scholarly journals Effect of Metformin on Cardiac Metabolism and Longevity in Aged Female Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Xudong Zhu ◽  
Weiyan Shen ◽  
Zhu Liu ◽  
Shihao Sheng ◽  
Wei Xiong ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Matrix Composition ◽  
Metformin Treatment ◽  
Related Gene ◽  
Atp Production ◽  
Female Mice ◽  
Multiple Organs ◽  
Inflammatory Status

The antidiabetic drug metformin exerts pleiotropic effects on multiple organs, including the cardiovascular system. Evidence has shown that metformin improves healthspan and lifespan in male mice, yet its lifespan lengthening effect in females remains elusive. We herein demonstrated that metformin fails to extend the lifespan in female mice. Compared to 2-month-old young controls, 20-month-old female mice showed a spectrum of degenerative cardiac phenotypes alongside significant alterations in the extracellular matrix composition. Despite lowered reactive oxygen species production, long-term metformin treatment did not improve cardiac function in the aged female mice. In contrast, RNA sequencing analyses demonstrated that metformin treatment elevated the extracellular matrix-related gene while lowering oxidative phosphorylation-related gene expression in the heart. In addition, metformin treatment induced metabolic reprogramming that suppressed mitochondrial respiration but activated glycolysis (i.e., Warburg effect) in cultured primary cardiomyocytes and macrophages, thereby sustaining an inflammatory status and lowering ATP production. These findings suggest the unexpected detrimental effects of metformin on the regulation of cardiac homeostasis and longevity in female mice, reinforcing the significance of comprehensive testing prior to the translation of metformin-based novel therapies.

scholarly journals Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jennifer K. Dowling ◽  
Remsha Afzal ◽  
Linden J. Gearing ◽  
Mariana P. Cervantes-Silva ◽  
Stephanie Annett ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Mitochondrial Dynamics ◽  
Interleukin 10 ◽  
Metabolic Reprogramming ◽  
In Vivo Model ◽  
Macrophage Polarisation ◽  
Inflammatory Status ◽  
Inflammatory Macrophages

AbstractMitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

scholarly journals DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 926
Author(s):  
Veronica Vella ◽  
Marika Giuliano ◽  
Maria Luisa Nicolosi ◽  
Maria Giovanna Majorana ◽  
Małgorzata Anna Marć ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Cells ◽  
Cell Metabolism ◽  
Growth Factor Receptor ◽  
Metabolic Reprogramming ◽  
Atp Production ◽  
Igf System ◽  
Putative Target ◽  
Collagen Receptor ◽  
Discoidin Domain Receptor 1

The insulin receptor isoform A (IR-A), a dual receptor for insulin and IGF2, plays a role in breast cancer (BC) progression and metabolic reprogramming. Notably, discoidin domain receptor 1 (DDR1), a collagen receptor often dysregulated in cancer, is involved in a functional crosstalk and feed forward loop with both the IR-A and the insulin like growth factor receptor 1 (IGF1R). Here, we aimed at investigating whether DDR1 might affect BC cell metabolism by modulating the IGF1R and/or the IR. To this aim, we generated MCF7 BC cells engineered to stably overexpress either IGF2 (MCF7/IGF2) or the IR-A (MCF7/IR-A). In both cell models, we observed that DDR1 silencing induced a significant decrease of total ATP production, particularly affecting the rate of mitochondrial ATP production. We also observed the downregulation of key molecules implicated in both glycolysis and oxidative phosphorylation. These metabolic changes were not modulated by DDR1 binding to collagen and occurred in part in the absence of IR/IGF1R phosphorylation. DDR1 silencing was ineffective in MCF7 knocked out for DDR1. Taken together, these results indicate that DDR1, acting in part independently of IR / IGF1R stimulation, might work as a novel regulator of BC metabolism and should be considered as putative target for therapy in BC.

scholarly journals Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms Using Computational Systems Biology Approaches

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 35
Author(s):  
Sahar Aghakhani ◽  
Naouel Zerrouk ◽  
Anna Niarakis
Keyword(s):  
Rheumatoid Arthritis ◽  
Extracellular Matrix ◽  
Systems Biology ◽  
Healing Process ◽  
Metabolic Reprogramming ◽  
Critical Event ◽  
Wound Healing Process ◽  
Computational Systems Biology ◽  
Structural Framework ◽  
Computational Systems

Fibroblasts, the most abundant cells in the connective tissue, are key modulators of the extracellular matrix (ECM) composition. These spindle-shaped cells are capable of synthesizing various extracellular matrix proteins and collagen. They also provide the structural framework (stroma) for tissues and play a pivotal role in the wound healing process. While they are maintainers of the ECM turnover and regulate several physiological processes, they can also undergo transformations responding to certain stimuli and display aggressive phenotypes that contribute to disease pathophysiology. In this review, we focus on the metabolic pathways of glucose and highlight metabolic reprogramming as a critical event that contributes to the transition of fibroblasts from quiescent to activated and aggressive cells. We also cover the emerging evidence that allows us to draw parallels between fibroblasts in autoimmune disorders and more specifically in rheumatoid arthritis and cancer. We link the metabolic changes of fibroblasts to the toxic environment created by the disease condition and discuss how targeting of metabolic reprogramming could be employed in the treatment of such diseases. Lastly, we discuss Systems Biology approaches, and more specifically, computational modeling, as a means to elucidate pathogenetic mechanisms and accelerate the identification of novel therapeutic targets.

SARS-Coronavirus 2, A Metabolic Reprogrammer: A Review in the Context of the Possible Therapeutic Strategies

2021 ◽  
Vol 22 ◽  
Author(s):  
Poornima Gopi ◽  
TR Anju ◽  
Vinod Soman Pillai ◽  
Mohanan Veettil
Keyword(s):  
Virus Infection ◽  
Host Cell ◽  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Membrane Lipid ◽  
Therapeutic Strategies ◽  
Metabolic Reprogramming ◽  
Multiple Organs ◽  
The Cross ◽  
The Impact

: Novel coronavirus, SARS-CoV-2 is advancing at a staggering pace to devastate the health care system and foster the concerns over public health. In contrast to the past outbreaks, coronaviruses aren’t clinging themselves as a strict respiratory virus. Rather, becoming a multifaceted virus, it affects multiple organs by interrupting a number of metabolic pathways leading to significant rates of morbidity and mortality. Following infection they rigorously reprogram multiple metabolic pathways of glucose, lipid, protein, nucleic acid and their metabolites to extract adequate energy and carbon skeletons required for their existence and further molecular constructions inside a host cell. Although the mechanism of these alterations are yet to be known, the impact of these reprogramming is reflected in the hyper inflammatory responses, so called cytokine storm and the hindrance of host immune defence system. The metabolic reprogramming during SARS-CoV-2 infection needs to be considered while devising therapeutic strategies to combat the disease and its further complication. The inhibitors of cholesterol and phospholipids synthesis and cell membrane lipid raft of the host cell can, to a great extent, control the viral load and further infection. Depletion of energy source by inhibiting the activation of glycolytic and hexoseamine biosynthetic pathway can also augment the antiviral therapy. The cross talk between these pathways also necessitates the inhibition of amino acid catabolism and tryptophan metabolism. A combinatorial strategy which can address the cross talks between the metabolic pathways might be more effective than a single approach and the infection stage and timing of therapy will also influence the effectiveness of the antiviral approach. We herein focus on the different metabolic alterations during the course of virus infection that help to exploit the cellular machinery and devise a therapeutic strategy which promotes resistance to viral infection and can augment body’s antivirulence mechanisms. This review may cast the light into the possibilities of targeting altered metabolic pathways to defend virus infection in a new perspective.

scholarly journals Multiscale molecular profiling of pathological bone resolves sexually dimorphic control of extracellular matrix composition

2021 ◽  
Vol 14 (3) ◽  
pp. dmm048116 ◽  
Author(s):  
Aikta Sharma ◽  
Alice Goring ◽  
Peter B. Johnson ◽  
Roger J. H. Emery ◽  
Eric Hesse ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Ex Vivo ◽  
Second Harmonic ◽  
Collagen Fibre ◽  
Matrix Composition ◽  
Label Free ◽  
Fibre Number ◽  
Backscattered Electron ◽  
Matrix Mineralisation

ABSTRACTCollagen assembly during development is essential for successful matrix mineralisation, which determines bone quality and mechanocompetence. However, the biochemical and structural perturbations that drive pathological skeletal collagen configuration remain unclear. Deletion of vascular endothelial growth factor (VEGF; also known as VEGFA) in bone-forming osteoblasts (OBs) induces sex-specific alterations in extracellular matrix (ECM) conformation and mineralisation coupled to vascular changes, which are augmented in males. Whether this phenotypic dimorphism arises as a result of the divergent control of ECM composition and its subsequent arrangement is unknown and is the focus of this study. Herein, we used murine osteocalcin-specific Vegf knockout (OcnVEGFKO) and performed ex vivo multiscale analysis at the tibiofibular junction of both sexes. Label-free and non-destructive polarisation-resolved second-harmonic generation (p-SHG) microscopy revealed a reduction in collagen fibre number in males following the loss of VEGF, complemented by observable defects in matrix organisation by backscattered electron scanning electron microscopy. This was accompanied by localised divergence in collagen orientation, determined by p-SHG anisotropy measurements, as a result of OcnVEGFKO. Raman spectroscopy confirmed that the effect on collagen was linked to molecular dimorphic VEGF effects on collagen-specific proline and hydroxyproline, and collagen intra-strand stability, in addition to matrix carbonation and mineralisation. Vegf deletion in male and female murine OB cultures in vitro further highlighted divergence in genes regulating local ECM structure, including Adamts2, Spp1, Mmp9 and Lama1. Our results demonstrate the utility of macromolecular imaging and spectroscopic modalities for the detection of collagen arrangement and ECM composition in pathological bone. Linking the sex-specific genetic regulators to matrix signatures could be important for treatment of dimorphic bone disorders that clinically manifest in pathological nano- and macro-level disorganisation.This article has an associated First Person interview with the first author of the paper.

scholarly journals Plasmid-encoded H-NS controls extracellular matrix composition in a modern Acinetobacter baumannii urinary isolate

2021 ◽  
Author(s):  
Saida Benomar ◽  
Gisela Di Venanzio ◽  
Mario F. Feldman
Keyword(s):  
Extracellular Matrix ◽  
Antibiotic Resistance ◽  
Acinetobacter Baumannii ◽  
Gene Cluster ◽  
Biofilm Formation ◽  
Therapeutic Potential ◽  
Matrix Composition ◽  
Type Vi Secretion System ◽  
Gram Negative ◽  
Conjugative Plasmids

Acinetobacter baumannii is emerging as a multidrug-resistant (MDR) nosocomial pathogen of increasing threat to human health worldwide. The recent MDR urinary isolate UPAB1 carries the plasmid pAB5, a member of a family of large conjugative plasmids (LCP). LCP encode several antibiotic resistance genes and repress the type VI secretion system (T6SS) to enable their dissemination, employing two TetR transcriptional regulators. Furthermore, pAB5 controls the expression of additional chromosomally encoded genes, impacting UPAB1 virulence. Here we show that a pAB5-encoded H-NS transcriptional regulator represses the synthesis of the exopolysaccharide PNAG and the expression of a previously uncharacterized three-gene cluster that encodes a protein belonging to the CsgG/HfaB family. Members of this protein family are involved in amyloid or polysaccharide formation in other species. Deletion of the CsgG homolog abrogated PNAG production and CUP pili formation, resulting in a subsequent reduction in biofilm formation. Although this gene cluster is widely distributed in Gram-negative bacteria, it remains largely uninvestigated. Our results illustrate the complex cross-talks that take place between plasmids and the chromosomes of their bacterial host, which in this case can contribute to the pathogenesis of Acinetobacter . IMPORTANCE The opportunistic human pathogen Acinetobacter baumannii displays the highest reported rates of multidrug resistance among Gram-negative pathogens. Many A. baumannii strains carry large conjugative plasmids like pAB5. In recent years, we have witnessed an increase in knowledge about the regulatory cross-talks between plasmids and bacterial chromosomes. Here we show that pAB5 controls the composition of the bacterial extracellular matrix, resulting in a drastic reduction in biofilm formation. The association between biofilm formation, virulence, and antibiotic resistance is well-documented. Therefore, understanding the factors involved in the regulation of biofilm formation in Acinetobacter has remarkable therapeutic potential.

scholarly journals CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases

Circulation ◽  
2021 ◽  
Author(s):  
Nikolaus Berndt ◽  
Johannes Eckstein ◽  
Iwona Wallach ◽  
Sarah Nordmeyer ◽  
Marcus Kelm ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Energy Demand ◽  
Heart Diseases ◽  
Cardiac Metabolism ◽  
Production Reserve ◽  
Energy Status ◽  
Tissue Samples ◽  
Atp Production ◽  
Mechanic Energy

Background: Many heart diseases can develop a reduced pumping capacity of the heart muscle. A mismatch between ATP demand and ATP production of cardiomyocytes is one of the possible causes. Assessment of the relation between the myocardial ATP production (MV ATP ) and cardiac workload is important for better understanding disease development and choice of nutritional or pharmacological treatment strategies. As there is currently no method for the measurement of MV ATP in vivo , the use of physiology-based metabolic models in conjunction with protein abundance data is an attractive approach. Methods: We developed a comprehensive kinetic model of the cardiac energy metabolism (CARDIOKIN1), which recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts and in vivo studies with humans. We used the model to assess the energy status of the left ventricle (LV) of healthy subjects and patients with aortic stenosis (AS) and mitral valve insufficiency (MI). Maximal enzyme activities were individually scaled by means of protein abundances in LV tissue samples. The energy status of the LV was quantified by the ATP consumption at rest (MV ATP (rest)), at maximal workload (MV ATP (max)), and by the myocardial ATP production reserve (MAPR) representing the span between MV ATP (rest) and MV ATP (max). Results: Compared with controls, in both groups of patients, MV ATP (rest) was increased and MV ATP (max) was decreased resulting in a decreased MAPR, although all patients had preserved ejection fraction. Notably, the variance of the energetic status was high ranging from decreased to normal values. In both patient groups, the energetic status was tightly associated with mechanic energy demand. Moreover, a decrease of MV ATP (max) was associated with a decrease of the cardiac output indicating that cardiac functionality and energetic performance of the ventricle are closely coupled. Conclusions: Our analysis suggests that the ATP producing capacity of the LV of patients with valvular dysfunction is generally diminished and correlates positively with mechanic energy demand and cardiac output. However, large differences exist in the energetic state of the myocardium even in patients with similar clinical or image-based markers of hypertrophy and pump function.

Influence of tumorangiogenesis on extracellular matrix composition in malignant gliomas

1997 ◽  
Vol 99 ◽  
pp. S28
Author(s):  
Christel Herold-Mende ◽  
Daniela Riede ◽  
Margareta M. Mueller ◽  
Annette Buttler ◽  
Hans-Herbert Steiner ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Malignant Gliomas ◽  
Matrix Composition
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