapeutic doses of sildenafil with no other herbal components. Other medications were excluded as potential causes of the hepatic impairment. According to the Naranjo adverse drug reaction scale and the Roussel Uclaf Causality Assessment Method (RUCAM) the probability of association of Hepatotoxicity with Sildenafil was “possible” and “probable” respectively (Naranjo score of 4, RUCAM score of 7). Within three days of admission, the patient’s clinical status and liver function improved without any specific treatment. His liver function tests normalized 30 days post discharge. Further pharmacovigilance actions should be taken by regulatory authorities and pharmaceutical companies in order to determine the relation between sildenafil and hepatotoxicity. This case emphasizes the importance of raising public awareness on the potential dangers of “Tiger king” in particular, and other counterfeit medications or herbal supplements of unknown origin.
Controlled Drug Delivery Using Microdevices
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Therapeutic drugs administered systematically are evenly distributed to the whole body through blood circulation and have to cross many biological barriers before reaching the pathological site. Conventional drug delivery may make drugs inactive or reduce their potency as they may be hydrolyzed or degraded enzymatically and are rapidly excreted through the urinary system resulting in suboptimal concentration of drugs at the desired site. Controlled drug delivery aims to localize the pharmacological activity of the drug to the desired site at desired release rates. The advances made by micro/nanofluidic technologies have provided new opportunities for better-controlled drug delivery. Various components of a drug delivery system can be integrated within a single tiny micro/nanofluidic chip. This article reviews recent advances of controlled drug delivery made by microfluidic/nanofluidic technologies. We first discuss microreservoir-based drug delivery systems. Then we highlight different kinds of microneedles used for controlled drug delivery, followed with a brief discussion about the current limitations and the future prospects of controlled drug delivery systems.
Newest Strategies in the Search for Bioactive Saponins from the Tropical Plant Biodiversity
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
This review will focus on newest results leading to the discovery of new bioactive saponins by using a combination of successive advanced procedures in extraction, isolation, structure elucidation and bioassays. Microwave- and ultrasonic-assisted extractions, two recent advanced methods have been increasingly used in the last decade. Then, a multistep purification procedure was achieved by flash chromatography, vacuum liquid chromatography, low, medium- and high-pressure liquid chromatography on silica gel and reversed-phase silica gel RP-18 (VLC, LPLC, MPLC, HPLC). These successive chromatographic steps have been implemented in the author's laboratory in order to avoid the time-consuming traditional partitions between butanol and water, dialysis procedures or precipitations in diethyl/ether. The structural elucidation of complex saponins possessing from 5 to 8 sugar units is performed by a combination of extensive spectroscopic techniques including 1D- and 2D-NMR experiments (1H, 13C, DEPT, COSY, NOESY, TOCSY, HSQC, HMBC) and mass spectrometry (FAB-MS HRESIMS). The bioassays have been mainly carried out in the field of cancerology and inflammation, two closely related areas, and also in the field of immunology with recent literature results on Quillaja saponins in order to explore some structure/activity relationships. The more recent results of the author's laboratory will be presented with examples of saponins from the tropical plant biodiversity (Pittosporaceae, Polygalaceae, Mimosaceae, Sapindaceae, Apiaceae, Dioscoreaceae, and Asparagaceae). Furthermore, some new trends reported in the literature will be briefly reviewed concerning dereplication, and metabolomic approachs which are currently of considerable importance in the field of natural product discovery.
Dry Powder form of Polymeric Nanoparticles for Pulmonary Drug Delivery
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Delivery to the lungs is an efficient way to deliver drugs directly to the site of action or to the blood circulation. Because of limitations of direct administration of free drugs, particulate drug delivery systems such as DPI formulations based on nanoparticles (NPs) have been of interest for pulmonary drug delivery. The prolonged residence of NPs in the lungs due to ability to escape from the clearance mechanisms such as mucociliary escalator, macrophage uptake (a size of 1–2 m is ideal for macrophage phagocytosis), and translocation to the systemic circulation is amongst the key advantages of NPs. By this approach, the controlled pulmonary delivery of drugs, peptides, proteins, genes, siRNA, and vaccines is possible. Both natural (albumin, gelatin, alginate, collagen, cyclodextrin, and chitosan) and synthetic (poly (lactide-co-glycolide) (PLGA), polyacrylates and polyanhydrides) polymers have been used in formulation of pulmonary nanovectors. As direct pulmonary administration of NPs is not feasible, by using the safe excipients, NPs could be converted to dry powder inhaler (DPI) formulations. These can provide a promising deposition and stability of NPs. In this article, the DPI formulations based on polymeric nanoparticles have been reviewed and categorized based on the polymer type used for preparation of NPs.
Inhaled Biologics: From Preclinical to Product Approval
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Background: Delivery of pharmacologically active compounds to the lung for systemic effects is well known and recently has entered a new era with several products achieving regulatory approval. This review focuses on the barriers to pulmonary delivery of biologics. Methods: Lessons learned from the development of recently approved products will be reviewed to shed light on the current challenges that are faced when developing biological products for inhaled delivery. Results: The text and tables presented herein consolidate the current data and ongoing research regarding biological, inhaled products. Conclusion: With this basis, we also review the future prospects for pulmonary delivery of biologics for systemic delivery and how the biological and physical barriers may be overcome.
Water-Soluble Chitosan Enhances Bone Fracture Healing in Rabbit Model
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Background: Chitin and its derivatives participate and influence many important biological activities, such as antibiosis, modulating immunity, suppressing tumor growth, and promoting wound healing as well as promoting hemostasis. This study aimed at confirming the effects of water-soluble chitosan (ws-chitosan) on accelerating healing of induced fractures in New Zealand white rabbits. </p><p> Materials and methods: Thirty-six selected New Zealand rabbits (each with a 3mm bone defect in the middle segment of radius) were randomly divided into two groups (control group, n=18 and experimental group, n=18). The two groups of rabbits were given normal saline (1.00mg/kg) and ws-chitosan (0.28g/kg) every day through gastric tubes, respectively. Three postoperative observation time points of 7 days, 14 days and 28 days were selected. X-ray was applied to examine the healing effect; immunohistochemistry was introduced for observing the bone morphogenetic protein-2 (BMP-2) expression, and the fracture healing related biochemical indexes (serum ALP and calcium concentration) were measured and recorded. </p><p> Results: The X-ray results revealed that the fracture healing effect in experimental group was more remarkable than that in the control group on 7 days, 14 days and 28 days, postoperatively. The BMP-2 expression and the calcium concentration in experimental group on 7 and 14 days were clearly higher than those in the control group, while the serum ALP and calcium concentration in ws-chitosan group were distinctly higher than those in the control group on 7 and 14 days. No adverse events were observed in the study period. </p><p> Conclusion: Results showed that ws-chitosan can enhance facture healing in rabbit model, for it could not only increase ALP and calcium concentrations in serum, but also promote the osteoblast differentiation and BMP-2 expression for accelerating the healing process. </p><p>
Targeting Tumor Angiogenesis in Gastrointestinal Malignancies
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Gastrointestinal [GI] malignancies are common and frequently lethal neoplasms. As our understanding of GI cancers deepens, more pathways are discovered that play key roles in tumorigenesis and metastasis. Angiogenesis has emerged as a critical pathway in many cancers, particularly in GI cancers. The discovery of a complex network of signals, including vascular epithelial growth factor [VEGF], led to the emergence of a new class of cancer therapies targeting angiogenesis. Bevacizumab was the first to emerge, gaining US Food and Drug Administration [FDA] approval in 2004 for the treatment of advanced colorectal cancer; since then, several antiangiogenic agents have become clinically available, and numerous others are in clinical or preclinical testing. This review will focus on anti-angiogenesis therapies in GI malignancies.
Correlation between Systemic Lupus Erythematosus Activity and Plasma Levels of Monomeric Prolactin and Macroprolactin
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
The correlation of prolactin (PRL) levels with SLE activity is a controversial issue, which could be explained by the presence of macroprolactin (MPRL), a high molecular weight form of PRL with a lower in vivo biological activity. </p><p> Objectives: We aimed to evaluate the prevalence of hyperprolactinemia, PRL and MPRL levels in SLE patients, and to correlate these levels with disease activity as measured by the SLE Disease Activity Index (SLEDAI). </p><p> Material and Methods: We conducted a case-control, cross-sectional study with 73 SLE patients (L group), sixty-two of which were evaluated before and after treatment, and correlated the results with serum PRL and MPRL levels. These results were compared to those of 29 healthy women with ovulatory cycles (C group) and 34 women in the third trimester of pregnancy (G group). </p><p> Results: Mean PRL levels were: 8,8 ng/ml on C group; 12,0 ng/ml on L group (p = 0.02) and 158,5 ng/ml on G group. Hyperprolactinemia was present in 19.4% of SLE patients, but was not found on C group. The MPRL form was predominant among 20.5% of SLE patients, in none of the C group and in only 5.8% of pregnant women. There was a strong correlation between the PRL levels and SLE activity, regardless of the hormone’s molecular form. SLE treatment was able to reduce levels of all forms of PRL. The predominance of MPRL, however, did not change after treatment. </p><p> Conclusions: Despite its lower biological activity, MPRL levels correlated with LES activity as much as free prolactin. </p><p>
Vitamin D-Binding Protein Acts in the Actin Scavenge System and Can Have Increased Expression During Aspirin Therapy
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
While the clinical efficacy of aspirin in cerebral thrombosis prevention has been well established, its mechanism of action is still controversial. In an effort to better understand these mechanisms and to identify potential biomarkers, comparative proteomic analysis between 18 patients both pre-aspirin treatment at the time of cerebral thrombotic onset (control group) and post-aspirin treatment (experiment group) was carried out using two-dimensional gel electrophoresis (2-DE) in combination with matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDITOF/ MS). Of the 228 2-DE identified differentially expressed protein spots, 11 proteins showed more than a 1.5-fold difference. Of these, vitamin D-binding protein (DBP) and actin were further examined via Western blot and showed consistent results, with DBP levels significantly increased post-aspirin treatment (114.04 ± 16.69) relative to pre-treatment (66.33 ± 5.61) while actin showed the opposite trend (p < 0.01 for both comparisons). Next, co-immunoprecipitation analysis of DBP and actin showed direct binding. Furthermore, a protein–protein interaction network of DBP and the other differentially expressed proteins was constructed using Ingenuity Pathway Analysis software. These results suggest that DBP acts in the actin scavenge system and consequently the increase in DBP levels correlated with aspirin therapy in cerebral thrombotic patients. These findings also suggest that aspirin may prevent platelet aggregation and thrombosis through the actions of DBP and other DBP related proteins.
Prospects of Developing Medicinal Therapeutic Strategies and Pharmaceutical Design for Effective Gluten Intolerance Treatment
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Gluten intolerance is an umbrella term for gluten-related disorders manifested in health decline as a result of the gluten ingestion. The spectrum of gluten-related disorders includes three major groups: autoimmune (mainly, Celiac Disease, CD, also known as Celiac Sprue, dermatitis herpetiformis, or gluten-sensitive ataxia), allergic (wheat allergy, WA), and non-autoimmune non-allergic (non-celiac gluten sensitivity, NCGS, or gluten sensitivity, GS). Pathogenesis and diagnostics of CD and WA are well established in contrast to NCGS, pathogenicity of which is still poorly understood and its symptoms are frequently misdiagnosed since most of the NCGS cases are currently identified via the process of CD and WA exclusion. By now, the only one proven effective way for CD treatment is gluten-free diet (GFD). However, such an increasingly gaining popularity diet is apparently unsuitable for NCGS treatment because in this case gluten does not always arise as the major or exclusive culprit of gastrointestinal disorder. Furthermore, it is some physicians’ opinion that GFD can be deficient in fiber and in other vitamins and minerals. In many cases, GFD is commercially inaccessible for the most needy, whereas strict adherence to the diet is complicated by the presence of small amounts of the gluten components in some foods and even medicines. In this regard, a number of research groups and pharmaceutical companies are extensively developing alternative medicinal approaches to GFD for effective gluten intolerance treatment. This review summarizes our understanding of gluten-related disorders, possible mechanisms of gluten intolerance activation and advantages of gluten intolerance medicinal treatment using novel drug candidates obtained with a proper pharmaceutical design.
Nanoparticles Based on Plasma Proteins for Drug Delivery Applications
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Background: Nanoparticulate delivery systems receive a lot of attention in pharmaceutical research and market due to their in vivo stability, ability to protect entrapped drug, and ease of cellular penetration. The hemocompatibility and the clearance half-life are important parameters of the nanodelivery systems that will be administered through intravenous route. Natural components, like blood plasma proteins are ideal sources of biomaterial for such systems with their long in vivo half-lives. Methods: The aim of this work is to review in vitro, in vivo and clinical findings of nanocarriers based on blood plasma proteins, namely albumin, lipoproteins, fibrin/fibrinogen, transferrin. Plasma protein based nanocarriers loaded with different bioactive molecules (i.e., anti-cancer, antiviral, anti-epileptic drugs, DNA) have been developed using different preparation methods like desolvation, emulsification, nab-technology, complexation methods. Results: Human serum albumin has attracted the most attention in the last decade as nanocarrier due to its biocompatibility, high binding capacity to various drugs, and easy derivatization by covalent methods. Commercial products of albumin nanoparticles have emerged on the market after its recognition. Low and high density lipoproteins have recently been considered as valuable natural material for preparing hemocompatible small (app 20 nm) lipid-protein vesicles. For other proteins of plasma, however, there are a limited number of studies that explored their potential as nanocarrier formulation. Therefore, there is huge research potential for investigating the proteins like globulins, fibrinogen and transferrin as part of nanocarrier core. Conclusion: Plasma protein based nanoparticulate delivery systems, especially albumin based ones have opened up and also will continue to open new treatment strategy options for treating cancer, AIDS and other complex life threatening diseases with advances in nanotechnology and science.
STAT3 Activation in Circulating Monocytes Contributes to Neovascular Age-Related Macular Degeneration
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Infiltrating macrophages are critically involved in pathogenic angiogenesis such as neovascular agerelated macular degeneration (nAMD). Macrophages originate from circulating monocytes and three subtypes of monocyte exist in humans: classical (CD14<sup>+</sup>CD16<sup>-</sup>), non-classical (CD14<sup>-</sup>CD16<sup>+</sup>) and intermediate (CD14<sup>+</sup>CD16<sup>+</sup>) monocytes. The aim of this study was to investigate the role of circulating monocyte in neovascular age-related macular degeneration (nAMD). Flow cytometry analysis showed that the intermediate monocytes from nAMD patients expressed higher levels of CX3CR1 and HLA-DR compared to those from controls. Monocytes from nAMD patients expressed higher levels of phosphorylated Signal Transducer and Activator of Transcription 3 (pSTAT3), and produced higher amount of VEGF. In the mouse model of choroidal neovascularization (CNV), pSTAT3 expression was increased in the retina and RPE/choroid, and 49.24% of infiltrating macrophages express pSTAT3. Genetic deletion of the Suppressor of Cytokine Signalling 3 (SOCS3) in myeloid cells in the LysM-Cre<sup>+/-</sup>:SOCS3<sup>fl/fl</sup> mice resulted in spontaneous STAT3 activation and accelerated CNV formation. Inhibition of STAT3 activation using a small peptide LLL12 suppressed laserinduced CNV. Our results suggest that monocytes, in particular the intermediate subset of monocytes are activated in nAMD patients. STAT3 activation in circulating monocytes may contribute to the development of choroidal neovascularisation in AMD.
Lipid-based Vesicular Nanocargoes as Nanotherapeutic Targets for the Effective Management of Rheumatoid Arthritis
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Background: Rheumatoid arthritis (RA) is an immune mediated joint-based chronic inflammatory disorder recognized by joint inflammation, destruction, pain and remission. Currently, numerous pharmacotherapeutic strategies have gained immense popularity in RA therapy and improving the patient life. </p><p> Methods: Besides, it exhibits numerous drawbacks such as requirement of high dose of drugs, unavoidable adverse effects and diseases remission. Thus, use of currently available pharmacotherapeutics employing conventional formulations can only provide therapeutic effects to a certain extent. </p><p> Results: Recent advancements in nanotechnology-based lipidic vesicular nanocarriers have led provided improved efficacy and safety for the anti-rheumatic drugs. These include liposomes, stealth liposomes, ethosomes, transfersomes, etc., which have shown their potential to improve the therapeutic efficacy of antirheumatic drugs with lesser toxicity. Although the results of animal models for use of lipid vesicular nanocarriers for drug targeting in RA have been found to be highly promising, but lack of sufficient data in a clinical setup are still evident to demonstrate their practical utility in patient populations. In this regard, considerable research studies are required for evaluating the efficacy and safety of the aforementioned nanocarriers in RA through clinical studies. </p><p> Conclusion: The present review, therefore, covers the brief pathophysiology of RA, current medication and their challenges in RA therapy. Besides, an extensive account on recent advancements in novel lipid vesicular nanocarriers in RA therapy has also been addressed with special emphasis on the patent literature too. </p><p>
The Gender Bender effect in Periodontal Immune Response
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Background: The gender and sex of an individual is known to have a significant bearing on the immune system, responsible for protection against infections and disease. Contemporary evidence suggests there exists a sexual dimorphism in the hetero immune as well as autoimmune responses in human beings and females show stronger and more vigorous immune responses to antigenic stimulations, e.g infectious diseases and vaccination. The evidence supportive to gender based heterogeneity in immune responses specifically in context of periodontal disease, is mounting in contemporary literature. </p><p> Method: A thorough and methodical search for related scientific publications have been accomplished by using different key words and terms like sex or gender based immune differences in periodontal disease, both by manual methods and on various electronic databases. Primary research articles, narrative and systematic reviews of good quality, relevant to the subject were included. </p><p> Results: The aggregate effects of the factors related to gender such as the steroid hormones as well as gene based differences in both sexes as supported by published literature are in line with the observed variation in susceptibility for chronic periodontitis in both genders , with males showing more risk for disease than women. </p><p> Conclusion: Gender as a risk factor for periodontal disease needs to identified, its underlying mechanisms to contribute needs to be revealed, so that novel strategies for risk assessment, disease identification and individualized therapeutic approaches can be developed for optimized patient care. </p><p>
An Automated High-Throughput Sample Preparation Protocol for LC-MS/MS Analysis of Glycopeptides
Τρίτη, 12 Ιουλίου 2016, 3:48:33 μμ
Current sample preparation workflows for glycopeptide analyses have low levels of automation and low sample throughput. In this study, we have developed an automated glycopeptide preparation workflow for a 96-well plate liquid handling robotic system. The protocol is based on the filter-aided capture and elution method. The glycopeptides bound to lectins were trapped on the filter, and the filters were then incubated with PNGaseF to release the glycopeptides specifically. The experimental conditions were optimized for lectin: peptide ratios using a standard glycoprotein and colon tissue proteomes. Duplicates of ten samples were processed in parallel and subjected to LC-MS/MS analysis. The results of LC-MS/MS analysis showed that 96 samples can be processed in parallel in 6.5 hours.
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