Phytochemicals with nanoparticles and their potential applications in medicine – A review

Phytochemicals having multiple properties which are used to cure various diseases such as cancer, diabetes, neurodegeneration, angiogenesis, aging, inflammatory, cardiovascular and arthritic disease, etc., Extensive use of phytochemicals and their derivatives leads to unavailability or scarcity of products in nature. Despite this episode, the nanotechnology resolves the setback of handling phytochemicals by increasing their bioavailability, long-lost acting, target-specific and less or no toxicity. Here, we focused on the 24 known phytochemicals and preparation of NPs without discriminating the polymers and metals in NPs. All the phytochemicals did not fully satisfy the toxicological hazards, physical-pharmaceutical challenges, bioethical and health issues research. Hence these NPs and their NP incorporated phytochemicals need to be characterized in a way to give direct usage to the common man. Commercialization of NP formulations in pharmaceuticals needs statutory regulation norms for complete satisfaction and safety for end-users. As of now, many NP mediated pharmaceutical products are available in the market with full-fledged but still many unrevealed about their fate in the environment. In this review, the characterization of nanoparticles, the transparent benefit of nanoparticles (NPs), and their current application in various fields has been discussed.

Zinc and Cadmium in the Aetiology and Pathogenesis of Osteoarthritis and Rheumatoid Arthritis

Osteoarthritis (OA) and rheumatoid arthritis (RA) are inflammatory articular conditions with different aetiology, but both result in joint damage. The nutritionally essential metal zinc (Zn2+) and the non-essential metal cadmium (Cd2+) have roles in these arthritic diseases as effectors of the immune system, inflammation, and metabolism. Despite both metal ions being redox-inert in biology, they affect the redox balance. It has been known for decades that zinc decreases in the blood of RA patients. It is largely unknown, however, whether this change is only a manifestation of an acute phase response in inflammation or relates to altered availability of zinc in tissues and consequently requires changes of zinc in the diet. As a cofactor in over 3000 human proteins and as a signaling ion, zinc affects many pathways relevant for arthritic disease. How it affects the diseases is not just a question of zinc status, but also an issue of mutations in the many proteins that maintain cellular zinc homoeostasis, such as zinc transporters of the ZIP (Zrt-/Irt-like protein) and ZnT families and metallothioneins, and the multiple pathways that change the expression of these proteins. Cadmium interferes with zinc’s functions and there is increased uptake under zinc deficiency. Remarkably, cadmium exposure through inhalation is now recognized in the activation of macrophages to a pro-inflammatory state and suggested as a trigger of a specific form of nodular RA. Here, we discuss how these metal ions participate in the genetic, metabolic, and environmental factors that lead to joint destruction. We conclude that both metal ions should be monitored routinely in arthritic disease and that there is untapped potential for prognosis and treatment.

OP0099 FUNCTIONAL MAPPING OF SYNOVIAL FIBROBLAST POPULATIONS IN HEALTH AND ARTHRITIC DISEASE: INSIGHTS INTO THE PATHOGENIC REMODELING OF SYNOVIAL MICROENVIRONMENT

Background:Our previous studies highlighted the fundamental in vivo role of synovial fibroblasts (SFs) in TNF-mediated murine chronic arthritis1,2and recent findings identified different SF identities based on their transcriptomic profiles with distinct contributions in acute, autoimmunity-based, murine arthritis3.Objectives:In this study, we focus on delineating the map of SF subpopulations in healthy joint and in the course of arthritic disease and the underlying regulatory networks functioning towards pathogenicity.Methods:Sorted single cell suspensions (CD45-, Pdpl+) and their fragmented nuclei from synovial joints of WT, early and late arthritic hTNFtg mice were processed for scRNAseq and scATAC employing a droplet-based technology (10x Genomics). To define the transcriptional and epigenetic signatures originating from the two different assays, we developed an integrative analysis pipeline based on the Seurat software package (v3.1). Meta-analysis of previously reported data of K/BxN serum transfer of arthritis was employed to define commonalities and differences in SF subsets among murine modelled disease.Results:The transition from healthy to chronically affected synovial microenvironment (SME) due to overexpression of hTNF is characterized by a dynamic transformation of SF clusters. The Lining arthritic Thy1lowsynovial layer (L-SFs) is hyper-populated while Sub-Lining Thy1highSF clusters (SL-SFs) are remodeled towards catabolic and inflammatory phenotypes compared to naïve SF organization pattern. Interestingly, trajectory analysis revealed that the SL clusters, which normally exhibit a gradual developmental-like process towards different profiles, differentially change during disease. We identified that the previously reported proliferating SL cluster is absent in healthy synovium, dominates mainly in early stages of chronic arthritis and it is closely related to the L-SFs. Mapping of the gene regulatory networks by RNAseq was supported by scATAC analysis. Similarly, meta-analysis of SF profiles derived from naïve and the K/BxN-serum–treated mice showed significant differences, possibly reflecting the phenotypes of the two established models of arthritis.Conclusion:Our approach unravels for the first time the regulatory heterogeneity and gene expression profiling of SF subpopulations in normal synovium, and reveals deep biological insights of the functional re-organization of SME during development of disease. It further identifies the common and divergent features of the different subtypes of murine arthritis that may well reflect the diversity of RA subtypes and the response to therapies.References:[1]Armaka et al; J Exp Med (2008): 205(2):331-7.[2]Armaka et al; Nat Commun (2018): 9(1):618.[3]Croft et al; Nature (2019): 570(7760):246-251.Disclosure of Interests:None declared

Associations between Adipokines in Arthritic Disease and Implications for Obesity

Secretion from adipose tissue of adipokines or adipocytokines, comprising of bioactive peptides or proteins, immune molecules and inflammatory mediators, exert critical roles in inflammatory arthritis and obesity. This review considers the evidence generated over the last decade regarding the effects of several adipokines including leptin, adiponectin, visfatin, resistin, chemerin and apelin, in cartilage and bone homeostasis in the pathogenesis of rheumatoid arthritis and osteoarthritis, which has important implications for obesity.

Chikungunya Virus Fidelity Variants Exhibit Differential Attenuation and Population Diversity in Cell Culture and Adult Mice

ABSTRACTChikungunya virus (CHIKV) is a reemerging global health threat that produces debilitating arthritis in people. Like other RNA viruses with high mutation rates, CHIKV produces populations of genetically diverse genomes within a host. While several known CHIKV mutations influence disease severity in vertebrates and transmission by mosquitoes, the role of intrahost diversity in chikungunya arthritic disease has not been studied. In this study, high- and low-fidelity CHIKV variants, previously characterized by alteredin vitropopulation mutation frequencies, were used to evaluate how intrahost diversity influences clinical disease, CHIKV replication, and antibody neutralization in immunocompetent adult mice inoculated in the rear footpads. Both high- and low-fidelity mutations were hypothesized to attenuate CHIKV arthritic disease, replication, and neutralizing antibody levels compared to wild-type (WT) CHIKV. Unexpectedly, high-fidelity mutants elicited more severe arthritic disease than the WT despite comparable CHIKV replication, whereas a low-fidelity mutant produced attenuated disease and replication. Serum antibody developed against both high- and low-fidelity CHIKV exhibited reduced neutralization of WT CHIKV. Using next-generation sequencing (NGS), the high-fidelity mutations were demonstrated to be genetically stable but produced more genetically diverse populations than WT CHIKV in mice. This enhanced diversification was subsequently reproduced after serialin vitropassage. The NGS results contrast with previously reported population diversities for fidelity variants, which focused mainly on part of the E1 gene, and highlight the need for direct measurements of mutation rates to clarify CHIKV fidelity phenotypes.IMPORTANCECHIKV is a reemerging global health threat that elicits debilitating arthritis in humans. There are currently no commercially available CHIKV vaccines. Like other RNA viruses, CHIKV has a high mutation rate and is capable of rapid intrahost diversification during an infection. In other RNA viruses, virus population diversity associates with disease progression; however, potential impacts of intrahost viral diversity on CHIKV arthritic disease have not been studied. Using previously characterized CHIKV fidelity variants, we addressed whether CHIKV population diversity influences the severity of arthritis and host antibody response in an arthritic mouse model. Our findings show that CHIKV populations with greater genetic diversity can cause more severe disease and stimulate antibody responses with reduced neutralization of low-diversity virus populationsin vitro. The discordant high-fidelity phenotypes in this study highlight the complexity of inferring replication fidelity indirectly from population diversity.