Browsing by Author "Rawat, Atul"

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    1H NMR-Based Metabolic Signatures in the Liver and Brain in a Rat Model of Hepatic Encephalopathy
    (ACS, 2020) Pathania, Anjana; Rawat, Atul; Dahiya, Sitender Singh; Dhanda, Saurabh; Barnwal, Ravi Pratap; Baishya, Bikash; Sandhir, Rajat; Surgery, School of Medicine
    Hepatic encephalopathy (HE) is a debilitating neuropsychiatric complication associated with acute and chronic liver failure. It is characterized by diverse symptoms with variable severity that includes cognitive and motor deficits. The aim of the study is to assess metabolic alterations in the brain and liver using nuclear magnetic resonance (NMR) spectroscopy and subsequent multivariate analyses to characterize metabolic signatures associated with HE. HE was developed by bile duct ligation (BDL) that resulted in hepatic dysfunctions and cirrhosis as shown by liver function tests. Metabolic profiles from control and BDL rats indicated increased levels of lactate, branched-chain amino acids (BCAAs), glutamate, and choline in the liver, whereas levels of glucose, phenylalanine, and pyridoxine were decreased. In brain, the levels of lactate, acetate, succinate, citrate, and malate were increased, while glucose, creatine, isoleucine, leucine, and proline levels were decreased. Furthermore, neurotransmitters such as glutamate and GABA were increased, whereas choline and myo-inositol were decreased. The alterations in neurotransmitter levels resulted in cognitive and motor defects in BDL rats. A significant correlation was found among alterations in NAA/choline, choline/creatine, and NAA/creatine with behavioral deficits. Thus, the data suggests impairment in metabolic pathways such as the tricarboxylic acid (TCA) cycle, glycolysis, and ketogenesis in the liver and brain of animals with HE. The study highlights that metabolic signatures could be potential markers to monitor HE progression and to assess therapeutic interventions.
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    A Modified Collagen Dressing Induces Transition of Inflammatory to Reparative Phenotype of Wound Macrophages
    (Nature Research, 2019-10-04) Das, Amitava; Abas, Motaz; Biswas, Nirupam; Banerjee, Pradipta; Ghosh, Nandini; Rawat, Atul; Khanna, Savita; Roy, Sashwati; Sen, Chandan K.; Surgery, School of Medicine
    Collagen containing wound-care dressings are extensively used. However, the mechanism of action of these dressings remain unclear. Earlier studies utilizing a modified collagen gel (MCG) dressing demonstrated improved vascularization of ischemic wounds and better healing outcomes. Wound macrophages are pivotal in facilitating wound angiogenesis and timely healing. The current study was designed to investigate the effect of MCG on wound macrophage phenotype and function. MCG augmented recruitment of macrophage at the wound-site, attenuated pro-inflammatory and promoted anti-inflammatory macrophage polarization. Additionally, MCG increased anti-inflammatory IL-10, IL-4 and pro-angiogenic VEGF production, indicating a direct role of MCG in resolving wound inflammation and improving angiogenesis. At the wound-site, impairment in clearance of apoptotic cell bioburden enables chronic inflammation. Engulfment of apoptotic cells by macrophages (efferocytosis) resolves inflammation via a miR-21-PDCD4-IL-10 pathway. MCG-treated wound macrophages exhibited a significantly bolstered efferocytosis index. Such favorable outcome significantly induced miR-21 expression. MCG-mediated IL-10 production was dampened under conditions of miR-21 knockdown pointing towards miR-21 as a causative factor. Pharmacological inhibition of JNK attenuated IL-10 production by MCG, implicating miR-21-JNK pathway in MCG-mediated IL-10 production by macrophages. This work provides direct evidence demonstrating that a collagen-based wound-care dressing may influence wound macrophage function and therefore modify wound inflammation outcomes.
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    Oncostatin M Improves Cutaneous Wound Re-Epithelialization and Is Deficient under Diabetic Conditions
    (Elsevier, 2022) Das, Amitava; Madeshiya, Amit K.; Biswas, Nirupam; Ghosh, Nandini; Gorain, Mahadeo; Rawat, Atul; Mahajan, Sanskruti P.; Khanna, Savita; Sen, Chandan K.; Roy, Sashwati; Surgery, School of Medicine
    Impaired re-epithelialization characterized by hyperkeratotic non-migratory wound epithelium is a hallmark of non-healing diabetic wounds. In chronic wounds, copious release of oncostatin M (OSM) from wound macrophages is evident. OSM is a potent keratinocyte activator. This work sought to understand the signal transduction pathway responsible for wound-re-epithelialization, the primary mechanism underlying wound closure. Daily topical treatment of full-thickness excisional wounds of C57bl/6 mice with recombinant murine OSM improved wound re-epithelialization and accelerated wound closure by bolstering keratinocyte proliferation and migration. OSM activated the JAK-STAT pathway as manifested by STAT3 phosphorylation. Such signal transduction in the human keratinocyte induced TP63, the master regulator of keratinocyte function. Elevated TP63 induced integrin beta 1, a known effector of keratinocyte migration. In diabetic wounds, OSM was more abundant compared to the level in non-diabetic wounds. However, in diabetic wounds OSM activity was compromised by glycation. Aminoguanidine, a deglycation agent, rescued compromised keratinocyte migration caused by glycated OSM. Finally, topical application of recombinant OSM improved keratinocyte migration and accelerated wound closure in db/db mice. This work recognizes that despite its abundance at the wound-site, OSM is inactivated by glycation and topical delivery of exogenous OSM is likely to be productive in accelerating diabetic wound closure.