Adenosine deaminase modulates metabolic remodeling and orchestrates joint destruction in rheumatoid arthritis.

Rheumatoid Arthritis (RA) is a chronic autoimmune disease associated with inflammation and joint remodeling. Adenosine deaminase (ADA), a risk factor in RA, degrades adenosine, an anti-inflammatory molecule, resulting in an inflammatory bias. We present an integrative analysis of clinical data, cytokines, serum metabolomics in RA patients and mechanistic studies on ADA-mediated effects on in vitro cell culture models. ADA activity differentiated patients into low and high ADA sets. The levels of the cytokines TNFα, IFNγ, IL-10, TGFß and sRANKL were elevated in RA and more pronounced in high ADA sets. Serum metabolomic analysis shows altered metabolic pathways in RA which were distinct between low and high ADA sets. Comparative analysis with previous studies shows similar pathways are modulated by DMARDs and biologics. Random forest analysis distinguished RA from control by methyl-histidine and hydroxyisocaproic acid, while hexose-phosphate and fructose-6-phosphate distinguished high ADA from low ADA. The deregulated metabolic pathways of High ADA datasets significantly overlapped with high ADA expressing PBMCs GEO transcriptomics dataset. ADA induced the death of chondrocytes, synoviocyte proliferation, both inflammation in macrophages and their differentiation into osteoclasts and impaired differentiation of mesenchymal stem cells to osteoblasts and mineralization. PBMCs expressing elevated ADA had increased expression of cytokines and P2 receptors compared to synovial macrophages which has low expression of ADA. Our data demonstrates increased cytokine levels and distinct metabolic signatures of RA based on the ADA activity, suggests an important role for ADA in the pathophysiology of RA joints and as a potential marker and therapeutic target in RA patients.

Trace Element Studies on Tinospora cordifolia (Menispermaceae), Ocimum sanctum (Lamiaceae), Moringa oleifera (Moringaceae), and Phyllanthus niruri (Euphorbiaceae) Using PIXE.

Traditionally, Tinospora cordifolia (Willd.) Hook. F. & Thomson (Menispermaceae), Ocimum sanctum L. (Lamiaceae), Moringa oleifera Lam. (Moringaceae), and Phyllanthus niruri L. (Euphorbiaceae) are some of the commonly used medicinal plants in India for curing ailments ranging from common cold, skin diseases, and dental infections to major disorders like diabetes, hypertension, jaundice, rheumatism, etc. To understand and correlate their medicinal use, trace element studies on the aqueous extract of these medicinal plants have been carried out using particle-induced X-ray emission technique. A 2-MeV proton beam was used to identify and characterize major and minor elements namely Cl, K, Ca, Ti, Cr, Mn, Fe, Co, Ni, Cu, Zn, Br, and Sr in them. Results have revealed that these elements are present in varying concentrations in the selected plants. Notable results include very high concentrations of Cl, K, and Ca in all the leaf samples, appreciable levels of Mn in all plants, high Zn content in T. cordifolia, and the aqueous extract of Moringa leaves compared to others and relative higher concentrations of Cr in all the plants.