Pathophysiology to advanced intra-articular drug delivery strategies: Unravelling rheumatoid arthritis.

Rheumatoid arthritis (RA) is one of the most prevalent life-long autoimmune diseases with an unknown genesis. It primarily causes chronic inflammation, pain, and synovial joint-associated cartilage and bone degradation. Unfortunately, limited information is available regarding the etiology and pathogenesis of this chronic joint disorder. In the last few decades, an improved understanding of RA pathophysiology about key immune cells, antibodies, and cytokines has inspired the development of several anti-rheumatic drugs and biopharmaceuticals to act on RA-affected joints. However, life-long frequent systemic high doses of commercially available drugs are currently a limiting factor in the efficient management of RA. To address this issue, various single and double-barrier intra-articular drug delivery systems (IA-DDSs) such as nanocarriers, microparticles, hydrogels, and particles-hybrid hydrogel composite have been developed which can exclusively target the RA-affected joint cavity and release the precisely controlled therapeutic drug concentration for prolonged time whilst avoiding the systemic toxicity. This review provides a comprehensive overview of the pathogenesis of RA and discusses the rational design and development of biomaterials-based novel IA-DDs, ranging from conventional to advanced systems, for improved treatment of RA. Therefore, this review aims to unravel the pathophysiology of rheumatoid arthritis and explore cutting-edge IA-DD strategies exploiting biomaterials. It offers researchers a consolidated and up-to-date resource platform to analyze existing knowledge, identify research gaps, and contribute to the scientific literature.

In-Silico Prediction of Novel Fused Quinazoline Based Topoisomerase Inhibitors as Anticancer Agents.

BACKGROUND: The prospective uses of tryptanthrin and its analogues in cancer chemotherapy are well known, and they are also predicated on their capacity to reverse drug resistance in cancer therapy. OBJECTIVE: The current project entails developing a novel hybrid analogue that includes modifying the tryptanthrin molecule at the C-6 carbonyl position and is expected to exhibit substantial anticancer action. METHODS: In the ATPase domain of human topoisomerase II, a series of 162 substituted Schiff base analogues of tryptanthrin were developed, and molecular docking experiments were done using Gold 5.1 software interfaced with Hermes 1.6.2. (PDB ID: 1ZXM). RESULTS: Most of the compounds were found to have Goldscore above 100 and formed interactions with the residues like ASN91, ALA92, ASN95, ARG98, ASN120, ILE125, ILE141, PHE142, SER149, THR215, and ILE217. Compound RK-149 had highest Goldscore of 132.59, forming an interaction with ASN91 but had a lesser Goldscore as compared to the standard drug etoposide and had a better score than tryptanthrin. CONCLUSION: The nitrogen in the imine bond of the proposed compounds is responsible for significant interactions, demonstrating their anticancer potential.

Preparation of graphene oxide-graphene quantum dots hybrid and its application in cancer theranostics.

Currently, an enormous amount of cancer research based on two-dimensional nano-graphene oxide (GO), as well as zero-dimensional graphene quantum dots (GQDs), is being carried out in the fields of therapeutics and diagnostics. However, the exploration of their hybrid "functional" nanomaterials in the theranostic system is still rare. In the current study, a stable complex of GO and GQDs was formed by an electrostatic layer-by-layer assembly via a polyethylene imine bridge (GO-PEI-GQDs). Furthermore, we compared separate mono-equivalents of the GO-PEI-GQDs complex - GO and GQDs, in terms of cell imaging (diagnostics), photothermal, and oxidative stress response in breast cancer cells (MDA-MB-231). GO-PEI-GQDs showed an excellent photothermal response (44-49 °C) upon 808 nm laser (0.5 W cm-2) exposure for 5 min at a concentration up to 50 µg/mL. We report new synergistic properties of GO-PEI-GQDs such as stable fluorescence imaging and enhanced photothermal and cytotoxic activities on cancer cells. Composite materials made up of GO and GQDs combining diverse properties help to study 2D-0D heterosystems and improve specific therapeutic systems in theranostics.

Thiazole Containing Heterocycles with Antimalarial Activity.

BACKGROUND: Heterocyclic compounds are the main class of medicinally important compounds. Many heterocyclic compounds bearing a five-membered ring in their structure have a good spectrum of biological activities. Thiazole is an important class of five-membered heterocyclic compounds. Thiazole and its derivatives exhibited a broad range of biological activities due to the presence of various reaction posseses. Thiazole, heterocyclic nucleus is present in several potent pharmacologically active molecules such as Sulfathiazole (antimicrobial drug), Ritonavir (antiretroviral drug), Tiazofurin (antineoplastic drug) and Abafungin (antifungal drug) etc. The search for some novel biologically active thiazoles is to be continued in the field of medicinal chemistry for investigators. An aim of this review is to identify and try making a SAR (Structure Activity Relationship) of substituted thiazole nucleus as possible new antimalarials. METHOD: Author undertook a structured search of bibliographic databases for peerreviewed research literature using a focused review question and inclusion/exclusion criteria. The quality of retrieved papers was appraised using standard tools. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to analyse the interventions and findings of included studies using a conceptual framework. RESULT: Fifteen papers were included in the review; the majority were described about many biological activity of thiazole nucleus. Seven papers were find that had impacted upon the thaizoles as antimalarials. Some papers focused on the design, synthesis and antimalarial activity evaluation of thiazole derivatives. This review identified and made a SAR (Structure Activity Relationship) of substituted thiazole nucleus as possible new antimalarials. CONCLUSION: This review describes ongoing research in the search for novel thiazoles as targets and new antimalarial drug molecules.

Graphene Quantum Dots for Cell Proliferation, Nucleus Imaging, and Photoluminescent Sensing Applications.

We report a simple one-pot microwave assisted "green synthesis" of Graphene Quantum Dots (GQDs) using grape seed extract as a green therapeutic carbon source. These GQDs readily self-assemble, hereafter referred to as "self-assembled" GQDs (sGQDs) in the aqueous medium. The sGQDs enter via caveolae and clathrin-mediated endocytosis and target themselves into cell nucleus within 6-8 h without additional assistance of external capping/targeting agent. The tendency to self-localize themselves into cell nucleus also remains consistent in different cell lines such as L929, HT-1080, MIA PaCa-2, HeLa, and MG-63 cells, thereby serving as a nucleus labelling agent. Furthermore, the sGQDs are highly biocompatible and act as an enhancer in cell proliferation in mouse fibroblasts as confirmed by in vitro wound scratch assay and cell cycle analysis. Also, photoluminescence property of sGQDs (lifetime circa (ca.) 10 ns) was used for optical pH sensing application. The sGQDs show linear, cyclic and reversible trend in its fluorescence intensity between pH 3 and pH 10 (response time: ~1 min, sensitivity -49.96 ± 3.5 mV/pH) thereby serving as a good pH sensing agent. A simple, cost-effective, scalable and green synthetic approach based sGQDs can be used to develop selective organelle labelling, nucleus targeting in theranostics, and optical sensing probes.

Evolution of thiol-capped gold nanoclusters into larger gold nanoparticles under electron beam irradiation.

We report in situ transformation of glutathione-capped red-fluorescent gold nanoclusters (AuNCs) into larger gold nanoparticles (AuNPs) embedded on a copper grid under high energy electron beam of Field Emission Gun Transmission Electron Microscope (FEG-TEM). Electron beam irradiation causes coalescing of individual finer AuNCs into bigger discrete AuNPs as a function of electron dose rate and time. The coalescence was closely studied over time and the mechanism is discussed. The study will help to understand the structural and morphological changes that occur in AuNCs inside FEG-TEM due to prolonged electron beam exposure.

Structure-guided discovery of 1,3,5-triazine-pyrazole conjugates as antibacterial and antibiofilm agent against pathogens causing human diseases with favorable metabolic fate.

Impressed by the exceptional antibacterial activity exhibited by our earlier designed molecules originating from 1,3,5-triazine, the present study was undertaken to synthesize a novel series of 1,3,5-triazine-pyrazole conjugates to bring diversity around the core skeleton. The target analogues showed potent antibacterial activity against tested Gram-positive and Gram-negative microorganisms. The toxicity and metabolic site prediction studies were also held out to set an effective lead candidate for the future antibacterial drug discovery initiatives.

Utilisation of Home Laundry Effluent (HLE) as a catalyst for expeditious one-pot aqueous phase synthesis of highly functionalised 4-thiazolidinones.

BACKGROUND: The impact of global warming and associated climate changes have built up pressure to focus on the option of green chemistry over traditional one for long term sustainability of the environment. Considering the fact, for the first time, efficient HLE catalysed expeditious one-pot synthesis of highly functionalised 4-thiazolidinones has been developed. RESULTS: These hybrid molecules were synthesized in good to excellent yields. The ease of work-up of the reactions less time required and mild conditions are notable features of this protocol. It was inferred that halogen containing derivatives were well suited to this condensation-cyclization reaction with varying rates to afford 4-thiazolidine derivatives. In general, the substitution on the aldehyde part was shown as a main determinant for reaction time and the product yield. CONCLUSION: For the first time home laundry effluent (HLE) owing to the surfactant like property has been successfully utilised as catalyst for the synthesis of a series of novel 4-thiazolidinone derivatives through one pot, three component condensation-cyclization reaction. The uniqueness of the present protocol lies in the operational simplicity, ability to reduce the demand for organic solvents, reduce the energy and carbon footprint, and meet a wide range of economic needs.