“…4C). These three different classes of drugs share a common link with the DNA damage response pathway 27–29 , which is associated with insulin resistance and microvascular complications of DM 30 .Figure 4Blood transcriptome of patients with dual TB and DM burden compared to TB or DM alone. ( A ) Differentially expressed genes between patients with distinct clinical phenotypes (class).…”
Comorbid diabetes mellitus (DM) increases tuberculosis (TB) risk and adverse outcomes but the pathological interactions between DM and TB remain incompletely understood. We performed an integrative analysis of whole blood gene expression and plasma analytes, comparing South Indian TB patients with and without DM to diabetic and non-diabetic controls without TB. Luminex assay of plasma cytokines and growth factors delineated a distinct biosignature in comorbid TBDM in this cohort. Transcriptional profiling revealed elements in common with published TB signatures from cohorts that excluded DM. Neutrophil count correlated with the molecular degree of perturbation, especially in TBDM patients. Body mass index and HDL cholesterol were negatively correlated with molecular degree of perturbation. Diabetic complication pathways including several pathways linked to epigenetic reprogramming were activated in TBDM above levels observed with DM alone. Our data provide a rationale for trials of host-directed therapies in TBDM, targeting neutrophilic inflammation and diabetic complication pathways to address the greater morbidity and mortality associated with this increasingly prevalent dual burden of communicable and non-communicable diseases.
“…4C). These three different classes of drugs share a common link with the DNA damage response pathway 27–29 , which is associated with insulin resistance and microvascular complications of DM 30 .Figure 4Blood transcriptome of patients with dual TB and DM burden compared to TB or DM alone. ( A ) Differentially expressed genes between patients with distinct clinical phenotypes (class).…”
Comorbid diabetes mellitus (DM) increases tuberculosis (TB) risk and adverse outcomes but the pathological interactions between DM and TB remain incompletely understood. We performed an integrative analysis of whole blood gene expression and plasma analytes, comparing South Indian TB patients with and without DM to diabetic and non-diabetic controls without TB. Luminex assay of plasma cytokines and growth factors delineated a distinct biosignature in comorbid TBDM in this cohort. Transcriptional profiling revealed elements in common with published TB signatures from cohorts that excluded DM. Neutrophil count correlated with the molecular degree of perturbation, especially in TBDM patients. Body mass index and HDL cholesterol were negatively correlated with molecular degree of perturbation. Diabetic complication pathways including several pathways linked to epigenetic reprogramming were activated in TBDM above levels observed with DM alone. Our data provide a rationale for trials of host-directed therapies in TBDM, targeting neutrophilic inflammation and diabetic complication pathways to address the greater morbidity and mortality associated with this increasingly prevalent dual burden of communicable and non-communicable diseases.
“…While current views substantially modify the original premise (Barja, 2014;Gonzalez-Freire et al, 2015), oxidative damage is clearly linked to inflammation and age-associated disorders (Tatsch et al, 2015). Regardless of the initiating factors, age-associated chronic inflammation, termed inflammaging, contributes to the degeneration of tissues, and is provocative for much of the discomfort and many of the diseases of aging (O'Neill and Hardie, 2013).…”
Fanconi Anemia (FA) is a rare autosomal genetic disorder characterized by progressive bone marrow failure (BMF), endocrine dysfunction, cancer, and other clinical features commonly associated with normal aging. The anemia stems directly from an accelerated decline of the hematopoietic stem cell compartment. Although FA is a complex heterogeneous disease linked to mutations in 19 currently identified genes, there has been much progress in understanding the molecular pathology involved. FA is broadly considered a DNA repair disorder and the FA gene products, together with other DNA repair factors, have been implicated in interstrand cross-link (ICL) repair. However, in addition to the defective DNA damage response, altered epigenetic regulation, and telomere defects, FA is also marked by elevated levels of inflammatory mediators in circulation, a hallmark of faster decline in not only other hereditary aging disorders but also normal aging. In this review, we offer a perspective of FA as a monogenic accelerated aging disorder, citing the latest evidence for its multi-factorial deficiencies underlying its unique clinical and cellular features.
“…OS‐induced damage to DNA also contributes to neurodegeneration, promoting Parkinson's disease, Alzheimer's disease, and sporadic amyotrophic lateral sclerosis . Other health disorders arising from oxidative damage to DNA are cardiovascular diseases, Wilson's disease, Huntington's disease, inflammatory bowel disease, acquired immunodeficiency syndrome, diabetes and its complications, chronic obstructive pulmonary disease, and rheumatoid arthritis …”
Section: Introductionmentioning
confidence: 99%
“…6 OS-induced damage to DNA also contributes to neurodegeneration, promoting Parkinson's disease, [7][8][9] Alzheimer's disease, [10][11][12] and sporadic amyotrophic lateral sclerosis. 13 Other health disorders arising from oxidative damage to DNA are cardiovascular diseases, [14][15][16][17] Wilson's disease, 18,19 Huntington's disease, 20,21 inflammatory bowel disease, 22,23 acquired immunodeficiency syndrome, 24,25 diabetes 26 and its complications, [27][28][29] chronic obstructive pulmonary disease, 30 and rheumatoid arthritis. [31][32][33] The hydroxyl radical (˙OH) has been held responsible for the most common oxidative damage to DNA, 34,35 which involves different chemical routes and yields diverse products (Scheme 1).…”
Oxidative stress mediates chemical damage to DNA yielding a wide variety of products. In this work, the potential capability of melatonin and several of its metabolites to repair directly (chemically) oxidative lesions in DNA was explored. It was found that all the investigated molecules are capable of repairing guanine‐centered radical cations by electron transfer at very high rates, that is, diffusion‐limited. They are also capable of repairing C‐centered radicals in the sugar moiety of 2′‐deoxyguanosine (2dG) by hydrogen atom transfer. Although this was identified as a rather slow process, with rate constants ranging from 1.75 to 5.32 × 102 M−1 s−1, it is expected to be fast enough to prevent propagation of the DNA damage. Melatonin metabolites 6‐hydroxymelatonin (6OHM) and 4‐hydroxymelatonin (4OHM) are also predicted to repair OH adducts in the imidazole ring. In particular, the rate constants corresponding to the repair of 8‐OH‐G adducts were found to be in the order of 104 M−1 s−1 and are assisted by a water molecule. The results presented here strongly suggest that the role of melatonin in preventing DNA damage might be mediated by its capability, combined with that of its metabolites, to directly repair oxidized sites in DNA through different chemical routes.
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