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Cellular and Molecular Life Sciences :... Jul 2023The precise characterization of oxygen-sensing pathways and the identification of pO-regulated gene expression are both issues of critical importance. The O-sensing... (Review)
Review
The precise characterization of oxygen-sensing pathways and the identification of pO-regulated gene expression are both issues of critical importance. The O-sensing system plays crucial roles in almost all the pivotal human processes, including the stem cell specification, the growth and development of tissues (such as embryogenesis), the modulation of intermediate metabolism (including the shift of the glucose metabolism from oxidative to anaerobic ATP production and vice versa), and the control of blood pressure. The solid cancer microenvironment is characterized by low oxygen levels and by the consequent activation of the hypoxia response that, in turn, allows a complex adaptive response characterized mainly by neoangiogenesis and metabolic reprogramming. Recently, incredible advances in molecular genetic methodologies allowed the genome editing with high efficiency and, above all, the precise identification of target cells/tissues. These new possibilities and the knowledge of the mechanisms of adaptation to hypoxia suggest the effective development of new therapeutic approaches based on the manipulation, targeting, and exploitation of the oxygen-sensor system molecular mechanisms.
Topics: Humans; Gene Editing; Hypoxia; Oxygen; Cell Hypoxia; Neoplasms; Hypoxia-Inducible Factor 1, alpha Subunit; Von Hippel-Lindau Tumor Suppressor Protein; Tumor Microenvironment
PubMed: 37477829
DOI: 10.1007/s00018-023-04852-2 -
Frontiers in Immunology 2023Cellular metabolism plays a central role in the regulation of both innate and adaptive immunity. Immune cells utilize metabolic pathways to modulate the cellular... (Review)
Review
Cellular metabolism plays a central role in the regulation of both innate and adaptive immunity. Immune cells utilize metabolic pathways to modulate the cellular differentiation or death. The intricate interplay between metabolism and immune response is critical for maintaining homeostasis and effective antiviral activities. In recent years, immunometabolism induced by viral infections has been extensively investigated, and accumulating evidence has indicated that cellular metabolism can be hijacked to facilitate viral replication. Generally, virus-induced changes in cellular metabolism lead to the reprogramming of metabolites and metabolic enzymes in different pathways (glucose, lipid, and amino acid metabolism). Metabolic reprogramming affects the function of immune cells, regulates the expression of immune molecules and determines cell fate. Therefore, it is important to explore the effector molecules with immunomodulatory properties, including metabolites, metabolic enzymes, and other immunometabolism-related molecules as the antivirals. This review summarizes the relevant advances in the field of metabolic reprogramming induced by viral infections, providing novel insights for the development of antivirals.
Topics: Humans; Antiviral Agents; Viruses; Metabolic Networks and Pathways; Immunity; Virus Diseases
PubMed: 37559723
DOI: 10.3389/fimmu.2023.1228811 -
Journal of Virology Dec 2023Human poxvirus infections have caused significant public health burdens both historically and recently during the unprecedented global Mpox virus outbreak. Although...
Human poxvirus infections have caused significant public health burdens both historically and recently during the unprecedented global Mpox virus outbreak. Although vaccinia virus (VACV) infection of mice is a commonly used model to explore the anti-poxvirus immune response, little is known about the metabolic changes that occur during infection. We hypothesized that the metabolome of VACV-infected skin would reflect the increased energetic requirements of both virus-infected cells and immune cells recruited to sites of infection. Therefore, we profiled whole VACV-infected skin using untargeted mass spectrometry to define the metabolome during infection, complementing these experiments with flow cytometry and transcriptomics. We identified specific metabolites, including nucleotides, itaconic acid, and glutamine, that were differentially expressed during VACV infection. Together, this study offers insight into both virus-specific and immune-mediated metabolic pathways that could contribute to the clearance of cutaneous poxvirus infection.
Topics: Animals; Mice; Flow Cytometry; Gene Expression Profiling; Glutamine; Mass Spectrometry; Metabolic Reprogramming; Metabolome; Nucleotides; Skin; Vaccinia; Vaccinia virus; Viral Load
PubMed: 38009914
DOI: 10.1128/jvi.01272-23 -
International Journal of Molecular... May 2024Cancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This... (Review)
Review
Cancer cells adeptly manipulate their metabolic processes to evade immune detection, a phenomenon intensifying the complexity of cancer progression and therapy. This review delves into the critical role of cancer cell metabolism in the immune-editing landscape, highlighting how metabolic reprogramming facilitates tumor cells to thrive despite immune surveillance pressures. We explore the dynamic interactions within the tumor microenvironment (TME), where cancer cells not only accelerate their glucose and amino acid metabolism but also induce an immunosuppressive state that hampers effective immune response. Recent findings underscore the metabolic competition between tumor and immune cells, particularly focusing on how this interaction influences the efficacy of emerging immunotherapies. By integrating cutting-edge research on the metabolic pathways of cancer cells, such as the Warburg effect and glutamine addiction, we shed light on potential therapeutic targets. The review proposes that disrupting these metabolic pathways could enhance the response to immunotherapy, offering a dual-pronged strategy to combat tumor growth and immune evasion.
Topics: Humans; Neoplasms; Tumor Microenvironment; Immunotherapy; Animals; Warburg Effect, Oncologic; Glutamine; Tumor Escape; Metabolic Networks and Pathways
PubMed: 38791327
DOI: 10.3390/ijms25105288 -
Frontiers in Immunology 2023Sepsis is a major health problem in the United States (US), constituting a leading contributor to mortality among critically ill patients. Despite advances in treatment... (Review)
Review
Sepsis is a major health problem in the United States (US), constituting a leading contributor to mortality among critically ill patients. Despite advances in treatment the underlying pathophysiology of sepsis remains elusive. Reactive oxygen species (ROS) have a significant role in antimicrobial host defense and inflammation and its dysregulation leads to maladaptive responses because of excessive inflammation. There is growing evidence for crosstalk between the central nervous system and the immune system in response to infection. The hypothalamic-pituitary and adrenal axis and the sympathetic nervous system are the two major pathways that mediate this interaction. Epinephrine (Epi) and norepinephrine (NE), respectively are the effectors of these interactions. Upon stimulation, NE is released from sympathetic nerve terminals locally within lymphoid organs and activate adrenoreceptors expressed on immune cells. Similarly, epinephrine secreted from the adrenal gland which is released systemically also exerts influence on immune cells. However, understanding the specific impact of neuroimmunity is still in its infancy. In this review, we focus on the sympathetic nervous system, specifically the role the neurotransmitter norepinephrine has on immune cells. Norepinephrine has been shown to modulate immune cell responses leading to increased anti-inflammatory and blunting of pro-inflammatory effects. Furthermore, there is evidence to suggest that norepinephrine is involved in regulating oxidative metabolism in immune cells. This review attempts to summarize the known effects of norepinephrine on immune cell response and oxidative metabolism in response to infection.
Topics: Humans; Norepinephrine; Epinephrine; Inflammation; Sepsis; Oxidative Stress
PubMed: 38022663
DOI: 10.3389/fimmu.2023.1271098 -
Nutrients Dec 2023Endoplasmic reticulum (ER) stress plays a pivotal role in adipogenesis, which encompasses the differentiation of adipocytes and lipid accumulation. Sustained ER stress... (Review)
Review
Endoplasmic reticulum (ER) stress plays a pivotal role in adipogenesis, which encompasses the differentiation of adipocytes and lipid accumulation. Sustained ER stress has the potential to disrupt the signaling of the unfolded protein response (UPR), thereby influencing adipogenesis. This comprehensive review illuminates the molecular mechanisms that underpin the interplay between ER stress and adipogenesis. We delve into the dysregulation of UPR pathways, namely, IRE1-XBP1, PERK and ATF6 in relation to adipocyte differentiation, lipid metabolism, and tissue inflammation. Moreover, we scrutinize how ER stress impacts key adipogenic transcription factors such as proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPs) along with their interaction with other signaling pathways. The cellular ramifications include alterations in lipid metabolism, dysregulation of adipokines, and aged adipose tissue inflammation. We also discuss the potential roles the molecular chaperones cyclophilin A and cyclophilin B play in adipogenesis. By shedding light on the intricate relationship between ER stress and adipogenesis, this review paves the way for devising innovative therapeutic interventions.
Topics: Humans; Aged; Adipogenesis; Endoplasmic Reticulum Stress; Unfolded Protein Response; Signal Transduction; Inflammation
PubMed: 38140341
DOI: 10.3390/nu15245082 -
Kidney360 Aug 2023There is significant enrichment in metabolic pathways in early stages in the subtotal nephrectomy model of CKD. Proximal tubular mitochondrial respiration is suppressed...
KEY POINTS
There is significant enrichment in metabolic pathways in early stages in the subtotal nephrectomy model of CKD. Proximal tubular mitochondrial respiration is suppressed likely from mitochondrial dysfunction in substrate utilization and ATP synthesis. There is significant suppression of pyruvate dehydrogenase and increased glycolysis in proximal tubules.
BACKGROUND
CKD is a significant contributor to morbidity and mortality. A better understanding of mechanisms underlying CKD progression is indispensable for developing effective therapies. Toward this goal, we addressed specific gaps in knowledge regarding tubular metabolism in the pathogenesis of CKD using the subtotal nephrectomy (STN) model in mice.
METHODS
Weight- and age‐matched male 129X1/SvJ mice underwent sham or STN surgeries. We conducted serial GFR and hemodynamic measurements up to 16 weeks after sham and STN surgery and established the 4-week time point for subsequent studies.
RESULTS
For a comprehensive assessment of renal metabolism, we conducted transcriptomic analyses, which showed significant enrichment of pathways involved in fatty acid metabolism, gluconeogenesis, glycolysis, and mitochondrial metabolism in STN kidneys. Expression of rate-limiting fatty acid oxidation and glycolytic enzymes was increased in STN kidneys, and proximal tubules in STN kidneys exhibited increased functional glycolysis but decreased mitochondrial respiration, despite an increase in mitochondrial biogenesis. Assessment of the pyruvate dehydrogenase complex pathway showed significant suppression of pyruvate dehydrogenase, suggesting decreased provision of acetyl CoA from pyruvate for the citric acid cycle to fuel mitochondrial respiration.
CONCLUSION
Metabolic pathways are significantly altered in response to kidney injury and may play an important role in the disease progression.
Topics: Humans; Renal Insufficiency, Chronic; Kidney; Energy Metabolism
PubMed: 37222594
DOI: 10.34067/KID.0000000000000153 -
Frontiers in Endocrinology 2023Hepatocyte nuclear factor 4 alpha (HNF4α) is a multi-faceted nuclear receptor responsible for governing the development and proper functioning of liver and pancreatic... (Review)
Review
Hepatocyte nuclear factor 4 alpha (HNF4α) is a multi-faceted nuclear receptor responsible for governing the development and proper functioning of liver and pancreatic islet cells. Its transcriptional functions encompass the regulation of vital metabolic processes including cholesterol and fatty acid metabolism, and glucose sensing and control. Various genetic mutations and alterations in HNF4α are associated with diabetes, metabolic disorders, and cancers. From a structural perspective, HNF4α is one of the most comprehensively understood nuclear receptors due to its crystallographically observed architecture revealing interconnected DNA binding domains (DBDs) and ligand binding domains (LBDs). This review discusses key properties of HNF4α, including its mode of homodimerization, its binding to fatty acid ligands, the importance of post-translational modifications, and the mechanistic basis for allosteric functions. The surfaces linking HNF4α's DBDs and LBDs create a convergence zone that allows signals originating from any one domain to influence distant domains. The HNF4α-DNA complex serves as a prime illustration of how nuclear receptors utilize individual domains for specific functions, while also integrating these domains to create cohesive higher-order architectures that allow signal responsive functions.
Topics: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; Epithelial Cells; Fatty Acids; Lipid Metabolism
PubMed: 37732120
DOI: 10.3389/fendo.2023.1219092 -
MedRxiv : the Preprint Server For... Dec 2023Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict...
Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. The association of CYP2C19 and CYP2D6 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR=1.46, 95% CI [1.03, 2.06], p=0.033, heterogeneity I=0%, subgroup difference p=0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19 and CYP2D6, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. CYP2D6 structural variants cannot be imputed from genotype data, limiting inference of pharmacogenetic effects. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.
PubMed: 37425775
DOI: 10.1101/2023.06.26.23291890 -
Trends in Biochemical Sciences Nov 2023Biomembranes are complex materials composed of lipids and proteins that compartmentalize biochemistry. They are actively remodeled in response to physical and metabolic... (Review)
Review
Biomembranes are complex materials composed of lipids and proteins that compartmentalize biochemistry. They are actively remodeled in response to physical and metabolic cues, as well as during cell differentiation and stress. The concept of homeoviscous adaptation has become a textbook example of membrane responsiveness. Here, we discuss limitations and common misconceptions revolving around it. By highlighting key moments in the life cycle of a transmembrane protein, we illustrate that membrane thickness and a finely regulated membrane compressibility are crucial to facilitate proper membrane protein insertion, function, sorting, and inheritance. We propose that the unfolded protein response (UPR) provides a mechanism for endoplasmic reticulum (ER) membrane homeostasis by sensing aberrant transverse membrane stiffening and triggering adaptive responses that re-establish membrane compressibility.
Topics: Endoplasmic Reticulum Stress; Unfolded Protein Response; Homeostasis; Endoplasmic Reticulum; Membrane Proteins
PubMed: 37652754
DOI: 10.1016/j.tibs.2023.08.004