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.

Synthesis and characterization of an injectable microparticles integrated hydrogel composite biomaterial: In-vivo biocompatibility and inflammatory arthritis treatment.

Polymeric hydrogels and microparticles have been widely used for localized drug delivery applications for the treatment of arthritis. Nonetheless, owing to initial burst drug release, non-specific biodistribution and low retention time at the target site in body, these polymeric drug delivery systems have been found with low in-vivo performance. Hence, the above limitations need to be resolved by designing a smart novel drug delivery system which is the current need in biomedicine. Herein, a novel localized injectable thermoresponsive microparticles embedded hydrogel composite drug delivery system has been developed for the treatment of inflammatory arthritis. In the current study, methotrexate (MTX) loaded alginate microparticles (MTX-Microparticles) are embedded into thermoreversible hydrogel matrix (MTX-MPs-H) prepared by physical blending of sodium hyaluronate and methylcellulose (SHMC). Microparticles-hydrogel composite system exhibited appropriate in-vitro thermoreversibility (sol at 4 °C and gel at 37 °C), biocompatibility (>80 %), hemocompatibility, and controlled drug release profile. The in-vivo biocompatibility studies for 10 days revealed that composite system is non-toxic in nature. The developed MTX-MPs-H composite drug delivery system effectively decreased the swelling/ inflammation of the arthritis affected paw in wistar rats in comparison to only alginate microparticles and pure MTX up to 30 days.

Liposomal nanotheranostics for multimode targeted in vivo bioimaging and near-infrared light mediated cancer therapy.

Developing a nanotheranostic agent with better image resolution and high accumulation into solid tumor microenvironment is a challenging task. Herein, we established a light mediated phototriggered strategy for enhanced tumor accumulation of nanohybrids. A multifunctional liposome based nanotheranostics loaded with gold nanoparticles (AuNPs) and emissive graphene quantum dots (GQDs) were engineered named as NFGL. Further, doxorubicin hydrochloride was encapsulated in NFGL to exhibit phototriggered chemotherapy and functionalized with folic acid targeting ligands. Encapsulated agents showed imaging bimodality for in vivo tumor diagnosis due to their high contrast and emissive nature. Targeted NFGL nanohybrids demonstrated near infrared light (NIR, 750 nm) mediated tumor reduction because of generated heat and Reactive Oxygen Species (ROS). Moreover, NFGL nanohybrids exhibited remarkable ROS scavenging ability as compared to GQDs loaded liposomes validated by antitumor study. Hence, this approach and engineered system could open new direction for targeted imaging and cancer therapy.

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.

Plasmonic carbon nanohybrids for repetitive and highly localized photothermal cancer therapy.

Integrating metallic and non-metallic platform for cancer nanomedicine is a challenging task and bringing together multi-functionality of two interfaces is a major hurdle for biomaterial design. Herein, NIR light responsive advanced hybrid plasmonic carbon nanomaterials are synthesized, and their properties toward repetitive and highly localized photothermal cancer therapy are well understood. Graphene oxide nanosheets having thickness of ∼2 nm are synthesized using modified Hummers' method, thereafter functionalized with biodegradable NIR light responsive gold deposited plasmonic polylactic-co-glycolic acid nanoshells (AuPLGA NS, tuned at 808 nm) and NIR dye (IR780) to examine their repetitive and localized therapeutic efficacy as well resulting side effects to nearby healthy cells. It is observed that AuPLGA NS decorated graphene oxide nanosheets (GO-AuPLGA) and IR780 loaded graphene oxide nanosheets (GO-IR780) are capable in standalone complete photothermal ablation of cancer cells within 4 min. of 808 nm NIR laser irradiation and also without the aid of any anticancer drugs. However, GO-AuPLGA having the potential for repetitive photothermal treatment of a big tumor, ablate the cancer cells in highly localized fashion, without having side effects on neighboring healthy cells.

Constrictive pericarditis: retrospective study of 109 patients.

Background Chronic constrictive pericarditis is the most common diastolic disorder of the heart. Non-elasticity of the pericardium with impaired cardiac diastolic function is constriction. Chronic constrictive pericarditis is the result of scarring and fibrosis in mid and late diastole. The clinical presentation is similar to that of right heart failure. Historically, the etiology is helpful but not diagnostic. Echocardiography and a hemodynamic study are the main diagnostic tools. A thick pericardium of more than 4 mm is not necessarily constrictive, but thickness ≥7 mm is highly specific for constrictive features. Pericardiectomy is usually associated with early normalization of hemodynamics, which can be achieved via a mid-sternotomy or left anterolateral thoracotomy. Methods Data of 109 patients who underwent pericardiectomy from January 1987 to June 2016 were reviewed retrospectively. Results The outcome of our 109 cases consisted of mortality in 2 patients only. Conclusion Progressive, fibrotic, thickened, adherent inflammatory changes in response to various pathologies of the pericardium impairing diastolic filling can be treated by pericardiectomy. Pericardiectomy can be achieved by a mid-sternotomy or anterolateral thoracotomy without any difference in outcome. The initial hemodynamic and clinical result may not always be dramatic but continued improvement is definite because of progressive enlargement of left ventricular dimensions.

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.

A novel terephthalaldehyde based turn-on fluorescent chemosensor for Cu2+ and its application in imaging of living cells.

A new terephthaldehyde-based chemosensor 1 bearing an aminophenol recognition unit has been synthesized and applied to the fluorescent sensing of metal ions. Molecular system 1 acts as a highly selective and sensitive fluorescence turn-on sensor for Cu2+. The sensing mechanism has been explored. It is proposed that Cu2+ binds with the imine and hydroxyl moiety of 1 in 1 : 2 binding stoichiometry, thereby enhancing the fluorescence at 386 nm. The detection limit and association constant (Ka) of 1 with Cu2+ were found to be 0.62 µM and 6.67 × 104 M-1, respectively. Chemosensor 1 has shown excellent specificity towards Cu2+ and has been successfully applied to the determination of Cu2+ in live L929 cells.

Highly selective optical and reversible dual-path chemosensor for cyanide detection and its application in live cells imaging.

A new biocompatible fluorescent receptor 1 was synthesized by conjugating diaminomaleonitrile (DMN) with benzothiazole unit, and characterized by single X-ray. In DMF/water (1:1, v/v), the receptor 1 showed a selectivity turn-on fluorescence at 517nm in the presence of CN-. Receptor 1 showed a detection limit down to 0.16µM without any interference from other tested anions. The reversibility and reusability of 1 for the detection of CN- ion was also tested for five cycles indicating the probe 1 could be used in a reversible manner. Importantly, the receptor 1 showed excellent cells viability and was successfully applied for the detection of CN- in live mouse fibroblast cells L929 cells.

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.

Bidirectional Glenn with interruption of antegrade pulmonary blood flow: Which is the preferred option: Ligation or division of the pulmonary artery?

We report a rare complication of massive aneurysm of the proximal ligated end of the main pulmonary artery which occurred in the setting of a patient with a functionally univentricular heart and increased pulmonary blood flow undergoing superior cavopulmonary connection. Awareness of this possibility may guide others to electively transect the pulmonary artery in such a clinical setting.

Tuberculous constrictive pericarditis and atrial septal defect: Surgical challenge.

Tuberculous constrictive pericarditis with atrial septal defect is very rare. A 23-year-old man required pericardiectomy and atrial septal defect closure under cardiopulmonary bypass by cannulating the aorta and right atrium because femoral cannulation was not possible and the venae cavae could not be visualized. He was discharged in a satisfactory condition on the 15th postoperative day, but returned one month later with swelling all over his body and dyspnea on exertion. Echocardiography showed atrial septal defect patch dehiscence and a bidirectional shunt with a collection or mass compressing the right ventricle. Subxiphoid exploration was carried out, and the swelling subsided.

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.

An alternative technique for cannulation of the left superior caval vein by dislocating the heart into the right thoracic cavity.

We describe a technique of direct cannulation of the left superior vena cava in patients undergoing intracardiac repair of tetralogy of Fallot and univentricular type of repairs. The technique consists of dislocation of the heart into the right pleural cavity, thus allowing easy performance of left superior vena cava cannulation and pulmonary arterioplasty.