Biology subjects

Arumugam, T. V.

Publications and source records attributed to Arumugam, T. V..

3 recordsLinked to original sources

bioRxiv2021

Multiomics Analyses Reveal Dynamic Bioenergetic Pathways and Functional Remodeling of the Heart During Intermittent Fasting

AimsIntermittent fasting (IF) reduces cardiovascular risk factors in animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction, but the underlying molecular mechanisms are unknown. To delineate molecular and cellular adaptations of the heart to IF, we carried out system-wide comprehensive analyses of proteome and phosphoproteome, complemented with transcriptome profiling, followed by functional analysis. Methods and resultsIn order to understand molecular and cellular remodeling of the heart during IF, we employed advanced mass spectrometry for system-wide profiling of the proteome and phosphoproteome of heart tissues obtained from mice maintained for 6 months on either daily 12- or 16-hour fasting, every-other-day fasting or ad libitum control feeding regimens. We also performed transcriptome analyses using RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. IF regimens significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death, and inflammation. Comparison of differentially expressed proteome and transcriptome upon IF showed the higher correlation of pathway alternation in short IF regimen but the inverse correlation of metabolic processes such as fatty acid oxidation and immune processes in longer IF regimens. In addition, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. ConclusionOur systematic multi-omics study elucidates a molecular framework for understanding how IF impacts the hearts function and its vulnerability to injury and disease. Translational perspectiveIntermittent fasting is emerging as a desirable lifestyle adaptation to impact cardiovascular health through the modulation of molecular and cellular mechanisms, and by acting on disease risk factors. Evidence from numerous studies indicates that the fasting cycles are highly and consistently effective in protecting against cardiovascular diseases and improving cardiac health in animals and human. Using multi-omics, here we dissect distinct molecular adaptations of the heart to different intermittent fasting regimens. Our results unveil novel cardioprotective mechanisms and open up new avenues for innovative pharmacological approaches to prevent and treat cardiovascular diseases.

systems biology↗

bioRxiv2020

Time-dependent modulation of gut microbiome in response to systemic antifungal agents

The effects of antifungal agents on the human microbiome can be challenging to study due to confounding factors such as the underlying disease states and concomitant use of antibiotics and other therapies. We elucidated longitudinal modification of gut microbiome in response to a short course (5 days) of antifungal treatment in healthy male Sprague-Dawley (SD) rats by sequencing 16S rRNA V1-V3 and ITS2 hypervariable regions. SD rats were randomized into a control group and three antifungal treated (AT) groups including Amphotericin B (AmB), voriconazole and, our novel antifungal drug candidate SM21 once per day for 5 consecutive days. Fecal samples were collected at three different time points (day 0, day 1 and day 5). Microbial communities of both bacteria and fungi were compared between conditions. In silico analysis of differential microbial abundance and the predictive functional domains of microbial communities was further done by inferring metabarcoding profiles from 16S data. AT animals exhibited significant change in bacteriome alphadiversity although no divergence in community structure (beta-diversity) was observed compared with respective control groups (day 0). Specific bacterial clades and taxa were longitudinally and significantly modified in the AT animals. The AT bacterium of AmB and SM21 was particularly enriched in probiotic Lactobacillus strains including L. reuteri. The key pathways overrepresented in the bacteriome under AT animals were linked to cellular processes, environment information processing and metabolism. Moreover, AT treated mycobiome diversity decreased longitudinally with insignificant variations along the time course; different fungal taxa dominating at different timepoints in a wave-like fashion. However, acute antifungal treatments could not alter healthy gut microbial community structure. Hence, the healthy gut microbiome is capable of resisting a major dysbiotic shift during a short course of antifungal treatment.

microbiology↗

bioRxiv2020

AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response - particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1{beta} and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioural and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

neuroscience↗