Browse
Submit Data
Databases
API
Help

Dataset Information

7 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting MMP-Regulation of Inflammation to Increase Metabolic Tolerance to COVID-19 Pathologies: A Hypothesis.

ABSTRACT: Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.

SUBMITTER: Hardy E

PROVIDER: S-EPMC7998259 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance.

Project description:Indoleamine 2,3-dioxygenase (IDO) has immunoregulatory roles associated with tryptophan metabolism. These include counter-regulation (controlling inflammation) and acquired tolerance in T cells. Recent findings reveal that IDO can be triggered by innate responses during tumorigenesis, and also by attempted T cell activation, either spontaneous or due to immunotherapy. Here we review the current understanding of mechanisms by which IDO participates in the control of inflammation and in peripheral tolerance. Focusing on the tumor microenvironment, we examine the role of IDO in response to apoptotic cells and the impact of IDO on Treg cell function. We discuss how the counter-regulatory and tolerogenic functions of IDO can be targeted for cancer immunotherapy and present an overview of the current clinical progress in this area.

| S-EPMC4916957 | biostudies-literature

SteatoNet: the first integrated human metabolic model with multi-layered regulation to investigate liver-associated pathologies.

Project description:Current state-of-the-art mathematical models to investigate complex biological processes, in particular liver-associated pathologies, have limited expansiveness, flexibility, representation of integrated regulation and rely on the availability of detailed kinetic data. We generated the SteatoNet, a multi-pathway, multi-tissue model and in silico platform to investigate hepatic metabolism and its associated deregulations. SteatoNet is based on object-oriented modelling, an approach most commonly applied in automotive and process industries, whereby individual objects correspond to functional entities. Objects were compiled to feature two novel hepatic modelling aspects: the interaction of hepatic metabolic pathways with extra-hepatic tissues and the inclusion of transcriptional and post-transcriptional regulation. SteatoNet identification at normalised steady state circumvents the need for constraining kinetic parameters. Validation and identification of flux disturbances that have been proven experimentally in liver patients and animal models highlights the ability of SteatoNet to effectively describe biological behaviour. SteatoNet identifies crucial pathway branches (transport of glucose, lipids and ketone bodies) where changes in flux distribution drive the healthy liver towards hepatic steatosis, the primary stage of non-alcoholic fatty liver disease. Cholesterol metabolism and its transcription regulators are highlighted as novel steatosis factors. SteatoNet thus serves as an intuitive in silico platform to identify systemic changes associated with complex hepatic metabolic disorders.

| S-EPMC4263370 | biostudies-literature

Potential therapies targeting nuclear metabolic regulation in cancer.

Project description:The interplay between genetic alterations and metabolic dysregulation is increasingly recognized as a pivotal axis in cancer pathogenesis. Both elements are mutually reinforcing, thereby expediting the ontogeny and progression of malignant neoplasms. Intriguingly, recent findings have highlighted the translocation of metabolites and metabolic enzymes from the cytoplasm into the nuclear compartment, where they appear to be intimately associated with tumor cell proliferation. Despite these advancements, significant gaps persist in our understanding of their specific roles within the nuclear milieu, their modulatory effects on gene transcription and cellular proliferation, and the intricacies of their coordination with the genomic landscape. In this comprehensive review, we endeavor to elucidate the regulatory landscape of metabolic signaling within the nuclear domain, namely nuclear metabolic signaling involving metabolites and metabolic enzymes. We explore the roles and molecular mechanisms through which metabolic flux and enzymatic activity impact critical nuclear processes, including epigenetic modulation, DNA damage repair, and gene expression regulation. In conclusion, we underscore the paramount significance of nuclear metabolic signaling in cancer biology and enumerate potential therapeutic targets, associated pharmacological interventions, and implications for clinical applications. Importantly, these emergent findings not only augment our conceptual understanding of tumoral metabolism but also herald the potential for innovative therapeutic paradigms targeting the metabolism-genome transcriptional axis.

| S-EPMC10685089 | biostudies-literature

A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer.

Project description:The 5'-AMP-activated protein kinase (AMPK) is a master regulator of cellular homeostasis. Despite AMPK's known function in physiology, its role in pathological processes such as prostate cancer is enigmatic. However, emerging evidence is now beginning to decode the paradoxical role of AMPK in cancer and, therefore, inform clinicians if - and how - AMPK could be therapeutically targeted. Spatiotemporal regulation of AMPK complexes could be one of the mechanisms that governs this kinase's role in cancer. We hypothesize that different upstream stimuli will activate select subcellular AMPK complexes. This hypothesis is supported by the distinct subcellular locations of the various AMPK subunits. Each of these unique AMPK complexes regulates discrete downstream processes that can be tumour suppressive or oncogenic. AMPK's final biological output is then determined by the weighted net function of these downstream signalling events, influenced by additional prostate-specific signalling.

| S-EPMC5672799 | biostudies-literature

Natural products targeting inflammation-related metabolic disorders: A comprehensive review.

Project description:Currently, the incidence of metabolic disorders is increasing, setting a challenge to global health. With major advancement in the diagnostic tools and clinical procedures, much has been known in the etiology of metabolic disorders and their corresponding pathophysiologies. In addition, the use of in vitro and in vivo experimental models prior to clinical studies has promoted numerous biomedical breakthroughs, including in the discovery and development of drug candidates to treat metabolic disorders. Indeed, chemicals isolated from natural products have been extensively studied as prospective drug candidates to manage diabetes, obesity, heart-related diseases, and cancer, partly due to their antioxidant and anti-inflammatory properties. Continuous efforts have been made in parallel to improve their bioactivity and bioavailability using selected drug delivery approaches. Here, we provide insights on recent progress in the role of inflammatory-mediated responses on the initiation of metabolic disorders, with particular reference to diabetes mellitus, obesity, heart-related diseases, and cancer. In addition, we discussed the prospective role of natural products in the management of diabetes, obesity, heart-related diseases, and cancers and provide lists of potential biological targets for high throughput screening in drug discovery and development. Lastly, we discussed findings observed in the preclinical and clinical studies prior to identifying suitable approaches on the phytochemical drug delivery systems that are potential to be used in the treatment of metabolic disorders.

| S-EPMC10279840 | biostudies-literature

Metabolic hypothesis for human altriciality.

Project description:The classic anthropological hypothesis known as the "obstetrical dilemma" is a well-known explanation for human altriciality, a condition that has significant implications for human social and behavioral evolution. The hypothesis holds that antagonistic selection for a large neonatal brain and a narrow, bipedal-adapted birth canal poses a problem for childbirth; the hominin "solution" is to truncate gestation, resulting in an altricial neonate. This explanation for human altriciality based on pelvic constraints persists despite data linking human life history to that of other species. Here, we present evidence that challenges the importance of pelvic morphology and mechanics in the evolution of human gestation and altriciality. Instead, our analyses suggest that limits to maternal metabolism are the primary constraints on human gestation length and fetal growth. Although pelvic remodeling and encephalization during hominin evolution contributed to the present parturitional difficulty, there is little evidence that pelvic constraints have altered the timing of birth.

| S-EPMC3458333 | biostudies-literature

Targeting Alzheimer's Disease Neuro-Metabolic Dysfunction with a Small Molecule Nuclear Receptor Agonist (T3D-959) Reverses Disease Pathologies.

Project description:Alzheimer's disease (AD) could be regarded as a brain form of diabetes since insulin resistance and deficiency develop early and progress with severity of neurodegeneration. Preserving insulin's actions in the brain restores function and reduces neurodegeneration. T3D-959 is a dual nuclear receptor agonist currently in a Phase 2a trial in mild-to-moderate AD patients (ClinicalTrials.gov identifier NCT02560753). Herein, we show that T3D-959 improves motor function and reverses neurodegeneration in a sporadic model of AD. Long Evans rats were administered intracerebral (i.c.) streptozotocin (STZ) or normal saline (control) and dosed orally with T3D-959 (1.0 mg/kg/day) or saline for 21 or 28 days. Rotarod tests evaluated motor function. Histopathology with image analysis was used to assess neurodegeneration. T3D-959 significantly improved motor performance, and preserved both cortical and normalized white matter structure in i.c STZ-treated rats. T3D-959 treatments were effective when dosed therapeutically, whether initiated 1 day or 7 days after i.c. STZ. T3D-959's targeting neuro-metabolic dysfunctions via agonism of PPAR delta and PPAR gamma nuclear receptors provides potential disease modification in AD.

| S-EPMC4979550 | biostudies-literature

Harnessing Metabolic Regulation to Increase Hfq-Dependent Antibiotic Susceptibility in Pseudomonas aeruginosa.

Project description:The opportunistic human pathogen Pseudomonas aeruginosa is responsible for ~ 10% of hospital-acquired infections worldwide. It is notorious for its high level resistance toward many antibiotics, and the number of multi-drug resistant clinical isolates is steadily increasing. A better understanding of the molecular mechanisms underlying drug resistance is crucial for the development of novel antimicrobials and alternative strategies such as enhanced sensitization of bacteria to antibiotics in use. In P. aeruginosa several uptake channels for amino-acids and carbon sources can serve simultaneously as entry ports for antibiotics. The respective genes are often controlled by carbon catabolite repression (CCR). We have recently shown that Hfq in concert with Crc acts as a translational repressor during CCR. This function is counteracted by the regulatory RNA CrcZ, which functions as a decoy to abrogate Hfq-mediated translational repression of catabolic genes. Here, we report an increased susceptibility of P. aeruginosa hfq deletion strains to different classes of antibiotics. Transcriptome analyses indicated that Hfq impacts on different mechanisms known to be involved in antibiotic susceptibility, viz import and efflux, energy metabolism, cell wall and LPS composition as well as on the c-di-GMP levels. Furthermore, we show that sequestration of Hfq by CrcZ, which was over-produced or induced by non-preferred carbon-sources, enhances the sensitivity toward antibiotics. Thus, controlled synthesis of CrcZ could provide a means to (re)sensitize P. aeruginosa to different classes of antibiotics.

| S-EPMC6237836 | biostudies-literature

Sex-Specific Regulation of Inflammation and Metabolic Syndrome in Obesity.

Project description:OBJECTIVE:Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this study, we assessed the sex-specific relation between inflammation and metabolic dysregulation in obesity. Approach and Results: Three hundred two individuals were included, half with a BMI 27 to 30 kg/m2 and half with a BMI>30 kg/m2, 45% were women. The presence of metabolic syndrome was assessed according to the National Cholesterol Education Program-ATPIII criteria, and inflammation was studied using circulating markers of inflammation, cell counts, and ex vivo cytokine production capacity of isolated immune cells. Additionally, lipidomic and metabolomic data were gathered, and subcutaneous fat biopsies were histologically assessed. Metabolic syndrome is associated with an increased inflammatory profile that profoundly differs between women and men: women with metabolic syndrome show a lower concentration of the anti-inflammatory adiponectin, whereas men show increased levels of several pro-inflammatory markers such as IL (interleukin)-6 and leptin. Adipose tissue inflammation showed similar sex-specific associations with these markers. Peripheral blood mononuclear cells isolated from men, but not women, with metabolic syndrome display enhanced cytokine production capacity. CONCLUSIONS:We identified sex-specific pathways that influence inflammation in obesity. Excessive production of proinflammatory cytokines was observed in men with metabolic syndrome. In contrast, women typically showed reduced levels of the anti-inflammatory adipokine adiponectin. These different mechanisms of inflammatory dysregulation between women and men with obesity argue for sex-specific therapeutic strategies.

| S-EPMC7310302 | biostudies-literature

Targeting tumor phenotypic plasticity and metabolic remodeling in adaptive cross-drug tolerance.

Project description:Metastable phenotypic state transitions in cancer cells can lead to the development of transient adaptive resistance or tolerance to chemotherapy. Here, we report that the acquisition of a phenotype marked by increased abundance of CD44 (CD44Hi) by breast cancer cells as a tolerance response to routinely used cytotoxic drugs, such as taxanes, activated a metabolic switch that conferred tolerance against unrelated standard-of-care chemotherapeutic agents, such as anthracyclines. We characterized the sequence of molecular events that connected the induced CD44Hi phenotype to increased activity of both the glycolytic and oxidative pathways and glucose flux through the pentose phosphate pathway (PPP). When given in a specific order, a combination of taxanes, anthracyclines, and inhibitors of glucose-6-phosphate dehydrogenase (G6PD), an enzyme involved in glucose metabolism, improved survival in mouse models of breast cancer. The same sequence of the three-drug combination reduced the viability of patient breast tumor samples in an explant system. Our findings highlight a convergence between phenotypic and metabolic state transitions that confers a survival advantage to cancer cells against clinically used drug combinations. Pharmacologically targeting this convergence could overcome cross-drug tolerance and could emerge as a new paradigm in the treatment of cancer.

| S-EPMC7261372 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data