RESUMEN
Background: Glaucoma is the leading cause of permanent blindness. Primary angle closure glaucoma (PACG) is diagnosed only after the onset of symptoms and can result in irreversible blindness despite the standard intraocular pressure (IOP) reduction therapy. The identification of potential biomarkers associated with prognosis will help improve disease management. This study aimed to identify mechanisms associated with disease progression, potential biomarkers, and therapeutic targets of PACG. Methods: The clinical data assessment of IOP, cup/disc ratio (CDR), Retinal Nerve Fiber Layer (RNFL) thickness of control, and PACG group were collected and analyzed for significant differences. The ATP levels were estimated, and targeted metabolomic analysis was performed on aqueous humor and cytokines in plasma. The pathways obtained from the metabolomics data set were compared with those obtained for data sets from the literature. Clinical parameters were correlated with cytokine levels. Targeted metabolomic analysis of cell culture supernatant from TNFα-treated N9 microglia was carried out, and overlap analysis was performed with data obtained from PACG patients. Results: Elevated IOP, CDR, ATP, cytokines, and reduced RNFL thickness were found in PACG compared to controls. Analysis of PACG and TNFα-treated N9 microglial cell culture supernatant shows activation of immuno-metabolites. The metabolic pathways of PACG, TNFα, and ATP-treated microglia from the literature show considerable overlap. Biomarker analysis identified clinical parameters, ATP, cytokines, and immuno-metabolites. Conclusion: This study shows an association between elevated levels of ATP, cytokines, immuno-metabolism, and potential microglial inflammation with disease progression, rendering these levels potential biomarkers. P2 receptors, cytokines, and IDO1/2 could be potential therapeutic targets.
RESUMEN
Avascular necrosis of femoral head (AVNFH) is a debilitating disease of the young, affecting the quality of life significantly and eventually leading to total hip replacement surgery. The disease is diagnosed clinico-radiologically and MRI is the investigation of choice to diagnose the early stages of the disease. There is neither an early biomarker for detection nor is there a permanent cure for the disease and most of the patients are managed with various combinations of surgical and medical management protocols. In this review, we comprehensively address the etiopathogenesis, clinical characteristics, therapeutic procedures, bone characteristics, histopathology, multi-omic studies, finite element modeling, and systems analysis that has been performed in AVNFH. The etiology includes various factors that compromise the blood supply to the femoral head which also includes contributions by environmental and genetic factors. Multi-omic analysis has shown an association of deregulated pathways with the disease. The cell types involved include mesenchymal stem cells, osteoblasts, osteoclasts, endothelial and immune cells. Biochemical, hematological, histopathology, IHC, and other bone remodeling and degradation marker studies have been performed. A systems analysis using multi-omic data sets from published literature was carried out, the relevance of which is discussed to delineate potential mechanisms in etiopathogenesis, diagnosis, and effective management of this debilitating disease.
RESUMEN
Background: The most frequent lesion in the blood vessels feeding the myocardium is vascular stenosis, a condition that develops slowly but can prove to be deadly in a long run. Non-invasive biomarkers could play a significant role in timely diagnosis, detection and management for vascular stenosis events associated with cardiovascular disorders. Aims: The study aimed to investigate high sensitivity troponin I (hs-TnI), cardiac troponin I (c-TnI) and high sensitivity C-reactive protein (hs-CRP) that may be used solely or in combination in detecting the extent of vascular stenosis in CVD patients. Methodology: 274 patients with dyspnea/orthopnea complaints visiting the cardiologists were enrolled in this study. Angiographic study was conducted on the enrolled patients to examine the extent of stenosis in the five prominent vessels (LDA, LCX, PDA/PLV, RCA, and OM) connected to the myocardium. Samples from all the cases suspected to be having coronary artery stenosis were collected, and subjected to biochemical evaluation of certain cardiac inflammatory biomarkers (c-TnI, hsTn-I and hs-CRP) to check their sensitivity with the level of vascular stenosis. The extent of mild and culprit stenosis was detected during angiographic examination and the same was reported in the form significant (≥50% stenosis in the vessels) and non-significant (<50% stenosis in the vessels) Carotid Stenosis. Ethical Clearance for the study was provided by Dr. Ram Manohar Lohia Institute of Medical Sciences Institutional Ethical Committee. Informed consent was obtained from all the participants enrolled in the study. Results: We observed that 85% of the total population enrolled in this study was suffering from hypertension followed by 62.40% detected with sporadic episodes of chest pain. Most of the subjects (42% of the total population) had stenosis in their LAD followed by 38% who had stenosis in their RCA. Almost 23% patients were reported to have stenosis in their LCX followed by OM (18% patients), PDA/PLV (13%) and only 10% patients had blockage problem in their diagonal. 24% of the subjects were found to have stenosis in a single vessel and hence were categorized in the Single Vessel Disease (SVD) group while 76% were having stenosis in two or more than two arteries (Multiple Vessel Disease). hs-TnI level was found to be correlated with the levels of stenosis and was higher in the MVD group as compared to the SVD group. Conclusion: hs-TnI could be used as a novel marker as it shows prominence in detecting the level of stenosis quite earlier as compared to c-TnI which gets detected only after a long duration in the CVD patients admitted for angiography. hs- CRP gets readily detected as inflammation marker in these patients and hence could be used in combination with hs-TnI to detect the risk of developing coronary artery disease.
RESUMEN
Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease leading to inflammation, cartilage cell death, synoviocyte proliferation, and increased and impaired differentiation of osteoclasts and osteoblasts leading to joint erosions and deformities. Transcriptomics, proteomics, and metabolomics datasets were analyzed to identify the critical pathways that drive the RA pathophysiology. Single nucleotide polymorphisms (SNPs) associated with RA were analyzed for the functional implications, clinical outcomes, and blood parameters later validated by literature. SNPs associated with RA were grouped into pathways that drive the immune response and cytokine production. Further gene set enrichment analysis (GSEA) was performed on gene expression omnibus (GEO) data sets of peripheral blood mononuclear cells (PBMCs), synovial macrophages, and synovial biopsies from RA patients showed enrichment of Th1, Th2, Th17 differentiation, viral and bacterial infections, metabolic signalling and immunological pathways with potential implications for RA. The proteomics data analysis presented pathways with genes involved in immunological signaling and metabolic pathways, including vitamin B12 and folate metabolism. Metabolomics datasets analysis showed significant pathways like amino-acyl tRNA biosynthesis, metabolism of amino acids (arginine, alanine aspartate, glutamate, glutamine, phenylalanine, and tryptophan), and nucleotide metabolism. Furthermore, our commonality analysis of multi-omics datasets identified common pathways with potential implications for joint remodeling in RA. Disease-modifying anti-rheumatic drugs (DMARDs) and biologics treatments were found to modulate many of the pathways that were deregulated in RA. Overall, our analysis identified molecular signatures associated with the observed symptoms, joint erosions, potential biomarkers, and therapeutic targets in RA.Communicated by Ramaswamy H. Sarma.
RESUMEN
Glaucoma is the second leading cause of blindness. Exfoliation syndrome (XFN) is a risk factor for exfoliation glaucoma (XFG) which is a secondary open angle glaucoma. XFG is difficult to manage with a worse prognosis. Though 40% of the XFN progress to XFG, there are no predictive markers to identify the susceptible patients. Herein, we analyze clinical data, ATP levels in aqueous humor and cytokines in plasma to identify alteration that help distinguish XFN from XFG. Our results show characteristic clinical features of XFG compared to XFN and controls. Elevated levels of ATP in aqueous humor were observed in XFG compared to XFN and cataract controls while elevated levels of plasma cytokines were observed in XFG compared to XFN, cataract controls and healthy controls. Microglia are immune cells in the retina implicated in glaucoma. TNFα plays a predominant role in microglial inflammation and is implicated in neurodegeneration. Using in vitro N9 microglial cell culture model, we demonstrate that TNFα modulated expression of cytokines and chemotaxis is dependent on P2 receptors like P2X7, P2Y12 and P2Y6. In addition, ATP also induce expression of TNFα which might act as a feed forward loop. The TNFα induced inflammation is dependent on downstream signaling modules like PI3K, JNK and ROS. Taken together, our results show that elevated ATP in aqueous humor, plasma cytokines and inflammation potentially involving microglia distinguish XFG from XFN. Purinergic receptors might be potential therapeutic targets in XFG.