Current Pharmaceutical Design - Volume 25, Issue 27, 2019

Background: Ferritin is a molecule that plays many roles being the storage for iron, signalling molecule, and modulator of the immune response. Methods: Different electronic databases were searched in a non-systematic way to find out the literature of interest. Results: The level of ferritin rises in many inflammatory conditions including autoimmune disorders. However, in four inflammatory diseases (i.e., adult-onset Still’s diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and sepsis), high levels of ferritin are observed suggesting it as a remarkable biomarker and pathological involvement in these diseases. Acting as an acute phase reactant, ferritin is also involved in the cytokine-associated modulator of the immune response as well as a regulator of cytokine synthesis and release which are responsible for the inflammatory storm. Conclusion: This review article presents updated information on the role of ferritin in inflammatory and autoimmune diseases with an emphasis on hyperferritinaemic syndrome.

Background: Migraine is a diffuse and disabling disease. Its pathophysiology is complex and involves both central and peripheral dysfunctions. Objective: This review will discuss the pathogenesis of migraine from the origin of the neuro-inflammatory theory, to the modern pathophysiological model and the latest therapies. Methods: PUBMED and EMBASE (up to May 2019) were searched for: migraine, inflammation, immunomodulation. An additional search was carried out from the bibliography of previous review articles. Results: Migraine was thought to be mainly a vascular disorder, according to the so-called “vascular theory”. Based on animal models, a new hypothesis called “the neuro-inflammatory” was conceived at the end of the 20th century. The growing knowledge about the trigeminovascular system and its role in the inflammatory-pain pathway, allowed to identify other specific neurotransmitters, such as the Calcitonin Gene-Related Peptide and Pituitary Adenylate Cyclase-Activating Peptide. Evidence was provided that the inflammatory-pain system could become sensitised and, due to this sensitisation, the pain could also perpetuate, even in the absence of any triggers of the migraine attack. At last, brain immune cells modification during cortical spreading depression in migraine was demonstrated, along with the existence and function of the glymphatic system. The better comprehension of the immune system abnormalities allowed the development of new immunomodulating drugs: the monoclonal antibodies against the CGRP or the CGRP receptor. Moreover, new insights into the molecular mechanism of CGRP, and the function of C-fibres and Aδ-fibres, highlighted the mechanism of action of Botulinum Toxin type A in the treatment of chronic migraine.

Background: Chemokines are a family of low molecular weight proteins that induce chemotaxis of inflammatory cells, which mainly depends on the recognition of a chemo-attractant gradient and interaction with the substratum. In Rheumatoid Arthritis (RA), abundant chemokines are expressed in synovial tissue, cause inflammatory cells migration into the inflamed joint that necessitates the formation of new blood vessels i.e. angiogenesis. Over the decades, studies showed that continuous inflammation may lead to the loss of tissue architecture and function, causing severe disability and cartilage destruction. In spite of the advancement of modern drug therapy, thousands of arthritic patients suffer mortality and morbidity globally. Thus, there is an urgent need for the development of novel therapeutic agents for the treatment of RA. Methods: This review is carried out throughout a non-systematic search of the accessible literature, will provide an overview of the current information of chemokine in RA and also exploring the future perspective of the vital role of targeting chemokine in RA treatment. Results: Since, chemokines are associated with inflammatory cells/leucocyte migration at the site of inflammation in chronic inflammatory diseases and hence, blockade or interference with chemokines activity showing a potential approach for the development of new anti-inflammatory agents. Currently, results obtained from both preclinical and clinical studies showed significant improvement in arthritis. Conclusion: This review summarizes the role of chemokines and their receptors in the pathogenesis of RA and also indicates possible interactions of chemokines/receptors with various synthetic and natural compounds that may be used as a potential therapeutic target in the future for the treatment of RA.

Background: Autoimmune diseases result from the interplay of cellular effectors like T and B cells, regulatory cells in addition to molecular factors like cytokines and regulatory molecules. Methods: Different electronic databases were searched in a non-systematic way to find out the literature of interest. Results: Pathogenesis of autoimmune diseases involves typical factors such as genetic background including HLA and non HLA system genes, environmental factors such as infectious agents and inflammatory cells mainly T and B lymphocytes abnormally activated leading to immune dysfunction. Other recently reported less typical factors such as micro-RNAs, circular RNAs, myeloperoxidase, vimentine and microbiome dysbiosis seem to be potential target therapies. Conclusion: We aimed in this manuscript to review common factors in the pathogenesis of autoimmune diseases.

Nanomaterial-based drug delivery holds tremendous promise for improving targeting capacity, biodistribution, and performance of therapeutic/diagnostic agents. Accelerating the clinical translation of current nanomedicine requires an in-depth understanding of the mechanism underlying the dynamic interaction between nanomaterials and cells in a physiological/pathophysiological-relevant condition. The introduction of the advanced microfluidic platform with miniaturized, well-controlled, and high-throughput features opens new investigation and application opportunities for nanomedicine evaluation. This review highlights the current state-of-theart in the field of 1) microfluidic-assisted in vitro assays that are capable of providing physiological-relevant flow conditions and performing high-throughput drug screening, 2) advanced organ-on-a-chip technology with the combination of microfabrication and tissue engineering techniques for mimicking microenvironment and better predicting in vivo response of nanomedicine, and 3) the integration of microdevice with various detection techniques that can monitor cell-nanoparticle interaction with high spatiotemporal resolution. Future perspectives regarding optimized on-chip disease modeling and personalized nanomedicine screening are discussed towards further expanding the utilization of the microfluidic-based platform in assessing the biological behavior of nanomaterials.

Background: Osteoarthritis (OA) is a common joint disease characterized by cartilage degeneration. Long non-coding RNAs (lncRNAs) have been associated with inflammatory diseases, including OA. Here, we investigated the potential molecular role of lncRNAs in OA pathogenesis. Methods: ATDC5 cells were treated with lipopolysaccharides (LPS), and qPCR was used to identify and determine expression of potential lncRNAs involved in LPS-induced chondrocyte injury. Cell viability, apoptosis, and expression of cartilage-related genes and inflammatory cytokines were assessed after CTD-2574D22.4 knockdown. Results: After LPS stimulation, CTD-2574D22.4 was found to be the second highest up-regulated gene, and the enhanced expression was validated in OA chondrocytes. Moreover, CTD-2574D22.4 inhibition significantly rescued cell viability, suppressed by LPS stress, and markedly attenuated LPS-induced apoptosis. The expression of cartilage-degrading enzymes MMP-13 and ADAMTS-5 were increased, while type II collagen was reduced after LPS treatment. This trend was largely reversed by CTD-2574D22.4 knockdown. Additionally, mRNA and protein levels of key inflammatory cytokines (TNF-a, IL-6, and IL-1β) were significantly elevated in the LPS group and partially relieved upon CTD-2574D22.4 knockdown. Conclusion: CTD2574D22.4 knockdown ameliorates LPS-induced cartilage injury by protecting chondrocytes from apoptosis via anti-inflammation and anti- cartilage-degrading pathways. Thus, CTD2574D22.4 might be a potential diagnostic and therapeutic target for OA.

Background: Owing to its multifactorial intricate pathogenesis, combined therapeutic regimen is considered appropriate for the treatment of osteoporosis. However, a multi-drug regimen is also associated with adverse effects due to the non-specific distribution of drugs. Therefore, the present study aims for efficient codelivery of risedronate (RDN) (a potent bone anti-resorptive drug) and teriparatide (TPD) (anabolic agent) as hyaluronic acid (HA)-modified chitosan nanoparticles (NPs). Methods: RDN/TPD NPs were synthesized using the high- pressure homogenization – solvent evaporation technique. The fabricated NPs were then characterized and optimized for suitable physicochemical characteristics. The optimized NPs were then evaluated for bone remodeling potential via assessment of time-mannered modulation in proliferation, differentiation, and mineralization of osteoblasts. Results: Results showed that HA-RDN/TPD NPs exhibited excellent physicochemical characteristics (nanoscopic size, stable zeta potential, high entrapment efficiency, and smooth spherical shape) and remained stable upon storage in the refrigerator. Assessment of various aspects of the cell growth cycle (i.e., proliferation, differentiation, and mineralization) evidenced promising bone regeneration efficacy of HA-RDN/TPD NPs. Conclusion: This new strategy of employing simultaneous delivery of anti-resorptive and bone-forming agents would open new horizons for scientists, researchers, and healthcare providers as an efficient pharmacotherapy for the treatment of osteoporosis.

Background: Aggregation of Amyloid β (Aβ) peptide is a crucial feature of Alzheimer disease (AD) pathogenesis. In fact, Aβ peptides are misfolded and aggregated to frame Amyloid fibrils, which is considered as one of the major contributing events in the onset of AD. All these observations have prompted the researchers to design therapeutic molecules with robust anti-Aβ aggregation potential. Interestingly, in the last few decades, drug repurposing has turned into a fruitful and savvy approach for the treatment of several diseases. Bexarotene is an anticancer drug that has been under consideration for its ability to suppress Aβ-peptide aggregation. However, the exact mechanistic aspect of suppression of Aβ-peptide accumulation has not yet been completely revealed. Methods: In the present study, we have attempted to decipher the mechanistic aspects of the anti-aggregation potential of bexarotene by using the computational biology approach. Results: We have observed the effect of ‘Aβ-bexarotene’ interaction on the aggregation ability of the Aβ-peptide and decoded the involvement of receptor for advanced glycation end products (RAGE) and beta-secretase (BACE-1). A deep structural analysis of Aβ upon binding with bexarotene revealed critical binding sites and structural twists involved in Aβ aggregation. It is evident from the present that bexarotene could significantly restrain the process of primary nucleation of Aβ. In addition, bexarotene showed a strong interaction with RAGE and BACE-1, suggesting them as plausible targets for the neuro-therapeutic action of bexarotene. Conclusion: Hence, we could safely suggest that bexarotene is a potent drug candidate that could reduce Aβ- peptide aggregation by applying different mechanistic pathways. These results might boost the portfolio of pharmaceutical companies looking for the development of new chemical entities against AD.