Avascular necrosis of the femur head (AVNFH) is a disease of the bone leading to collapse of femoral head necessitating total hip replacement. Our analysis has shown a clear association of homocysteine with the disease as demonstrated by its correlation with histopathology and biophysical parameters as well as IHC. AVNFH bone showed iron accumulation and iron inhibited stem cell differentiation to osteoblasts as well as mineralization (bone formation) by stem cell differentiated osteoblasts. Our work could eventually pave the way for developing homocysteine reduction therapy and localized iron chelation therapy to manage the disease. We observed similar deregulation of iron metabolism in Perthes disease, a rare condition occurring at childhood. It is essentially version of AVNFH.
Rheumatoid arthritis (RA) is a disease of the joints which leads to death of cartilage, promotes proliferation of synoviocytes and differentiation of macrophages to osteoclasts. Our experiments showed inflammation and metabolic changes in patient’s cohort. High levels of ADA enzyme caused death of cartilage, proliferation of synoviocytes and differentiation of macrophages to osteoclasts (bone degrading cells) in vitro. Based on these findings we propose ADA induced joint remodeling in RA might be bringing about inflammation and metabolic remodeling.
Huntington’s disease and ALS are two important neurodegenerative diseases associated with amyloidogenesis (formation of protein aggregates). Clinical data as well as metabolomic analysis showed metabolic deregulation that could be correlated with structural changes (Atrophy) in affected regions of the brain. Metabolic addition experiments revealed that various metabolites modulate protein aggregation; and restoration of normal metabolism influences clearance of aggregates. Taken together, our results demonstrate that these metabolites could be potential modifiers of the disease; and a diet-based approach may be employed to manage the disease. We have also screened medicinal plants used in traditional Ayurveda, Tibetan and Chinese medicine for treating neurodegenerative diseases in terms of their ability to clear amyloid aggregates successfully.
Multiple sclerosis (MS) is a demyelinating neurodegenerative disease, where the myelin coating on neuronal axons is degraded. TNFa, an inflammatory cytokine is elevated in MS patients. Anti-TNFa -antibody treatment is a standard line of treatment for the disease, which incidentally is very expensive. We have shown that TNFa induced inflammation is dependent on certain receptors (P2X7, P2Y12 and P2Y6). Curprisone mice model of MS treated with Clopidogrel (a widely used blood thinner) which is a P2Y12 inhibitor showed metabolic profile similar to controls and reduced demyelination. Clopidogrel could emerge as a potential therapeutic agent in MS.
Glaucoma is the second leading cause of blindness after cataract. POAG affects 70% of the glaucoma affected population. Exfoliation syndrome (XFN) is a risk factor for exfoliation glaucoma (XFG) a secondary form of glaucoma. Altough 50% of XFN develops into XFG, there are no predictive biomarkers. Elevated Intra Ocular Pressure (IOP) and ATP are associated with glaucoma. Targeted metabolomic analysis showed 58 metabolites were significantly different on comparison between XFN and XFG. Some of the metabolites includes those from tryptophan-kynurenine pathway. Microglia which are immune cells of brain when treated with ATP staged an inflammatory response and expressed genes in the tryptophan-kynurenine pathway as well as in metabolic remodeling involving metabolites from the tryptophan-kynurenine pathway.
Over all, the results point in the direction of ATP mediated microglial inflammatory response and metabolic remodeling involving kynurenine pathway in the development and progression of glaucoma. These metabolites might emerge as potential biomarkers to predict disease progression as well as candidates therapeutic targeting. POAG targeted metabolomic analysis showed changes in about 25 metabolites. Dimethyl arginine (DMAG) an inhibitor of nitric oxide synthase (NOS) was found to be elevated in aqueous humor. N9 microglial cells treated with DMAG showed elevated levels of extracellular ATP, upregulating expression of many P2 receptors and expression of genes in kynurenine pathway. It appears that NOS inhibition might be critical for bringing about increased IOP, extracellular ATP, inflammation and progression of POAG. Metabolomic analysis of PACG was carried out and ELISA results showed elevated levels of TNFa, IFNg and TGFb. The key outcome was providing plausible explanations to the role of TNFa in microglial inflammation and mechanism involved in manifestation of inflammation leading to retinal ganglion cell death.