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Carbon Nanotubes In Treatment Of Arthritis: An Overview
... Carbon nanotubes (CNTs) have been explored as promising nanocarriers for the delivery of bioactives [122][123][124][125]. It has been shown that multi-walled carbon nanotubes (MWCNTs) induce the development of pro-fibrotic and inflammatory mediators and histopathological modifications in infected animal lungs. ...
Simple Summary
Cancer is a global public health issue. The development and use of in vitro cellular models with pre-clinical animal models are essential to elucidate the complex biology of cancer and test new diagnostic and therapeutic options. Three-dimensional (3D) tumor models are particularly important as they can accurately mimic the behavior of solid tumors. This review article critically discusses the suitability of 3D spheroid models in oncological research.
Abstract
Advanced tissue engineering processes and regenerative medicine provide modern strategies for fabricating 3D spheroids. Several different 3D cancer models are being developed to study a variety of cancers. Three-dimensional spheroids can correctly replicate some features of solid tumors (such as the secretion of soluble mediators, drug resistance mechanisms, gene expression patterns and physiological responses) better than 2D cell cultures or animal models. Tumor spheroids are also helpful for precisely reproducing the three-dimensional organization and microenvironmental factors of tumors. Because of these unique properties, the potential of 3D cell aggregates has been emphasized, and they have been utilized in in vitro models for the detection of novel anticancer drugs. This review discusses applications of 3D spheroid models in nuclear medicine for diagnosis and therapy, immunotherapy, and stem cell and photodynamic therapy and also discusses the establishment of the anticancer activity of nanocarriers.
... The electric and chemical properties of multi-walled carbon nanotubes (MWCNTs) are more complex due to the presence of many layers of graphene sheets that compose their structure. Nanotubes of this sort can range in size anywhere from 5 to 50 nm [106]. The structural complexity and variety in this class are a result of wrapping one CNT around another, with an interlayer dispersion of 3.4 Å. MWCNTs are, therefore, not as well understood. ...
Recent developments in nanotechnology and process chemistry have expanded the scope of nanostructures to the biomedical field. The ability of nanostructures to precisely deliver drugs to the target site not only reduces the amount of drug needed but also reduces systemic adverse effects. Carbon nanostructures gained traction in pharmaceutical technology in the last decade due to their high stability, ease of synthesis, tunable surface chemistry, and biocompatibility. Fullerene, nanotubes, nanodiamonds, nanodots, and nanoribbons are among the major carbon nanostructures that have been extensively studied for applications in tissue engineering, biosensing, bioimaging, theranostics, drug delivery, and gene therapy. Due to the fluorescent properties of functionalized nanostructures, they have been extensively studied for use as probes in cellular imaging. Moreover, these nanostructures are promising candidates for delivering drugs to the brain, bones, and deep-seated tumors. Still, research gaps need to be addressed regarding the toxicity of these materials in animals as well as humans. This review highlights the physicochemical properties of carbon nanostructures and their categories, methods of synthesis, various techniques for surface functionalization, major biomedical applications, mechanisms involving the cellular uptake of nanostructures, pharmacokinetic considerations, recent patents involving carbon-based nanostructures in the biomedical field, major challenges, and future perspectives.
Plants face a variety of abiotic stresses, which generate reactive oxygen species (ROS), and ultimately obstruct normal growth and development of plants. To prevent cellular damage caused by oxidative stress, plants accumulate certain compatible solutes known as osmolytes to safeguard the cellular machinery. The most common osmolytes that play crucial role in osmoregulation are proline, glycine-betaine, polyamines, and sugars. These compounds stabilize the osmotic differences between surroundings of cell and the cytosol. Besides, they also protect the plant cells from oxidative stress by inhibiting the production of harmful ROS like hydroxyl ions, superoxide ions, hydrogen peroxide, and other free radicals. The accumulation of osmolytes is further modulated by phytohormones like abscisic acid, brassinosteroids, cytokinins, ethylene, jasmonates, and salicylic acid. It is thus important to understand the mechanisms regulating the phytohormone-mediated accumulation of osmolytes in plants during abiotic stresses. In this review, we have discussed the underlying mechanisms of phytohormone-regulated osmolyte accumulation along with their various functions in plants under stress conditions.
Dexamethasone (DEX), a non-particulate glucocorticoid (GC) to inhibit anti-inflammatory response, has been widely used for the treatment of various diseases such as arthritis, cancer, asthma, chronic obstructive pulmonary disease, cerebral edema, and multiple sclerosis. However, prolonged and/or high-dose GC therapy can cause various serious adverse effects (adrenal insufficiency, hyperglycemia, Cushing’s syndrome, osteoporosis, Charcot arthropathy, etc). In this study, developed DEX-carbon nanotube (CNT) conjugates improved intracellular drug delivery via increased caveolin-dependent endocytosis and ultimately suppressed the expression of major pro-inflammatory cytokines in tumor necrosis factor-α (TNF-α)-stimulated human fibroblast-like synoviocytes (FLS) at low drug concentrations. Specifically, DEX on polyethylene-glycol (PEG)-coated CNTs induced caveolin uptake, recovered mitochondrial disruption, and inhibited reactive oxygen species production by targeting mitochondria that was released from the early endosome in TNF-α-stimulated FLS. The obtained results clearly demonstrated that DEX-PEG-coated CNTs significantly inhibited the inflammation by FLS in rheumatoid arthritis (RA) by achieving greater drug uptake and efficient intracellular drug release from the endosome, thus suggesting a mechanism of effective low-dose GC therapy to treat inflammatory diseases, including RA and osteoarthritis.
Repetitive intra-articular corticosteroid injections are inevitable for treating synovial inflammation in advanced arthritis. However, short-and long-term use of corticosteroids usually triggers serious side effects (i.e., adrenal insufficiency, hyperglycemia, Cushing syndrome, osteoporosis, Charcot arthropathy, etc.). This study demonstrated that conjugation of a corticosteroid (triamcinolone) on polyethylene-glycol (PEG)-fabricated multi-walled carbon nanotubes enhances intracellular drug delivery via increased lysosome transport and ultimately suppresses the expression of major pro-inflammatory cytokines (i.e., TNF-a, IL-1b, and IL-6) and matrix metalloproteinase-1 and-3 from fibroblast-like synoviocytes at a very low drug dose. Specifically, conjugation of triamcinolone and multi-walled carbon nanotubes inactivated nuclear factor-kB via inhibition of the phosphorylation of mitogen-activated protein kinases and the serine/threonine kinase Akt. In summary, low-dose triamcinolone conjugation with carbon nanotubes significantly inhibited the inflammatory response of fibroblast-like synoviocytes by achieving highly efficient intracellular trafficking and suggested a potential drug candidate for resolving side effects associated with conventional arthritis treatment.
Lecithin organogels (LOs) are semi-solid systems with immobilized organic liquid phase in 3-D network of self-assembled gelators. This paper attempts to study the various attributes of LOs, starting from selection of materials, optimization of influential components to LO specific characterization. After screening of various components (type of gelators, organic and aqueous phase) and construction of phase diagrams, a D-optimal mixture design was employed for the systematic optimization of the LO composition. The response surface plots were constructed for various response variables, viz. viscosity, gel strength, spreadability and consistency index. The optimized LO composition was searched employing overlay plots. Subsequent validation of the optimization study employing check-point formulations, located using grid search, indicated high degree of prognostic ability of the experimental design. The optimized formulation was characterized for morphology, drug content, rheology, spreadability, pH, phase transition temperatures, and physical and chemical stability. The outcomes of the study were interesting showing high dependence of LO attributes on the type and amount of phospholipid, Poloxamer™, auxillary gelators and organic solvent. The optimized LO was found to be quite stable, easily applicable and biocompatible. The findings of the study can be utilized for the development of LO systems of other drugs for the safer and effective topical delivery.
The goal of this special issue is to present, in a comprehensive fashion, the latest data on Adult onset Still’s Disease, within the broader context of the current concepts of autoinflammatory diseases and the immune mechanisms associated with them. A detailed review of Th-17 immune mechanisms and their association with autoinflammation by Waite and Skokos [1] is followed by two articles on potential disease biomarkers, serum ferritin, and IL-18 by Mehta and Efthimiou [2] and Colafrancesco et al., respectively. Mavragani et al. contributed with an up-to-date comprehensive report of Adult Still’s, while Gurion et al. [3] go in depth over its pediatric counterpart, systemic JIA. Rossi-Semerano et al. examine whether both entities fall within the autoinflammatory spectrum and Giampietro et al. provide us with a detailed account of the leading treatments targeting IL-1, the common denominator.
Adult-onset Still’s disease (AoSD) is a rare but clinically well-known, polygenic, systemic autoinflammatory disease. It is typically characterized by four main (cardinal) symptoms: spiking fever ≥39 °C, arthralgia or arthritis, skin rash, and hyperleukocytosis (≥10,000 cells/mm³). However, many other clinical features are possible, and it can appear in all age groups with potentially severe inflammatory onset accompanied by a broad spectrum of disease manifestation and complications. Hence, it remains a diagnostic challenge, and the clinician should first rule out infectious, tumoral, or inflammatory differential diagnoses. Determination of the total and glycosylated ferritin levels, although not pathognomonic, can help in diagnosis. New biomarkers have recently been described, but they need to be validated. The disease evolution of AoSD can be monocyclic, polycyclic, or chronic. In chronic disease, a joint involvement is often predominant, and erosions are noted in one-third of patients. Many progresses have been made in the understanding of the pathogenesis over the last decades. This chapter provides a comprehensive insight into the complex and heterogeneous nature of AoSD describing the identified cytokine signaling pathways and biomarkers. It also discusses the current evidence for the usage of biologics in AoSD to provide guidance for treatment decisions, taking into account both the efficacy and the safety of the different therapeutic options.
Objective:
We aimed to determine whether calprotectin and α-defensins could discriminate septic from other inflammatory arthritides.
Methods:
Synovial fluids with a predominance of neutrophils from patients with septic arthritis, pseudogout and RA were prospectively collected. Neutrophil-related proteins calprotectin and human neutrophil α-defensins levels were assessed in synovial fluids. Demographic parameters and biomarkers with P-value ⩽0.05 for differentiating septic from non-septic arthritis were included in a multivariable model. Multivariable logistic regression with stepwise selection was performed to build the final combined model.
Results:
A total of 74 patients were included: septic arthritis (n = 26), pseudogout (n = 28) and RA (n = 20). Patients with septic arthritis were more likely to be male and young, and to display higher synovial neutrophil count. Calprotectin was significantly increased in patients with septic arthritis. The multivariable model included calprotectin, synovial fluid neutrophil count and gender. Calprotectin was the only biomarker that discriminated septic arthritis from non-septic inflammatory arthritides, with 76% sensitivity, 94% specificity and a positive likelihood ratio = 12.2 at the threshold for calprotectin of 150 mg/l.
Conclusion:
Synovial fluid calprotectin is a relevant biomarker to discriminate septic arthritis from other inflammatory arthritides. This biomarker should be tested in an independent cohort.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation which ultimately leads to severe disability and premature mortality. It has a global prevalence of around 1% with the incidence among women being 2-3 times more than in men. The pathogenesis of the disease involves preclinical RA, genetic factors, and environmental factors. The RA has no known cure and the primary aim of treatment remains to attain lowest possible disease activity and recovery if possible. The present review highlights the literature on the different treatment options available for the treatment of RA, their mechanisms of action, side effects, and novel drug delivery systems that are in use for drug administration with the main focus on novel drug delivery systems of non-steroidal anti-inflammatory drugs. Different classes of drugs such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and disease modifying anti-rheumatic drugs (DMARDs), and biologics are discussed with examples of most widely used drugs among each class. Conventional drug therapy has many disadvantages like low solubility and permeability, poor bioavailability, degradation by gastrointestinal enzymes, first pass metabolism, food interactions, and toxicity. Novel drug delivery systems like microspheres, nanoparticles, dendrimers, liposomes, and so on are promising tools as they have been successful in overcoming the disadvantages associated with conventional drug delivery system. The present review squares the various novel drug delivery systems that have been explored for administering anti-rheumatic drugs and the advantages associated with these novel drug delivery systems in comparison to conventional drug delivery systems.
Currently, nanomedicines exhibit implausible capability in overcoming the hurdles faced in gene therapy, cancer treatments, as well as other life-threatening diseases. Worldwide, the unique features of carbon nanotubes (CNTs) are still being explored by researchers to tap their potential. Different types of CNTs exhibit capabilities in the transportation of vaccines, bioactives, and nucleic acids deep into the cell to previously unreachable targets. This review sheds light on the different aspects of biomedical applications and toxicities associated with functionalized CNTs. To better understand the biomedical scope of CNTs, more research into the toxicological behavior of CNTs as well as functionalized CNTs is needed. The exploration of appropriate cell lines to investigate specific receptors and intracellular targets as well as long-term toxicity beyond the proof-of-concept is needed. These issues facing the translation of surface-engineered CNT nanoarchitectures are vital to moving CNT applications from the laboratory to the clinic. The future of pharmaceutical as well as biomedical applications of CNTs will certainly depend upon whether we are able to prove their safety beyond doubt. And if we succeed through vigorous research efforts, then CNTs will have tremendous application as a freely available and economic biomaterial.
Juvenile idiopathic arthritis (JIA) is a heterogeneous condition and represents the most common rheumatologic disease in childhood. A variety of cardiac manifestations have been described in JIA. Pericarditis and myocarditis are the most common systemic subset and cardiac failure is a life-threatening complication of macrophage activation syndrome. Valvular heart disease, most frequently aortic insufficiency, has occasionally been seen in rheumatoid factor-positive polyarthritis and juvenile ankylosing spondylitis. The significance of the observed impairment in systolic and diastolic ventricle function is unclear as JIA is not associated with increased prevalence of ischemic heart disease or cardiomyopathy. The risk of premature atherosclerosis is also uncertain. Although some studies have shown endothelial and vascular dysfunction, the carotid intima-media thickness was not found to be consistently thicker than in healthy controls. In spite of decreased anaerobic fitness, the exercise capacity of children with chronic arthritis is preserved irrespective of the stage of disease activity.
This study was aimed at developing and investigating folate anchored carbon nanotubes for targeting an anti-arthritic drug, Methotrexate (MTX) to inflammatory arthritic region. The folic acid (FA) was conjugated to amidated multi-walled carbon nanotubes (MWCNTs) and confirmed by Fourier transform infrared (FTIR), 1 H NMR spectroscopy and X-ray diffraction analysis. The MTX was loaded into the pristine and functionalized-MWCNTs and extensively characterized in vitro and in vivo studies. The drug entrapment efficiency was found high in folate conjugated MWCNTs. In vitro drug release in PBS (pH 7.4) from pristine MWCNTs and folate conjugated MWCNTs formulation was found to be 66.35 ± 2.3 and 56.88 ± 1.9% in 24 h, respectively. Folate conjugated MWCNTs significantly increased (p50.005) the percentage inhibition of arthritis, biological half-life and volume of distribution of MTX as compared to MTX-loaded naked MWCNTs as well as free MTX. In in vivo biodistribution studies, MTX was found to be significantly higher (p50.005) in arthritic joints from folate functionalized MWCNTs as compared to free drug as well as drug-loaded naked MWCNTs. The present outcomes highlights the propensity of drug-loaded functionalized MWCNTs to alter the pharmacokinetics as well as sustained and targeted drug delivery system as well.
This work reports on the fabrication and performance of a simple amperometric immunosensor device to be potentially used for the detection of serum anti-citrullinated peptide antibodies (ACPAs), which are specific for rheumatoid arthritis (RA) autoimmune disease. Sera of RA patients contain antibodies to different citrullinated peptides and proteins such as fibrin or filaggrin. Herein, a chimeric fibrin-filaggrin synthetic peptide (CFFCP1) was used as a recognition element anchored to the surface of a multiwalled carbon nanotube-polystyrene (MWCNT-PS) based electrochemical transducer. The transducer fabrication process is described in detail together with its successful electrochemical performance in terms of repeatability and reproducibility of the corresponding amperometric response. The resulting immunosensor approach was initially tested in sera of rabbits previously inoculated with the synthetic peptide and eventually applied to the detection of ACPAs in human sera. A comparative study was carried out using control serum from a blood donor, which demonstrated the selectivity of the immunosensor response and its sensitivity for the detection of anti-CFFCP1 antibodies present in RA patients.
Rheumatoid arthritis is the most common inflammatory arthritis and is a major cause of disability. It existed in early Native American populations several thousand years ago but might not have appeared in Europe until the 17th century. Early theories on the pathogenesis of rheumatoid arthritis focused on autoantibodies and immune complexes. T-cell-mediated antigen-specific responses, T-cell-independent cytokine networks, and aggressive tumour-like behaviour of rheumatoid synovium have also been implicated. More recently, the contribution of autoantibodies has returned to the forefront. Based on the pathogenic mechanisms, specific therapeutic interventions can be designed to suppress synovial inflammation and joint destruction in rheumatoid arthritis.
The coalescence, seen frequently in the caudal vertebrae of the giant dinosaur Dipiodocus longus, has been re-examined. A comparison with vertebral fusion in contemporary species suggests that the changes in the dinosaur were of traumatic rather than rheumatoid type.
Esseva re-examinate le frequentemente vidite coalescentia de vertebras caudal del dinosauro gigante Diplodocus longus. Le comparation con fusion vertebral in species contemporanee suggere que le alterationes in le dinosauro esseva de henere traumatic plus tosto que rheumatoide.
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