Metabolic Responses Research Articles

Immunotherapy response and resistance in patients with advanced uveal melanoma: a retrospective cohort study.

Metastatic uveal melanoma (mUM) is associated with poor prognosis. Ipilimumab/nivolumab has shown antitumor efficacy in phase II studies. Tebentafusp resulted in longer overall survival (OS) compared to investigator`s choice in a phase III study. We sought to describe the radiological response patterns of mUM patients treated with immunotherapy. Patients with mUM treated with ipilimumab/nivolumab and tebentafusp between July 2018 and December 2022, with available radiological assessment per RECISTv1.1 and/or imPERCIST5, were retrospectively identified and included. Progression-free survival (PFS) and OS rates, liver-specific response and pathological assessment in available liver biopsies were evaluated. In the ipilimumab/nivolumab group, median PFS (mPFS) was 2.9 months (95% CI 2.2-28.6) and mOS 28.9 months (95% CI 12.7-NR). Complete (CMR) and partial (PMR) metabolic response per imPERCIST5, and partial response (PR) per RECISTv1.1 were associated with longer PFS and OS by trend, compared to morphologically and metabolically stable or progressive disease. In the tebentafusp group, mPFS was 2.7 months (95% CI 2.2-3) and mOS 18.6 months (95% CI 11.5-NR). PMR and PR were associated with longer PFS by trend. In both treatments, the overall treatment response was associated with the radiological response at the liver site. In available liver tumor biopsies, differences in pathological and radiological responses were noted. ImPERCIST5 and RECIST v1.1 are valuable tools in the radiological response assessment, but both methods display limitations. Accurate biomarkers to stratify patients at risk for disease progression and future translational studies to investigate mechanisms of response and resistance are required.

Superior metabolic improvement of polycystic ovary syndrome traits after GLP1-based multi-agonist therapy

Polycystic ovary syndrome (PCOS) is a heterogeneous condition, defined by oligo-/anovulation, hyper-androgenism and/or polycystic ovaries. Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes, which severely compromise the clinical course of affected women. Yet, therapeutic options remain mostly symptomatic and of limited efficacy for the metabolic and reproductive alterations of PCOS. We report here the hormonal, metabolic and gonadal responses to the glucagon-like peptide-1 (GLP1)-based multi-agonists, GLP1/Estrogen (GLP1/E), GLP1/gastric inhibitory peptide (GLP1/GIP) and GLP1/GIP/Glucagon, in two mouse PCOS models, with variable penetrance of metabolic and reproductive traits, and their comparison with metformin. Our data illustrate the superior efficacy of GLP1/E vs. other multi-agonists and metformin in the management of metabolic complications of PCOS; GLP1/E ameliorates also ovarian cyclicity in an ovulatory model of PCOS, without direct estrogenic uterotrophic effects. In keeping with GLP1-mediated brain targeting, quantitative proteomics reveals changes in common and distinct hypothalamic pathways in response to GLP1/E between the two PCOS models, as basis for differential efficiency. Altogether, our data set the basis for the use of GLP1-based multi-agonists, and particularly GLP1/E, in the personalized management of PCOS.

Pharmacological inhibition reveals participation of the endocytic compartment in positive feedback IL-6 secretion in human skeletal myotubes

IL-6 is an important cytokine involved in metabolic, immunological, and cell-fate responses. It is released upon stimulation by skeletal muscle cells through partially characterized mechanisms. In some cell types, IL-6 has been reported to activate a positive feedback loop involving endocytic vesicles, but evidence is mostly based on transcription and signal transduction mechanisms and is very scarce in muscle cells. Our aim was to directly demonstrate the presence of positive feedback in the ATP-induced release of IL-6 into the supernatant of human skeletal muscle cultures. The total release (production) of IL-6 was reduced for higher volumes of supernatant, when the secreted IL-6 molecules are more diluted, and enhanced when the supernatant volume was lower. In addition, secretion was impaired both by tocilizumab, a blocker of human IL-6 receptors, and by the soluble form of the receptor. The secretion in response to ATP was also inhibited by treatment with the endocytosis inhibitor dynasore, and by disruption of the acidic gradient of the endocytic compartment using different methods (chloroquine, NH4Cl or monensin). IL-6 secretion was also impaired by NED-19, a specific inhibitor of the two pore channels receptor mediating Ca2+ release from the endolysosomal compartment. IL-6 and ATP increased IL-6 mRNA levels, an effect blocked by tocilizumab. Altogether, our results demonstrate that ATP-secreted IL-6 activates a positive loop based on IL-6 receptors, endocytosis, two pore channels and IL-6 transcription. Given the importance of muscle IL-6 as a systemic regulator and as an inflammatory mediator, our study can help to understand muscle pathophysiology.

RNA m6A-mediated post-transcriptional repression of glucocorticoid receptor in LPS-activated Kupffer cells on broilers

Glucocorticoid receptors are distributed in various cells of the body and participate in the regulation of metabolism and immunity in response to glucocorticoids. RNA m6A methylation participates in various metabolic and inflammatory responses, yet it remains elusive whether m6A is involved in GR regulation during immune activation. Here, we observed uncoupled GR responses with increased mRNA yet suppressed protein levels in the LPS-challenged broilers chicken liver, in association with global elevation of RNA m6A methylation, especially in the expression of METTL3 and YTHDF2. Further analysis using isolated primary hepatocytes and Kupffer cells revealed that such uncoupled GR responses and m6A hypermethylation occurred specifically in KCs. The same GR and m6A responses were reproduced in LPS-activated KC cell line, implying a possible role of m6A in the post-transcriptional suppression of GR in KC. Indeed, m6A inhibitor cycloleucine alleviated LPS-induced GR protein suppression, whilst GR antagonist RU486 had no effect on global m6A methylation in KC. We observed that YTHDF2 siRNA can alleviate LPS-induced GR mRNA stability decrease. Subsequently, specific m6A sites on GR were predicted and verified. Mutation m6A sites and luciferase reporter assay was also applied to validate these findings. Mechanistically, m6A methylation on the transcripts of GR impairs its mRNA stability in a YTHDF2-dependent manner, which leads to the decrease of its protein. Our study indicates successive roles of RNA m6A modification in the down regulation of GR expression, which provides new drug targets for epigenetic therapy of liver inflammation.

Deleterious Biological Effects of Endocrine Disruptors: An Insight into Human Health Risks.

Endocrine-disrupting chemicals (EDCs) are environmental pollutants. Since EDCs are present in various consumer products, contamination of human beings is very common. EDCs have deleterious effects on various systems of the body, especially the endocrine and reproductive systems. EDCs interfere with the synthesis, metabolism, binding, or cellular responses of natural estrogens and alter various pathways. Biological samples such as blood, saliva, milk, placental tissue, and hair are frequently used for biomonitoring and the detection of EDCs. Early detection and intervention may help in preventing congenital anomalies and birth defects. The common methods for determining the presence of EDCs in body fluids include gas chromatography, high-performance liquid chromatography, and mass spectrometry. Understanding the health effects and dangers of EDC is important, given their widespread use. This mini-review aims to summarize the adverse biological effects of several important classes of EDCs and highlights future perspectives for appropriate control.

Electric fields to support microalgae growth with a differentiated biochemical composition

Microalgae are a group of microorganisms well-known for their high metabolic plasticity and biomass with commercial interest for several industries. In the present work, the influence of in-situ electric field application (INEF) on the growth and biochemical composition of Pavlova gyrans was, for the first time, assessed. Electrical protocols were tested, namely by applying INEF in different growth stages, in varying treatment times and even by combining it with dark phase of cells' photoperiod. INEF did not promote a stimulatory effect on growth but influenced the biochemical composition of P. gyrans – maximum increases of 74.9 and 66.2 % in the chlorophyll a and carotenoid content and of 4.72, 18.7 and 5.41 % in the lipid, carbohydrate and protein content were observed in independent experiments. Hence, with this study, the potential of INEF application as a strategy to modulate growth and to promote biochemical composition alterations was proven. Industrial relevanceMicroalgae, with their unique ability to efficiently convert sunlight and carbon dioxide into biomass, offer a sustainable platform for the synthesis of diverse bioactive compounds. By subjecting microalgae to controlled electric stress conditions, their metabolic pathways can be redirected towards the production of specific target compounds. This strategy has the potential to enhance the yield of high-value molecules, including biofuels, pharmaceuticals, nutraceuticals, and pigments, whilst minimizing resource inputs. Additionally, metabolic stress responses in microalgae often trigger the accumulation of secondary metabolites with bioactive properties. Harnessing the metabolic plasticity of microalgae through controlled stress manipulation represents a cutting-edge strategy for sustainable and economically viable bioproduction systems that align with the goals of green chemistry and circular economy principles.

Heterogeneity in extracellular matrix and immune microenvironment of anterior vaginal wall revealed by single-cell sequencing in women with stress urinary incontinence

Stress urinary incontinence (SUI), characterized by involuntary urine leakage during increased abdominal pressure, remains poorly understood regarding its pathophysiology and treatment. In this study, we utilized single-cell sequencing to analyze the transcriptomic profiles of different cell types in anterior vaginal wall of SUI patients, aiming to explore the heterogeneity of the extracellular matrix (ECM) and immune microenvironment in SUI pathogenesis. Our results identified eleven cell types, including connective tissue cells, immune cells, and glial cells. Specifically, fibroblasts, smooth muscle cells, epithelial cells and T cells displayed transcriptional characteristics highly relevant to SUI pathogenesis. We observed that most cell types participate in ECM metabolism and immune-inflammatory responses, indicating a synergistic role of multiple vaginal cell types in SUI. Furthermore, altered intercellular communication, particularly between fibroblasts and T cells, was noted in SUI. This study provides novel single-cell insights into SUI and identifies potential biomarkers and therapeutic targets for future research.

Novel Therapeutic Target for ALI/ARDS: Forkhead Box Transcription Factors.

ALI/ARDS can be a pulmonary manifestation of a systemic inflammatory response or a result of overexpression of the body's normal inflammatory response involving various effector cells, cytokines, and inflammatory mediators, which regulate the body's immune response through different signalling pathways. Forkhead box transcription factors are evolutionarily conserved transcription factors that play a crucial role in various cellular processes, such as cell cycle progression, proliferation, differentiation, migration, metabolism, and DNA damage response. Transcription factors control protein synthesis by regulating gene transcription levels, resulting in diverse biological outcomes. The Fox family plays a role in activating or inhibiting the expression of various molecules related to ALI/ARDS through phosphorylation, acetylation/deacetylation, and control of multiple signalling pathways. An in-depth analysis of the integrated Fox family's role in ALI/ARDS can aid in the development of potential diagnostic and therapeutic targets for the condition.

C G composition in transposon-derived genes is increased in FXD with perturbed immune system.

Increasing incidence of Fragile X disorders (FXD) and of immune-mediated disorders in FXD suggests that additional factors besides FMR1 mutations contribute to the pathogenesis. Here, we discovered that the expression levels or splicing of specific transposon element (TE)-derived genes, regulating purine metabolism and immune responses against viral infections are altered in FXD. These genes include HLA genes clustered in chr6p21.3 and viral responsive genes in chr5q15. Remarkably, these TE-derived genes contain a low A T/C G suggesting base substitutions of A T to C G. The TE-derived genes with changed expression levels contained a higher content of 5'-CG-3' dinucleotides in FXD compared to healthy donors. This resembles the genomes of some RNA viruses, which maintain high contents of CG dinucleotides to sustain their latent infection exploiting antiviral responses. Thus, past viral infections may have persisted as TEs, provoking immune-mediated disorders in FXD.

The role of NMDA receptors in fish stress response: Assessments based on physiology of the caudal neurosecretory system and defensive behavior.

Stress strongly influences the physiology and behavior of animals, and leads into a pathological condition and disease. NMDA receptors (NMDARs) play a crucial role in the modulation of neural activity. To understand the role of NMDARs in fish stress response, we used NMDARs agonist aspartate to test the functional role of its input on the Dahlgren cell population in the caudal neurosecretory system (CNSS) of the olive flounder. In addition, the effect of the NMDARs antagonist D-AP5 on the expression of genes of the main secretory products of the CNSS after stress was investigated by using qPCR technology and the effect of the NMDARs antagonist D-AP5 on post-stress behavior was explored by behavioral methods. Ex vivo electrophysiological experiments showed that the NMDARs agonist aspartate enhanced the firing frequency of Dahlgren cells. Additionally, aspartate treatment increased the incidence of cells exhibiting bursting firing pattern, this result is corroborated by the observed upregulation in the expression of ion channels and major hormone genes in the CNSS. Furthermore, the excitatory influence of aspartate was effectively counteracted by NMDARs antagonist D-AP5. Interestingly, NMDARs antagonist D-AP5 treatment also significantly decreased the plasma cortisol levels and the expression of CRH, UI, and UII in CNSS after acute stress. Treatment with D-AP5 effectively attenuated the stress response, as evidenced by alterations in respiratory metabolism, sand-burying behavior, swimming distance, simulated capture, and escape response. In conclusion, modulation of Dahlgren cell excitability in the CNSS by NMDARs contributes to the regulation of the stress response, NMDARs antagonist D-AP5 can effectively suppress stress response in flounder by regulating the stress hormone expression and secretion. CLINICAL TRIAL REGISTRATION: Project code SHOU-DW-2022-032.

Plant Beneficial Desert Actinomycete, Modestobacter caceresii KNN 45-2bT, Promote Growth of Tomato (Lycopersicum esculentum Mill.) under Drought Condition

Drought stress is currently the most serious challenge to global food security and agricultural productivity. Desert actinobacteria have gained attention as potential candidates for enhancing plant growth in water stress environments. In this regard, a desert actinomycete, namely Modestobacter caceresii strain KNN 45-2bT, was selected to investigate its plant growth promoting abilities and drought tolerance. Next, this desert strain was inoculated to tomato (Lycopersicum esculentum Mill.) under drought, and the results included increases in root length, shoot and root fresh weight, shoot and root dry weight, total fresh weight and dry weight, fruit weight, proline accumulation, total soluble sugar content and trolox content. Stress treatments on the bacterized tomato plants also resulted in the reduction of hydrogen peroxide accumulation. Putative proteins coding sequences conferring plant growth promoting (PGP) traits (IAA production, phosphate solubilization, siderophore production, nitrogen fixation) and drought response (biosynthesis of proline metabolism, oxidative and osmotic stress response) were also detected from their genomic analyses. In conclusion, these results provide credence to the idea that the inoculation of tomato plants with plant beneficial desert actinomycete is an effective method of combating the negative effects of drought stress.

Brain metabolic response to repetitive transcranial magnetic stimulation to lesion network in cervical dystonia

BackgroundA previous study identified a brain network underlying cervical dystonia (CD) based on causal brain lesions. This network was shown to be abnormal in idiopathic CD and aligned with connections mediating treatment response to deep brain stimulation, suggesting generalizability across etiologies and relevance for treatment. The main nodes of this network were located in the deep cerebellar structures and somatosensory cortex (S1), the latter of which can be easily reached via non-invasive brain stimulation. To date, there are no studies testing brain stimulation to networks identified using lesion network mapping. ObjectivesTo assess target engagement by stimulating the S1 and testing the brain's acute metabolic response to repetitive transcranial magnetic stimulation in CD patients and healthy controls. MethodsThirteen CD patients and 14 controls received a single session of continuous theta burst (cTBS) and sham to the right S1. Changes in regional brain glucose metabolism were measured using [18F]FDG-PET. ResultscTBS increased metabolism at the stimulation site in CD (P = 0.03) but not in controls (P = 0.15; group difference P = 0.01). In subcortical regions, cTBS increased metabolism in the brainstem in CD only (PFDR = 0.04). The remote activation was positively associated with dystonia severity and efficacy of sensory trick phenomenon in CD patients. ConclusionsOur results provide further evidence of abnormal sensory system function in CD and show that a single session of S1 cTBS is sufficient to induce measurable changes in brain glucose metabolism. These findings support target engagement, motivating therapeutic trials of cTBS to the S1 in CD.

Wolbachia modify host cell metabolite profiles in response to short-term temperature stress.

Wolbachia are common heritable endosymbionts that influence many aspects of ecology and evolution in various insects, yet Wolbachia-mediated intracellular metabolic responses to temperature stress have been largely overlooked. Here, we introduced the Wolbachia strain wLhui from the invasive Liriomyza huidobrensis (Blanchard) into a Drosophila Schneider 2 cell line (S2) and investigated the metabolite profile of wLhui-infected (S2_wLhui) and uninfected cell lines (S2_wu) under short-term exposure to either high (37°C), moderate (27°C), or low (7 and 17°C) temperatures. We find that Wolbachia infection, temperature stress, and their interactions significantly affect cellular metabolic profiles. Most significantly, when comparing the changes in metabolites between S2_wLhui and S2_wu, glycerophospholipids, amino acids, and fatty acids associated with metabolic pathways, microbial metabolism in diverse environments, and other pathways were significantly accumulated at either low or high temperatures. Our findings suggest Wolbachia-induced cellular physiological responses to short-term temperature stress, which may in turn affect the fitness and adaptive ability of its host as an invasive species.

Fatigue, Electomyographic, And Metabolic Responses To Repeated Bench Press Sets At Different Ranges Of Motion

Fatigue, Electomyographic, And Metabolic Responses To Repeated Bench Press Sets At Different Ranges Of Motion

Effects of thermal and UV stress on the polar and non-polar metabolome of photosymbiotic jellyfish and sea anemones

Recently, the impacts of climate change, notably ocean warming and solar ultraviolet radiation, have led to significant stress and mortality in cnidarians. The objective of this study is to decode the metabolic responses of sea anemones Entacmaea quadricolor and upside-down jellyfish Cassiopea andromeda upon exposure to thermal and ultraviolet stress. Gas chromatography-mass spectrometry and ultraperformance liquid chromatography coupled with high-resolution mass spectrometry targeting polar and non-polar metabolites were applied. In total, 72 polar and 242 lipophilic metabolites were detected in jellyfish and sea anemones, respectively. Amino acids are the major metabolite class in jellyfish, and triacylglycerides are the predominant lipids in jellyfish and anemones. Exposure to stressors led to metabolic alterations, marked by elevated amino acids in jellyfish and increased amino acids and sugar alcohols in sea anemones at 34 °C and after four days of ultraviolet radiation. Non-polar metabolome analysis indicated distinct responses to ultraviolet radiation and thermal stress in both species.

ER stress aggravates NOD1-mediated inflammatory response leading to impaired nutrient metabolism in hepatoma cells

Nucleotide-binding Oligomerization Domain 1 (NOD1) is a cytosolic pattern recognition receptor that senses specific bacterial peptidoglycan moieties, leading to the induction of inflammatory response. Besides, sensing peptidoglycan, NOD1 has been reported to sense metabolic disturbances including the ER stress-induced unfolded protein response (UPR). However, the underpinning crosstalk between the NOD1 activating microbial ligands and the metabolic cues to alter metabolic response is not yet comprehensively defined. Here, we show that underlying ER stress aggravated peptidoglycan-induced NOD1-mediated inflammatory response in hepatoma cells. The HepG2 cells, undergoing ER stress induced by thapsigargin exhibited an amplified inflammatory response induced by peptidoglycan ligand of NOD1 (i.e. iE-DAP). This aggravated inflammatory response disrupted lipid and glucose metabolism, characterized by de novo lipogenic response, and increased gluconeogenesis in HepG2 cells. Further, we characterized that the aggravation of NOD1-induced inflammatory response was dependent on inositol-requiring enzyme 1-α (IRE1-α) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) activation, in conjunction with calcium flux. Altogether, our findings suggest that differential UPR activation makes liver cells more sensitive towards bacterial-derived ligands to pronounce inflammatory response in a NOD1-dependent manner that impairs hepatic nutrient metabolism.

Metabolic Responses To Endurance Exercise Anchored To Vigorous Ratings Of Perceived Exertion

Metabolic Responses To Endurance Exercise Anchored To Vigorous Ratings Of Perceived Exertion

Insights into the carbon and nitrogen metabolism pathways in mixed-autotrophy/heterotrophy anammox consortia in response to temperature reduction

While the multi-coupled anammox system boasts a substantial research foundation, the specific characteristics of its synergistic metabolic response to decreased temperatures, particularly within the range of 13-15°C, remained elusive. In this study, we delve into the intricate carbon and nitrogen metabolism pathways of mixed-autotrophy/heterotrophy anammox consortia under conditions of temperature reduction. Our macrogenomic analyses reveal a compelling phenomenon: the stimulation of functional genes responsible for complete denitrification, suggesting an enhancement of this process during temperature reduction. This adaptation likely contributes to maintaining system performance amidst environmental challenges. Further metabolic functional recombination analyses highlight a dramatic shift in microbial community composition, with denitrifying MAGs (metagenome-assembled genomes) experiencing a substantial increase in abundance (up to 200 times) compared to autotrophic MAGs. This proliferation underscores the strong stimulatory effect of temperature reduction on denitrifying species. Notably, autotrophic MAGs play a pivotal role in supporting the glycolytic processes of denitrifying MAGs, underscoring the intricate interdependencies within the consortia. Moreover, metabolic variations in amino acid composition among core MAGs emerge as a crucial adaptation mechanism. These differences facilitate the preservation of enzyme activity and enhance the consortia's resilience to low temperatures. Together, these findings offer a comprehensive understanding of the microbial synergistic metabolism within mixed-autotrophy/heterotrophy anammox consortia under temperature reduction, shedding light on their metabolic flexibility and resilience in dynamic environments.

Cardiorespiratory And Metabolic Responses To Blood-flow Restricted Running In Female Distance Runners

Cardiorespiratory And Metabolic Responses To Blood-flow Restricted Running In Female Distance Runners

Metabolic responses of sea anemone and jellyfish to temperature and UV bleaching: Insights into stress adaptation using LCMS-based metabolomics, molecular networking and chemometrics

IntroductionClimate change poses various threats to marine life, particularly in shallow tropical waters. Objective: The impact of increased temperature and ultraviolet (UV) exposure on two photosymbiotic Cnidarians, a common bubble-tip anemone and an upside-down jellyfish, was investigated. MethodsTo illustrate the response of aquatic organisms, the metabolomes of unstressed Entacmaea quadricolor and Cassiopea andromeda were compared for detailed metabolite profiling. UHPLC-MS coupled with chemometrics and GNPS molecular networking was employed for sample classification and identification of markers unique to stress responses in each organism. ResultsSeveral compounds with bioactive functions, including peptides and terpenoids, were reported for the first time in both organisms, viz. cyclic tetraglutamate, campestriene, and ceramide aminoethyl phosphonate (CEAP d18:2/16:0). Both anemone and jellyfish were subjected to either elevated UV-B light intensity up to 6.6 KJ m−2 or increased temperatures (28 °C, 30 °C, 32 °C, and 34 °C) over 4 days. Phospholipids, steroids, and ceramides emerged as chief markers of both types of stress, as revealed by the multivariate data analysis. Lysophosphatidylcholine (LPC 16:0), LPC (18:0/0:0), and echinoclasterol sulfate appeared as markers in both UV and thermal stress models of the anemone, whereas methyl/propyl cholestane-hexa-ol were discriminatory in the UV stress model only. In the case of jellyfish, nonpolar glycosyl ceramide GlcCer (d14:1/28:6) served as a marker for UV stress, whereas polar peptides were elevated in the thermal stress model. Interestingly, both models of jellyfish share a phospholipid, lysophosphatidylethanolamine (LPE 20:4), as a distinctive marker for stress, reported to be associated indirectly with the activity of innate immune response within other photosymbiotic Cnidaria such as corals and appears to be a fundamental stress response in marine organisms. ConclusionThis study presents several bioinformatic tools for the first time in two cnidarian organisms to provide not only a broader coverage of their metabolome but also broader insights into cnidarian bleaching in response to different stressors, i.e., heat and UV light, by comparing their effects in anemone versus jellyfish.