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Background: Polyploidization, a process where cells acquire additional chromosome sets, is a unique characteristic of hepatocytes. This process has been increasingly recognized as an adaptive mechanism for maintaining liver function during aging, a period characterized by cellular senescence, DNA damage, and metabolic dysregulation. Purpose: This review explores the molecular mechanisms underlying hepatocyte polyploidization and its potential role in promoting resilience against the aging-related decline in liver function. We assess how polyploid hepatocytes contribute to genomic stability, stress resistance, and metabolic adaptation, highlighting their relevance to liver aging. Main body: Hepatocyte polyploidization occurs through mechanisms such as cytokinesis failure and endoreplication, leading to binuclear or mononuclear polyploid cells. Polyploid hepatocytes exhibit enhanced DNA repair capacity, which helps mitigate the accumulation of age-related genomic damage. The increased gene dosage in polyploid cells facilitates better stress responses, particularly against oxidative stress and genotoxic insults. Metabolic adaptations, including enhanced xenobiotic metabolism and lipid regulation, further support the liver's ability to maintain homeostasis during aging. Additionally, polyploid cells demonstrate altered epigenetic landscapes and proteostasis mechanisms, contributing to improved cellular function and reduced susceptibility to senescence. These adaptations collectively enhance liver resilience against age-related metabolic and structural challenges. Conclusion: Hepatocyte polyploidization represents a critical protective mechanism in liver aging, promoting cellular adaptations that safeguard against genomic instability, metabolic dysfunction, and oxidative stress. Understanding the molecular pathways driving polyploidization could pave the way for novel therapeutic strategies to combat age-related liver disorders and enhance health span. Article Highlights: - Polyploid hepatocytes exhibit enhanced DNA repair and stress resistance, aiding liver resilience during aging. - Metabolic adaptations in polyploid cells improve detoxification and lipid regulation in the aging liver. - Polyploidization reduces the liver's susceptibility to aging-related senescence and functional decline. [ABSTRACT FROM AUTHOR]

Multipartite genomes are thought to confer evolutionary advantages to bacteria by providing greater metabolic flexibility in fluctuating environments and enabling rapid adaptation to new ecological niches and stress conditions. This genome architecture is commonly found in plant symbionts, including nitrogen-fixing rhizobia, such as Rhizobium leguminosarum bv. trifolii TA1 (RtTA1), whose genome comprises a chromosome and four extrachromosomal replicons (ECRs). In this study, the transcriptomic responses of RtTA1 to partial nutrient limitation and low acidic pH were analyzed using high-throughput RNA sequencing. RtTA1 growth under these conditions resulted in the differential expression of 1035 to 1700 genes (DEGs), which were assigned to functional categories primarily related to amino acid and carbohydrate metabolism, ribosome and cell envelope biogenesis, signal transduction, and transcription. These results highlight the complexity of the bacterial response to stress. Notably, the distribution of DEGs among the replicons indicated that ECRs played a significant role in the stress response. The transcriptomic data align with the Rhizobium pangenome analysis, which revealed an over-representation of functional categories related to transport, metabolism, and regulatory functions on ECRs. These findings confirm that ECRs contribute substantially to the ability of rhizobia to adapt to challenging environmental conditions. [ABSTRACT FROM AUTHOR]

The purpose of the study was to examine differences in body fat percentage (BF%) across groups stratified by resting metabolic rate (RMR) when normalized to body weight. National Collegiate Athletic Association Division III athletes (n = 190; Age: 19.8 ± 1.4 year; Body Mass: 79.3 ± 20.2 kg; Height: 175.0 ± 9.3 cm, Body Mass Index: 25.6 ± 4.9 kg/m2) participated in this cross-sectional mixed cohort study. Body composition was assessed using air displacement plethysmography. RMR was assessed using indirect calorimetry. For each sex, tertiles were determined and used to create low, moderate, and high relative RMR groups as follows: low (M: <26 kcal/kg; F: <24 kcal/kg), moderate (M: 26.1–29.0 kcal/kg; F: 24.1–27.0 kcal/kg), and high (M: >29.1 kcal/kg; F: >27.1 kcal/kg). The mean ± standard deviation RMR for male and female athletes was 27.9 ± 3.2 and 25.9 ± 2.8 kcals/kg when expressed relative to body weight. When stratified by sex, males in the low RMR group had significantly higher BF% values than those in the moderate (mean difference, [95% confidence intervals]) (7.2, [2.4, 12.0] kcal/kg; p < 0.01) and high RMR groups (7.7, [2.9, 12.5] kcal/kg; p < 0.001). Female athletes in the moderate RMR group had higher body fat percentages than those in the high RMR group (mean difference, [95% confidence intervals]) (5.8, [2.4, 9.2] kcal/kg; p < 0.01). Female athletes in the moderate relative RMR group had higher BF% values than those in the higher relative RMR group (3.3, [−0.1, 6.7] kcal/kg; p = 0.049). Both male and female athletes with a low relative RMR had a higher BF%. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether heat stress, as defined by the temperature-humidity index (THI) during the close-up dry period, had any impact on the productive performance, fertility, and immunometabolic blood indices of dairy cows in the subsequent lactation. Lactation performance was associated with increasing THI values on − 21, − 14, and − 7 d before calving resulting in decreased milk yield by about 2.30, 2.60, and 2.90 kg, respectively. The THI on the − 7 d before the calving was negatively associated with fertility parameters such as delayed first estrus postpartum, an elongated calving interval by approximately 32 d, a higher number of services per conception by 1.00, and an elongated artificial insemination service period, days open, and inter-calving period by about 20, 52, and 52 d, respectively. The study found that the immunometabolic blood indices were associated with increasing THI values during the close-up dry period. The study showed that exposing dairy cows to close-up dry period heat stress had negative consequences on performance, fertility, and immunometabolic blood indices in the subsequent lactation. Therefore, it is recommended that herd management and barn microclimate changes be implemented earlier, starting from the late dry period, to mitigate the negative impact of heat stress. [ABSTRACT FROM AUTHOR]

Epilepsy is characterized by hypersynchronous neuronal discharges, which are associated with an increased cerebral metabolic rate of oxygen and ATP demand. Uncontrolled seizure activity (status epilepticus) results in mitochondrial exhaustion and ATP depletion, which potentially generate energy mismatch and neuronal loss. Many cells can adapt to increased energy demand by increasing metabolic capacities. However, acute metabolic adaptation during epileptic activity and its relationship to chronic epilepsy remains poorly understood. We elicited seizure-like events (SLEs) in an in vitro model of status epilepticus for eight hours. Electrophysiological recording and tissue oxygen partial pressure recordings were performed. After eight hours of ongoing SLEs, we used proteomics-based kinetic modeling to evaluate changes in metabolic capacities. We compared our findings regarding acute metabolic adaptation to published proteomic and transcriptomic data from chronic epilepsy patients. Epileptic tissue acutely responded to uninterrupted SLEs by upregulating ATP production capacity. This was achieved by a coordinated increase in the abundance of proteins from the respiratory chain and oxidative phosphorylation system. In contrast, chronic epileptic tissue shows a 25–40% decrease in ATP production capacity. In summary, our study reveals that epilepsy leads to dynamic metabolic changes. Acute epileptic activity boosts ATP production, while chronic epilepsy reduces it significantly. [ABSTRACT FROM AUTHOR]

Abstract Background Polyploidization, a process where cells acquire additional chromosome sets, is a unique characteristic of hepatocytes. This process has been increasingly recognized as an adaptive mechanism for maintaining liver function during aging, a period characterized by cellular senescence, DNA damage, and metabolic dysregulation. Purpose This review explores the molecular mechanisms underlying hepatocyte polyploidization and its potential role in promoting resilience against the aging-related decline in liver function. We assess how polyploid hepatocytes contribute to genomic stability, stress resistance, and metabolic adaptation, highlighting their relevance to liver aging. Main body Hepatocyte polyploidization occurs through mechanisms such as cytokinesis failure and endoreplication, leading to binuclear or mononuclear polyploid cells. Polyploid hepatocytes exhibit enhanced DNA repair capacity, which helps mitigate the accumulation of age-related genomic damage. The increased gene dosage in polyploid cells facilitates better stress responses, particularly against oxidative stress and genotoxic insults. Metabolic adaptations, including enhanced xenobiotic metabolism and lipid regulation, further support the liver’s ability to maintain homeostasis during aging. Additionally, polyploid cells demonstrate altered epigenetic landscapes and proteostasis mechanisms, contributing to improved cellular function and reduced susceptibility to senescence. These adaptations collectively enhance liver resilience against age-related metabolic and structural challenges. Conclusion Hepatocyte polyploidization represents a critical protective mechanism in liver aging, promoting cellular adaptations that safeguard against genomic instability, metabolic dysfunction, and oxidative stress. Understanding the molecular pathways driving polyploidization could pave the way for novel therapeutic strategies to combat age-related liver disorders and enhance health span. Graphical Abstract

Abstract This study aimed to investigate whether heat stress, as defined by the temperature-humidity index (THI) during the close-up dry period, had any impact on the productive performance, fertility, and immunometabolic blood indices of dairy cows in the subsequent lactation. Lactation performance was associated with increasing THI values on − 21, − 14, and − 7 d before calving resulting in decreased milk yield by about 2.30, 2.60, and 2.90 kg, respectively. The THI on the − 7 d before the calving was negatively associated with fertility parameters such as delayed first estrus postpartum, an elongated calving interval by approximately 32 d, a higher number of services per conception by 1.00, and an elongated artificial insemination service period, days open, and inter-calving period by about 20, 52, and 52 d, respectively. The study found that the immunometabolic blood indices were associated with increasing THI values during the close-up dry period. The study showed that exposing dairy cows to close-up dry period heat stress had negative consequences on performance, fertility, and immunometabolic blood indices in the subsequent lactation. Therefore, it is recommended that herd management and barn microclimate changes be implemented earlier, starting from the late dry period, to mitigate the negative impact of heat stress.

The study examined effects of thyroid manipulation with propylthiouracil (PTU) on the metabolic adaptability of transitional dairy cows to early lactation. The study included 30 primiparous Holstein-Friesian cows, which were divided into two groups: PTU+ (n = 15; received orally 4 mg/kg PTU during 20 days before expected calving) and PTU− (n = 15; did not receive orally PTU). Blood was sampled from each cow consecutively from − 20, − 17, − 13, − 5, − 4, − 3, − 2, and − 1 days before the expected term of calving, calving day (0), and + 1, + 2, + 3, + 4, + 5, + 10, + 15, + 30 and + 60 days after the calving to measure thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), insulin, glucose, beta-hydroxybutyrate (BHB), bilirubin, total protein and albumin concentrations. Liver samples were biopsied at −7 ± 2 and +7 day relative to calving from both groups of cows to determine deiodinase (DIO) expressions and fat and glycogen content. Additionally, milk yield was monitored during the first 60 days of lactation. PTU successfully induced thyroid suppression by significantly reducing T3 and T4 concentrations and hepatic DIO1 expressions and caused PTU+ cows to have significantly higher insulin and glucose concentration in the precalving period. After calving, PTU+ cows had higher insulin and glucose concentration, liver glycogen content and overall milk production, lower BHB concentration, BCS loss, and liver fat deposits. Accordingly, cows treated with PTU have a more favourable energy balance and metabolic adaptation to early lactation.

Aim: In most vertebrates, oxygen deprivation and subsequent re‐oxygenation are associated with mitochondrial impairment and excess production of reactive oxygen species (ROS) like hydrogen peroxide (H2O2). This in turn triggers a cascade of cell‐damaging events in a temperature‐dependent manner. The crucian carp (Carassius carassius) is one of few vertebrates that survives months without oxygen at cold temperatures and overcomes oxidative damage during re‐oxygenation periods. Mitochondria of this anoxia‐tolerant species therefore serve as an excellent model in translational research to study adaptation and resilience to low oxygen conditions and thermal variability. Methods: Here, we used high‐resolution respirometry on isolated mitochondria from hearts of crucian carp and the anoxia‐intolerant mouse (Mus musculus), at 37 and 8°C; two temperatures relevant for transplantation medicine (i.e., graft preservation and subsequent rewarming). Results: We find: (1) a striking difference in H2O2 release between the two species at 37°C despite comparable mitochondrial efficiency and capacity, (2) a massive H2O2 release after inhibition of complex V in mouse at 37°C that is absent in crucian carp, and prevented in mouse by incubation at 8°C or uncoupling with a protonophore at 37°C, and (3) indications that differences in mitochondrial complex I and II capacity and thermal sensitivity influence the release of mitochondrial H2O2 relative to respiration. Conclusion: Our findings provide comparative insights into a spectrum of mitochondrial adaptations in vertebrates and the importance of thermal variability. Furthermore, the species‐ and temperature‐related changes associated with mitochondria highlighted in this study may help identify mitochondria‐based targets for translational medicine. [ABSTRACT FROM AUTHOR]

Background: Seeds of woody plant species, such as those in the Acer genus like Norway maple (Acer platanoides L.) and sycamore (Acer pseudoplatanus L.), exhibit unique physiological traits and responses to environmental stress. Thioredoxins (Trxs) play a central role in the redox regulation of cells, interacting with other redox-active proteins such as peroxiredoxins (Prxs), and contributing to plant growth, development, and responses to biotic and abiotic stresses. However, there is limited understanding of potential variations in this system between seeds categorized as recalcitrant and orthodox, which could provide insights into adaptive strategies. Methods: Using proteomic analysis and DDA methods we investigated the Trx-h1 target proteins in seed axes. We complemented the results of the proteomic analysis with gene expression analysis of the Trx-h1, 1-Cys-Prx, and TrxR NTRA genes in the embryonic axes of maturing, mature, and stored seeds from two Acer species. Results and discussion: The expression of Trx-h1 and TrxR NTRA throughout seed maturation in both species was low. The expression of 1-Cys-Prx remained relatively stable throughout seed maturation. In stored seeds, the expression levels were minimal, with slightly higher levels in sycamore seeds, which may confirm that recalcitrant seeds remain metabolically active during storage. A library of 289 proteins interacting with Trx-h1 was constructed, comprising 68 from Norway maple and 221 from sycamore, with distinct profiles in each seed category. Recalcitrant seed axes displayed a wide array of metabolic, stress response, and signaling proteins, suggesting sustained metabolic activity during storage and the need to address oxidative stress. Conversely, the orthodox seed axes presented a protein profile, reflecting efficient metabolic shutdown, which contributes to their extended viability. The results of the study provide new insights into seed viability and storage longevity mechanisms. They enhance the understanding of seed biology and lay the foundation for further evolutionary research on seeds of different categories. [ABSTRACT FROM AUTHOR]

Cellular metabolism is a crucial determinant of immune cell fate and function. Extensive studies have demonstrated that metabolic decisions influence immune cell activation, differentiation, and cellular capacity, in the process impacting an organism’s ability to stave off infection or recover from injury. Conversely, metabolic dysregulation can contribute to the severity of multiple disease conditions including autoimmunity, alloimmunity, and cancer. Emerging data also demonstrate that metabolic cues and profiles can influence the success or failure of adoptive cellular therapies. Importantly, immunometabolism is not one size fits all; and different immune cell types, and even subdivisions within distinct cell populations utilize different metabolic pathways to optimize function. Metabolic preference can also change depending on the microenvironment in which cells are activated. For this reason, understanding the metabolic requirements of different subsets of immune cells is critical to therapeutically modulating different disease states or maximizing cellular function for downstream applications. Fatty acid oxidation (FAO), in particular, plays multiple roles in immune cells, providing both pro- and anti-inflammatory effects. Herein, we review the major metabolic pathways available to immune cells, then focus more closely on the role of FAO in different immune cell subsets. Understanding how and why FAO is utilized by different immune cells will allow for the design of optimal therapeutic interventions targeting this pathway. [ABSTRACT FROM AUTHOR]

Impaired mitochondrial function is a hallmark of aging and a major contributor to neurodegenerative diseases. We have shown that disrupted mitochondrial dynamics typically found in aging alters the fate of neural stem cells (NSCs) leading to impairments in learning and memory. At present, little is known regarding the mechanisms by which neural stem and progenitor cells survive and adapt to mitochondrial dysfunction. Using Opa1‐inducible knockout as a model of aging and neurodegeneration, we identify a decline in neurogenesis due to impaired stem cell activation and progenitor proliferation, which can be rescued by the mitigation of oxidative stress through hypoxia. Through sc‐RNA‐seq, we identify the ATF4 pathway as a critical mechanism underlying cellular adaptation to metabolic stress. ATF4 knockdown in Opa1‐deficient NSCs accelerates cell death, while the increased expression of ATF4 enhances proliferation and survival. Using a Slc7a11 mutant, an ATF4 target, we show that ATF4‐mediated glutathione production plays a critical role in maintaining NSC survival and function under stress conditions. Together, we show that the activation of the integrated stress response (ISR) pathway enables NSCs to adapt to metabolic stress due to mitochondrial dysfunction and metabolic stress and may serve as a therapeutic target to enhance NSC survival and function in aging and neurodegeneration. [ABSTRACT FROM AUTHOR]

Cancer cells undergo metabolic adaptation to promote their survival and growth under energy stress conditions, yet the underlying mechanisms remain largely unclear. Here, we report that tripartite motif‐containing protein 2 (TRIM2) is upregulated in response to glutamine deprivation by the transcription factor cyclic AMP‐dependent transcription factor (ATF4). TRIM2 is shown to specifically interact with carnitine O‐palmitoyltransferase 1 (CPT1A), a rate‐limiting enzyme of fatty acid oxidation. Via this interaction, TRIM2 enhances the enzymatic activity of CPT1A, thereby regulating intracellular lipid levels and protecting cells from glutamine deprivation‐induced apoptosis. Furthermore, TRIM2 is able to promote both in vitro cell proliferation and in vivo xenograft tumor growth via CPT1A. Together, these findings establish TRIM2 as an important regulator of the metabolic adaptation of cancer cells to glutamine deprivation and implicate TRIM2 as a potential therapeutic target for cancer. [ABSTRACT FROM AUTHOR]

Abstract For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology. It is linked with insulin resistance through preferential abdominal fat accumulation that is worsened by obesity. Over the past two millennia, menstrual irregularity, male-type habitus and sub-infertility have been described in women and confirm that these clinical features of PCOS were common in antiquity. Recent findings in normal-weight hyperandrogenic PCOS women show that exaggerated lipid accumulation by subcutaneous (SC) abdominal stem cells during development to adipocytes in vitro occurs in combination with reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This PCOS phenotype may be an evolutionary metabolic adaptation to balance energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction. This review integrates fundamental endocrine-metabolic changes in healthy, normal-weight PCOS women with similar PCOS-like traits present in animal models in which tissue differentiation is completed during fetal life as in humans to support the evolutionary concept that PCOS has common ancestral and developmental origins.

Organelles form physical and functional contact between each other to exchange information, metabolic intermediates, and signaling molecules. Tethering factors and contact site complexes bring partnering organelles into close spatial proximity to establish membrane contact sites (MCSs), which specialize in unique functions like lipid transport or Ca2+ signaling. Here, we discuss how MCSs form dynamic platforms that are important for lipid metabolism. We provide a perspective on how import of specific lipids from the ER and other organelles may contribute to remodeling of mitochondria during nutrient starvation. We speculate that mitochondrial adaptation is achieved by connecting several compartments into a highly dynamic organelle network. The lipid droplet appears to be a central hub in coordinating the function of these organelle neighborhoods. [ABSTRACT FROM AUTHOR]

Extreme environmental conditions have profound impacts on shaping the evolutionary trajectory of organisms. Exposure to these conditions elicits stress responses, that can trigger phenotypic changes in novel directions. The Mexican Tetra, Astyanax mexicanus, is an excellent model for understanding evolutionary mechanisms in response to extreme or new environments. This fish species consists of two morphs; the classical surface‐dwelling fish and the blind cave‐dwellers that inhabit dark and biodiversity‐reduced ecosystems. In this review, we explore the specific stressors present in cave environments and examine the diverse adaptive strategies employed by cave populations to not only survive but thrive as successful colonizers. By analyzing the evolutionary responses of A. mexicanus, we gain valuable insights into the genetic, physiological, and behavioral adaptations that enable organisms to flourish under challenging environmental conditions. Research Highlights: Unique adaptations in cave populations of Astyanax mexicanus makes them a remarkable model to study the mechanisms underlying stress adaptation to environmental challenges. This review explores the remarkable adaptive strategies that allows the cavefish to successfully survive the challenging environmental shift at the time of cave colonization. [ABSTRACT FROM AUTHOR]

For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. Highlights: 1. Attempting to delineate the complex and multidimensional interplays between metabolites (or metabolic enzymes) and predominant immune cell populations. 2. Metabolic checkpoints of immune cells are described and the contribution of these metabolic targets to determine the metabolic adaptations of distinct immune cells in specific tissue environments is emphasized. 3. Proposed cancer-immunometabolism subcycle, enriching the theoretical foundation of the cancer-immunology field. 4. Metabolism-induced disturbances in the acid-base balance of the tumor microenvironment have non-redundant effects on immunotherapy. 5. Pending challenges and clinical concerns in metabolic insights were addressed. [ABSTRACT FROM AUTHOR]

BackgroundSeeds of woody plant species, such as those in the Acer genus like Norway maple (Acer platanoides L.) and sycamore (Acer pseudoplatanus L.), exhibit unique physiological traits and responses to environmental stress. Thioredoxins (Trxs) play a central role in the redox regulation of cells, interacting with other redox-active proteins such as peroxiredoxins (Prxs), and contributing to plant growth, development, and responses to biotic and abiotic stresses. However, there is limited understanding of potential variations in this system between seeds categorized as recalcitrant and orthodox, which could provide insights into adaptive strategies.MethodsUsing proteomic analysis and DDA methods we investigated the Trx-h1 target proteins in seed axes. We complemented the results of the proteomic analysis with gene expression analysis of the Trx-h1, 1-Cys-Prx, and TrxR NTRA genes in the embryonic axes of maturing, mature, and stored seeds from two Acer species.Results and discussionThe expression of Trx-h1 and TrxR NTRA throughout seed maturation in both species was low. The expression of 1-Cys-Prx remained relatively stable throughout seed maturation. In stored seeds, the expression levels were minimal, with slightly higher levels in sycamore seeds, which may confirm that recalcitrant seeds remain metabolically active during storage. A library of 289 proteins interacting with Trx-h1 was constructed, comprising 68 from Norway maple and 221 from sycamore, with distinct profiles in each seed category. Recalcitrant seed axes displayed a wide array of metabolic, stress response, and signaling proteins, suggesting sustained metabolic activity during storage and the need to address oxidative stress. Conversely, the orthodox seed axes presented a protein profile, reflecting efficient metabolic shutdown, which contributes to their extended viability. The results of the study provide new insights into seed viability and storage longevity mechanisms. They enhance the understanding of seed biology and lay the foundation for further evolutionary research on seeds of different categories.

Cellular metabolism is a crucial determinant of immune cell fate and function. Extensive studies have demonstrated that metabolic decisions influence immune cell activation, differentiation, and cellular capacity, in the process impacting an organism’s ability to stave off infection or recover from injury. Conversely, metabolic dysregulation can contribute to the severity of multiple disease conditions including autoimmunity, alloimmunity, and cancer. Emerging data also demonstrate that metabolic cues and profiles can influence the success or failure of adoptive cellular therapies. Importantly, immunometabolism is not one size fits all; and different immune cell types, and even subdivisions within distinct cell populations utilize different metabolic pathways to optimize function. Metabolic preference can also change depending on the microenvironment in which cells are activated. For this reason, understanding the metabolic requirements of different subsets of immune cells is critical to therapeutically modulating different disease states or maximizing cellular function for downstream applications. Fatty acid oxidation (FAO), in particular, plays multiple roles in immune cells, providing both pro- and anti-inflammatory effects. Herein, we review the major metabolic pathways available to immune cells, then focus more closely on the role of FAO in different immune cell subsets. Understanding how and why FAO is utilized by different immune cells will allow for the design of optimal therapeutic interventions targeting this pathway.

Mitochondria are present in all mammalian cells except matured red blood cells. Mitochondria consist of several metabolic pathways for glucose, fatty acids, amino acids, and bioenergetic pathways for ATP synthesis, membrane potential, and reactive oxygen production. In the liver, hepatic mitochondria play a key role in hepatic steatosis because mitochondrial metabolism produces acetyl-CoA which is the building block for synthesis of lipids and cholesterol. Mitochondria inner membrane is impermeable of metabolites, reducing equivalents, and small molecules such as phosphate, and sulfate. Thus, mitochondrial shuttles and carriers function as the routes of influx and efflux of these metabolites and molecules across the inner membrane. The signal regulation of these shuttles and mitochondrial enzymes could play a key role in coordinating the mitochondrial metabolism to adapt the cytosolic part of metabolic pathways in liver metabolic stress. Intriguingly, the interaction of mitochondria protein SH3 domain-binding protein 5 (SAB/SH3BP5) and c-Jun N-terminal kinase (JNK) was found as a pivotal role in sustained activation of JNK and phosphorylated-JNK (P-JNK) mediated activation of lipogenic pathway in nutritional excess. Knockout or knockdown of SAB prevented or reversed the hepatic steatosis, inflammation, and fibrosis, and improved metabolic intolerance and energy expenditure. Moreover, blocking the SAB peptide prevents palmitic acid-induced P-JNK interaction with SAB and inhibition of mitochondrial bioenergetics, implying the P-JNK effect on mitochondrial metabolism. This review focuses on the flow of mitochondrial metabolites in metabolic stress conditions and the contribution of mitochondria and mitochondrial stress signals in hepatic steatosis.

The purpose of the study was to examine differences in body fat percentage (BF%) across groups stratified by resting metabolic rate (RMR) when normalized to body weight. National Collegiate Athletic Association Division III athletes (n = 190; Age: 19.8 ± 1.4 year; Body Mass: 79.3 ± 20.2 kg; Height: 175.0 ± 9.3 cm, Body Mass Index: 25.6 ± 4.9 kg/m2) participated in this cross-sectional mixed cohort study. Body composition was assessed using air displacement plethysmography. RMR was assessed using indirect calorimetry. For each sex, tertiles were determined and used to create low, moderate, and high relative RMR groups as follows: low (M: 29.1 kcal/kg; F: >27.1 kcal/kg). The mean ± standard deviation RMR for male and female athletes was 27.9 ± 3.2 and 25.9 ± 2.8 kcals/kg when expressed relative to body weight. When stratified by sex, males in the low RMR group had significantly higher BF% values than those in the moderate (mean difference, [95% confidence intervals]) (7.2, [2.4, 12.0] kcal/kg; p < 0.01) and high RMR groups (7.7, [2.9, 12.5] kcal/kg; p < 0.001). Female athletes in the moderate RMR group had higher body fat percentages than those in the high RMR group (mean difference, [95% confidence intervals]) (5.8, [2.4, 9.2] kcal/kg; p < 0.01). Female athletes in the moderate relative RMR group had higher BF% values than those in the higher relative RMR group (3.3, [−0.1, 6.7] kcal/kg; p = 0.049). Both male and female athletes with a low relative RMR had a higher BF%.

This study aimed to determine whether heat stress affected the values and correlations of metabolic, endocrinological, and inflammatory parameters as well as the rectal and body surface temperature of cows in the early and middle stages of lactation. This experiment was conducted in May (thermoneutral period), June (mild heat stress), and July (moderate to severe heat stress). In each period we included 15 cows in early lactation and 15 in mid-lactation. The increase in rectal and body surface temperatures (°C) in moderate to severe heat stress compared to the thermoneutral period in different regions was significant (p < 0.01) and the results are presented as mean and [95%CI]: rectal + 0.9 [0.81–1.02], eye + 6 [5.74–6.25], ear + 13 [11.9–14.0], nose + 3.5 [3.22–3.71], forehead + 6.6 [6.43–6.75], whole head + 7.5 [7.36–7.68], abdomen + 8.5 [8.25–8.77], udder + 7.5 [7.38–7.65], front limb + 6 [5.89–6.12], hind limb + 3.6 [3.46–3.72], and whole body + 9 [8.80–9.21]. During heat stress (in both mild and moderate to severe stress compared to a thermoneutral period), an increase in the values of extracellular heat shock protein 70 (eHsp70), tumor necrosis factor α (TNFα), cortisol (CORT), insulin (INS), revised quantitative insulin sensitivity check index (RQUICKI), urea, creatinine, total bilirubin, aspartate transpaminase (AST), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), and creatin kinase (CK) occurred, as well as a decrease in the values of triiodothyronine (T3), thyroxine (T4), non-esterified fatty acids (NEFA), glucose (GLU), β-Hydroxybutyrate (BHB), calcium, phosphorus, total protein (TPROT), albumin (ALB), triglycerides (TGCs), and cholesterol (CHOL). In cows in early lactation compared to cows in mid-lactation, there was a significantly larger increase (p < 0.01) in the values of eHsp70, TNFα, GLU, RQUICKI, and GGT, while the INS increase was smaller during the three experimental periods. The decrease in the values of Ca, CHOL, and TGC was more pronounced in cows in early lactation compared to cows in mid-lactation during the three experimental periods. Rectal temperature was related to eHsp70 (r = 0.38, p < 0.001) and TNFα (r = 0.36, p < 0.01) and showed non-significant poor correlations with other blood parameters. Blood parameters correlate with body surface temperature, with the following most common results: eHsp70 and TNFα showed a moderately to strongly significant positive correlation (r = 0.79–0.96, p < 0.001); CORT, INS, and Creat showed fairly to moderately significant positive correlations; T3, T4, NEFA and GLU showed fairly to moderately significant negative correlations (r = 0.3–0.79; p < 0.01); RQUICKI, urea, AST, and GGT showed fairly and significantly positive correlations; and TGC, CHOL, TPROT, and ALB showed fairly and significantly negative correlations (r = 0.3–0.59; p < 0.01). Measuring the surface temperature of the whole body or head can be a useful tool in evaluating the metabolic response of cows because it has demonstrated an association with inflammation (TNFα, eHsp70), endocrine response (CORT, T3, T4), the increased use of glucose and decreased use of lipids for energy purposes (INS, NEFA, GLU, and RQUICKI), and protein catabolism (ALB, TPROT, urea, Creat), which underlies thermolysis and thermogenesis in cows under heat stress. In future research, it is necessary to examine the causality between body surface area and metabolic parameters. [ABSTRACT FROM AUTHOR]

The deep-sea environment is an extremely difficult habitat for microorganisms to survive in due to its intense hydrostatic pressure. However, the mechanisms by which these organisms adapt to such extreme conditions remain poorly understood. In this study, we investigated the metabolic adaptations of Microbacterium sediminis YLB-01, a cold and stress-tolerant microorganism isolated from deep-sea sediments, in response to high-pressure conditions. YLB-01 cells were cultured at normal atmospheric pressure and 28 ℃ until they reached the stationary growth phase. Subsequently, the cells were exposed to either normal pressure or high pressure (30 MPa) at 4 ℃ for 7 days. Using NMR-based metabolomic and proteomic analyses of YLB-01 cells exposed to high-pressure conditions, we observed significant metabolic changes in several metabolic pathways, including amino acid, carbohydrate, and lipid metabolism. In particular, the high-pressure treatment stimulates cell division and triggers the accumulation of UDP-glucose, a critical factor in cell wall formation. This finding highlights the adaptive strategies used by YLB-01 cells to survive in the challenging high-pressure environments of the deep sea. Specifically, we discovered that YLB-01 cells regulate amino acid metabolism, promote carbohydrate metabolism, enhance cell wall synthesis, and improve cell membrane fluidity in response to high pressure. These adaptive mechanisms play essential roles in supporting the survival and growth of YLB-01 in high-pressure conditions. Our study offers valuable insights into the molecular mechanisms underlying the metabolic adaptation of deep-sea microorganisms to high-pressure environments. Key points: • NMR-based metabolomic and proteomic analyses were conducted on Microbacterium sediminis YLB-01 to investigate the significant alterations in several metabolic pathways in response to high-pressure treatment. • YLB-01 cells used adaptive strategies (such as regulated amino acid metabolism, promoted carbohydrate metabolism, enhanced cell wall synthesis, and improved cell membrane fluidity) to survive in the challenging high-pressure environment of the deep sea. • High-pressure treatment stimulated cell division and triggered the accumulation of UDP-glucose, a critical factor in cell wall formation, in Microbacterium sediminis YLB-01 cells. [ABSTRACT FROM AUTHOR]

Environmental perturbations are encountered by microorganisms regularly and will require metabolic adaptations to ensure an organism can survive in the newly presenting conditions. In order to study the mechanisms of metabolic adaptation in such conditions, various experimental and computational approaches have been used. Genome-scale metabolic models (GEMs) are one of the most powerful approaches to study metabolism, providing a platform to study the systems level adaptations of an organism to different environments which could otherwise be infeasible experimentally. In this review, we are describing the application of GEMs in understanding how microbes reprogram their metabolic system as a result of environmental variation. In particular, we provide the details of metabolic model reconstruction approaches, various algorithms and tools for model simulation, consequences of genetic perturbations, integration of '-omics' datasets for creating context-specific models and their application in studying metabolic adaptation due to the change in environmental conditions. [ABSTRACT FROM AUTHOR]

Tilapia tolerate hypoxia; thus, they are an excellent model for the study of hypoxic adaptation. In this study, we determined the effect of acute hypoxia stress on the antioxidant capacity, metabolism, and gill/liver ultrastructure of male genetically improved farmed tilapia (GIFT, Oreochromis niloticus). Fish were kept under control (dissolved oxygen (DO): 6.5 mg/L) or hypoxic (DO: 1.0 mg/L) conditions for 72 h. After 2 h of hypoxia stress, antioxidant enzyme activities in the heart and gills decreased, while the malondialdehyde (MDA) content increased. In contrast, in the liver, antioxidant enzyme activities increased, and the MDA content decreased. From 4 to 24 h of hypoxia stress, the antioxidant enzyme activity increased in the heart but not in the liver and gills. Cytochrome oxidase activity was increased in the heart after 4 to 8 h of hypoxia stress, while that in the gills decreased during the later stages of hypoxia stress. Hypoxia stress resulted in increased Na+-K+-ATP activity in the heart, as well as hepatic vacuolization and gill lamella elongation. Under hypoxic conditions, male GIFT exhibit dynamic and complementary regulation of antioxidant systems and metabolism in the liver, gills, and heart, with coordinated responses to mitigate hypoxia-induced damage. [ABSTRACT FROM AUTHOR]

The transition of females from childbirth to lactation is a physiologically complex period characterised by metabolic, endocrine and immunological changes. In addition, difficult labour drains the female and can lead to hypolactia. The purpose of the study was to determine the effect of probiotics on lactation recovery and metabolic changes in the body of females. Among the methods used are: the determination of lactation level, the physiological method for determining live weight, the biochemical method for blood testing; and the statistical method. The application of Bacillus subtilis AX 20, Bacillus licheniformis EA 22 contributes to an increase in milk productivity in cows on day 7-9 of the study by 12.9%, on day 10-12 – by 15.03%, on day 13-15 – by 13.93%, on day 16-18 – by 13.5% and on day 19-21 – by 21.35% compared to the control. The total protein content in experimental cows increased by 18.92%, globulins – by 37.26 (p≤0.05), compared to the initial indicators. The activity of alanine aminotransferase, urea, and urea nitrogen in animals of the control and experimental groups was within the normal range during the experiment. The application of Bacillus megaterium NCH 55 to sows with hypolactation contributes to lactation recovery in sows. In the experimental group, piglets showed a lag in growth of 18.5% on the third day and 11.39% on the tenth day due to hypolactation. Starting from day 15, there was an increase in the live weight of suckling piglets due to the restoration of lactation in sows by 20.56%, on day 20 – by 20.43%, on day 25 – by 30.56%, on day 30 – by 31.91%, compared to the control. In the blood serum of experimental sows, the content of total protein increased by 10%, globulins – by 19.13%, total cholesterol – by 40.11%, urea by 48.0%, compared to the beginning of studies (p≤0.05). The activity of alanine aminotransferase in the experiment increased by 8.95% (p≤0.05), alkaline phosphatase decreased by 27.46% (p≤0.05), compared to the beginning of the study. In the blood of experimental sows, the level of circulating immune complexes increased by 42.85% and a decrease in seromucoids by 30.43%. The practical value of the study lies in the use of probiotics to restore the milk productivity of cows and sows after childbirth

Abstract Objective Metabolic and morphological adaptations of the intestine have been suggested to play a role in the various therapeutic benefits of Roux‐en‐Y Gastric Bypass (RYGB) surgery. However, the precise underlying mechanisms remain unclear. In this study, the effects of physical properties of ingested food and redirection of biliopancreatic secretions on intestinal remodeling were investigated in RYGB operated rats. Methods RYGB employing two different Roux Limb (RL) lengths was performed on high fat diet induced obese rats. Post‐operatively, rats were fed either Solid or isocaloric Liquid diets. Metabolic and morphological remodeling of intestine was compared across both diet forms (Solid and Liquid diets) and surgical models (Short RL and Long RL). Results RYGB surgery in rats induced weight loss and improved glucose tolerance which was independent of physical properties of ingested food and biliopancreatic secretions. Intestinal glucose utilization after RYGB was not determined by either food form or biliopancreatic secretions. The GLUT‐1 expression in RL was not influenced by physical properties of food. Furthermore, both physical properties of food and biliopancreatic secretions showed no effects on intestinal morphological adaptations after RYGB. Conclusion Results of this study demonstrate that physical properties of food and bile redirection are not major determinants of intestinal remodeling after RYGB in rats.

ABSTRACTThe surge in inflammatory bowel diseases, like Crohn’s disease (CD), is alarming. While the role of the gut microbiome in CD development is unresolved, the frequent isolation of adherent-invasive Escherichia coli (AIEC) strains from patient biopsies, together with their propensity to trigger gut inflammation, underpin the potential role of these bacteria as disease modifiers. In this review, we explore the spectrum of AIEC pathogenesis, including their metabolic versatility in the gut. We describe how AIEC strains hijack the host defense mechanisms to evade immune attrition and promote inflammation. Furthermore, we highlight the key traits that differentiate AIEC from commensal E. coli. Deciphering the main components of AIEC virulence is cardinal to the discovery of the next generation of antimicrobials that can selectively eradicate CD-associated bacteria.

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Food insecurity (FI) is associated with obesity among women in high-income countries. This seemingly paradoxical association can be explained by the insurance hypothesis, which states that humans possess evolved mechanisms that increase fat storage to buffer against energy shortfall when access to food is unpredictable. The evolutionary logic underlying the insurance hypothesis is well established and experiments on animals confirm that exposure to unpredictable food causes weight gain, but the mechanisms involved are less clear. Drawing on data from humans and other vertebrates, we review a suite of behavioural and physiological mechanisms that could increase fat storage under FI. FI causes short-term hyperphagia, but evidence that it is associated with increased total energy intake is lacking. Experiments on animals suggest that unpredictable food causes increases in retained metabolizable energy and reductions in energy expenditure sufficient to fuel weight gain in the absence of increased food intake. Reducing energy expenditure by diverting energy from somatic maintenance into fat stores should improve short-term survival under FI, but the trade-offs potentially include increased disease risk and accelerated ageing. We conclude that exposure to FI plausibly causes increased adiposity, poor health and shorter lifespan. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women, characterized by hyperandrogenism, oligo-anovulation and insulin resistance and closely linked with preferential abdominal fat accumulation. As an ancestral primate trait, PCOS was likely further selected in humans when scarcity of food in hunter–gatherers of the late Pleistocene additionally programmed for enhanced fat storage to meet the metabolic demands of reproduction in later life. As an evolutionary model for PCOS, healthy normal-weight women with hyperandrogenic PCOS have subcutaneous (SC) abdominal adipose stem cells that favor fat storage through exaggerated lipid accumulation during development to adipocytes in vitro. In turn, fat storage is counterbalanced by reduced insulin sensitivity and preferential accumulation of highly lipolytic intra-abdominal fat in vivo. This metabolic adaptation in PCOS balances energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction; its accompanying oligo-anovulation allowed PCOS women from antiquity sufficient time and strength for childrearing of fewer offspring with a greater likelihood of childhood survival. Heritable PCOS characteristics are affected by today's contemporary environment through epigenetic events that predispose women to lipotoxicity, with excess weight gain and pregnancy complications, calling for an emphasis on preventive healthcare to optimize the long-term, endocrine-metabolic health of PCOS women in today's obesogenic environment. [ABSTRACT FROM AUTHOR]

Objective To investigate the metabolic adaptation of normal pregnancy and the pathogenesis of gestational diabetes mellitus (GDM) from the first to the third trimester. Methods　This was a case-control study. A total of 1 471 pregnant women who visited at the Department of Obstetrics of Peking University First Hospital in the first trimester from September 2017 to June 2018. Those with complete serum samples in the first, second and third trimester and who delivered in the hospital were taken as research objects. They were divided into a GDM group and a normal control group according to their glucose metabolism status. Fasting plasma glucose (FPG) and fasting insulin (FINS) in first, second and third trimester were detected, and 75 g oral glucose tolerance test (OGTT) was performed at 24 weeks and later to explore metabolic adaptation in pregnancy and the pathogenesis of GDM. Homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) were calculated. T-test and Mann-Whitney U test were used to compare between groups. Results　A total of 510 subjects were included in the study. There were 260 cases in GDM group and 250 cases in normal control group. In terms of blood glucose, FPG, 1 h-postprandial plasma glucose (1hPG) and 2 h-postprandial plasma glucose (2hPG) of 75g OGTT in GDM group were significantly higher than those in control group [5.14 (4.80, 5.34) vs 4.63 (4.43, 4.84), 9.56 (8.17, 10.48) vs 7.64 (6.57, 8.63), 8.05 (6.88, 9.08) vs 6.46 (5.82, 7.22) mmol/L, P<0.001]. The level of FPG in both GDM and normal control groups decreased gradually with gestational age (FPG of different trimesters were all P<0.017), but the level of FPG in GDM group was significantly higher than that in control group from first to third trimester [5.27 (4.99, 5.55) vs 5.10 (4.87, 5.30), 5.14 (4.80, 5.34) vs 4.63 (4.43, 4.84),4.77 (4.52, 5.08) vs 4.48 (4.31, 4.70) mmol/L, P<0.001]. In terms of insulin resistance and dynamic changes in islet beta cell function, all FINS levels, HOMA-IR and HOMA-β increased gradually from the first to the third trimester, peaking in the third trimester, whether GDM or normal control group. FINS in the second trimester and HOMA-IR from the first to the third trimester in GDM group were higher than those in control group (all P<0.05), whereas HOMA-β in the second and the third trimesters were lower than those in control group (all P<0.001). Conclusions　Physiological insulin resistance occurs in normal pregnancy, and beta cells compensate to maintain normal blood glucose. However, there was more severe insulin resistance and higher FPG in GDM group from the first trimester, and beta cell insufficiency in the second and third trimesters. It is suggested that although GDM is diagnosed in second trimester and later, its pathological and physiological abnormalities are already present in the first trimester. [ABSTRACT FROM AUTHOR]

In nature, carotenoids are present as trans- and cis-isomers. Various physical and chemical factors like light, heat, acids, catalytic agents, and photosensitizers can contribute to the isomerization of carotenoids. Living organisms in the process of evolution have developed different mechanisms of adaptation to light stress, which can also involve isomeric forms of carotenoids. Particularly, light stress conditions can enhance isomerization processes. The purpose of this work is to review the recent studies on cis/trans isomerization of carotenoids as well as the role of carotenoid isomers for the light capture, energy transfer, photoprotection in light-harvesting complexes, and reaction centers of the photosynthetic apparatus of plants and other photosynthetic organisms. The review also presents recent studies of carotenoid isomers for the biomedical aspects, showing cis- and trans-isomers differ in bioavailability, antioxidant activity and biological activity, which can be used for therapeutic and prophylactic purposes. [ABSTRACT FROM AUTHOR]

Uric acid is the main means of nitrogen excretion in uricotelic vertebrates (birds and reptiles) and the end product of purine catabolism in humans and a few other mammals. While uricase is inactivated in mammals unable to degrade urate, the presence of orthologous genes without inactivating mutations in avian and reptilian genomes is unexplained. Here we show that the Gallus gallus gene we name cysteine-rich urate oxidase (CRUOX) encodes a functional protein representing a unique case of cysteine enrichment in the evolution of vertebrate orthologous genes. CRUOX retains the ability to catalyze urate oxidation to hydrogen peroxide and 5-hydroxyisourate (HIU), albeit with a 100-fold reduced efficiency. However, differently from all uricases hitherto characterized, it can also facilitate urate regeneration from HIU, a catalytic property that we propose depends on its enrichment in cysteine residues. X-ray structural analysis highlights differences in the active site compared to known orthologs and suggests a mechanism for cysteine-mediated self-aggregation under H2O2-oxidative conditions. Cysteine enrichment was concurrent with the transition to uricotelism and a shift in gene expression from the liver to the skin where CRUOX is co-expressed with β-keratins. Therefore, the loss of urate degradation in amniotes has followed opposite evolutionary trajectories: while uricase has been eliminated by pseudogenization in some mammals, it has been repurposed as a redox-sensitive enzyme in the reptilian skin. [ABSTRACT FROM AUTHOR]

Abstract Background Caloric restriction (CR) has been known to promote health by reprogramming metabolism, yet little is known about how the epigenome and microbiome respond during metabolic adaptation to CR. Results We investigate chromatin modifications, gene expression, as well as alterations in microbiota in a CR mouse model. Collectively, short-term CR leads to altered gut microbial diversity and bile acid metabolism, improving energy expenditure. CR remodels the hepatic enhancer landscape at genomic loci that are enriched for binding sites for signal-responsive transcription factors, including HNF4α. These alterations reflect a dramatic reprogramming of the liver transcriptional network, including genes involved in bile acid metabolism. Transferring CR gut microbiota into mice fed with an obesogenic diet recapitulates the features of CR-related bile acid metabolism along with attenuated fatty liver. Conclusions These findings suggest that CR-induced microbiota shapes the hepatic epigenome followed by altered expression of genes responsible for bile acid metabolism.

Malignant pleural mesothelioma (MPM) is a lethal and rare cancer, even if its incidence has continuously increased all over the world. Asbestos exposure leads to the development of mesothelioma through multiple mechanisms, including chronic inflammation, oxidative stress with reactive oxygen species (ROS) generation, and persistent aberrant signaling. Together, these processes, over the years, force normal mesothelial cells' transformation. Chronic inflammation supported by "frustrated" macrophages exposed to asbestos fibers is also boosted by the release of pro-inflammatory cytokines, chemokines, growth factors, damage-associated molecular proteins (DAMPs), and the generation of ROS. In addition, the hypoxic microenvironment influences MPM and immune cells' features, leading to a significant rewiring of metabolism and phenotypic plasticity, thereby supporting tumor aggressiveness and modulating infiltrating immune cell responses. This review provides an overview of the complex tumor–host interactions within the MPM tumor microenvironment at different levels, i.e., soluble factors, metabolic crosstalk, and oxidative stress, and explains how these players supporting tumor transformation and progression may become potential and novel therapeutic targets in MPM. [ABSTRACT FROM AUTHOR]

T cells are critical players in adaptive immunity, driving the tissue injury and organ damage of patients with autoimmune diseases. Consequently, investigations on T cell activation, differentiation, and function are valuable in uncovering the disease pathogenesis, thus exploring promising therapeutics for autoimmune diseases. In recent decades, accumulating studies have pinpointed immunometabolism as the fundamental determinant in controlling T cell fate. Specifically, mitochondria, as a hub of intracellular metabolism, connect glucose, lipid, and amino acid metabolic pathways. Herein, we summarize metabolic adaptations of mitochondrial oxidative phosphorylation and the relevant glucose, lipid, and amino acid metabolism during T cell activation, differentiation, and function. Further, we focused on current updates of the molecular bases for metabolic reprogramming in autoimmune T cells and advances in exploring metabolic-targeted therapeutics against autoimmune diseases. This might facilitate the in-depth understanding of autoimmune pathogeneses and the clinical management of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Corticosteroids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and are routinely prescribed to breast cancer patients undergoing chemotherapy treatment to alleviate side effects. Triple-negative breast cancers (TNBCs) account for 15% to 20% of diagnoses and lack expression of estrogen and progesterone receptors as well as amplified HER2, but they often express high GR levels. GR is a mediator of TNBC progression to advanced metastatic disease; however, the mechanisms underpinning this transition to more aggressive behavior remain elusive. We previously showed that tissue/cellular stress (hypoxia, chemotherapies) as well as factors in the tumor microenvironment (transforming growth factor β [TGF-β], hepatocyte growth factor [HGF]) activate p38 mitogen-activated protein kinase (MAPK), which phosphorylates GR on Ser134. In the absence of ligand, pSer134-GR further upregulates genes important for responses to cellular stress, including key components of the p38 MAPK pathway. Herein, we show that pSer134-GR is required for TNBC metastatic colonization to the lungs of female mice. To understand the mechanisms of pSer134-GR action in the presence of GR agonists, we examined glucocorticoid-driven transcriptomes in CRISPR knock-in models of TNBC cells expressing wild-type or phospho-mutant (S134A) GR. We identified dexamethasone- and pSer134-GR-dependent regulation of specific gene sets controlling TNBC migration (NEDD9 , CSF1 , RUNX3) and metabolic adaptation (PDK4 , PGK1 , PFKFB4). TNBC cells harboring S134A-GR displayed metabolic reprogramming that was phenocopied by pyruvate dehydrogenase kinase 4 (PDK4) knockdown. PDK4 knockdown or chemical inhibition also blocked cancer cell migration. Our results reveal a convergence of GR agonists (ie, host stress) with cellular stress signaling whereby pSer134-GR critically regulates TNBC metabolism, an exploitable target for the treatment of this deadly disease. [ABSTRACT FROM AUTHOR]

Adequate protein intake is essential for the maintenance of whole-body protein mass. Different methodological approaches are used to substantiate the evidence for the current protein recommendations, and it is continuously debated whether older adults require more protein to counteract the age-dependent loss of muscle mass, sarcopenia. Thus, the purpose of this critical narrative review is to outline and discuss differences in the approaches and methodologies assessing the protein requirements and, hence, resulting in controversies in current protein recommendations for healthy older adults. Through a literature search, this narrative review first summarises the historical development of the Food and Agriculture Organization/World Health Organization/United Nations University setting of protein requirements and recommendations for healthy older adults. Hereafter, we describe the various types of studies (epidemiological studies and protein turnover kinetic measurements) and applied methodological approaches founding the basis and the different recommendations with focus on healthy older adults. Finally, we discuss important factors to be considered in future studies to obtain evidence for international agreement on protein requirements and recommendations for healthy older adults. We conclude by proposing future directions to determine 'true' protein requirements and recommendations for healthy older adults. [ABSTRACT FROM AUTHOR]

Objective: Metabolic and morphological adaptations of the intestine have been suggested to play a role in the various therapeutic benefits of Roux‐en‐Y Gastric Bypass (RYGB) surgery. However, the precise underlying mechanisms remain unclear. In this study, the effects of physical properties of ingested food and redirection of biliopancreatic secretions on intestinal remodeling were investigated in RYGB operated rats. Methods: RYGB employing two different Roux Limb (RL) lengths was performed on high fat diet induced obese rats. Post‐operatively, rats were fed either Solid or isocaloric Liquid diets. Metabolic and morphological remodeling of intestine was compared across both diet forms (Solid and Liquid diets) and surgical models (Short RL and Long RL). Results: RYGB surgery in rats induced weight loss and improved glucose tolerance which was independent of physical properties of ingested food and biliopancreatic secretions. Intestinal glucose utilization after RYGB was not determined by either food form or biliopancreatic secretions. The GLUT‐1 expression in RL was not influenced by physical properties of food. Furthermore, both physical properties of food and biliopancreatic secretions showed no effects on intestinal morphological adaptations after RYGB. Conclusion: Results of this study demonstrate that physical properties of food and bile redirection are not major determinants of intestinal remodeling after RYGB in rats. [ABSTRACT FROM AUTHOR]

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/β1 and αV/β5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.

Background: To date, there is limited consensus on post-contest recovery recommendations for natural physique athletes. The available literature emphasizes the negative consequences of extreme dieting associated with physique contests, yet offers only speculative suggestions to facilitate physiological recovery post-contest. This scoping review evaluates evidence-based recommendations for recovery in post-physique contests. Methods: The online search engines and databases Google Scholar, PubMed, and Scopus were searched systematically and 12 peer reviewed journal articles were included in the review. Results: Six key factors were identified that directly impacted on physiological recovery post-contest: (1) body composition, (2) recovery dietary intake, (3) resting metabolic rate (RMR) restoration, (4) endocrine measures recovery, (5) menstrual cycle recovery, and (6) psychological aspects of recovery. Conclusions: Three dietary strategies have been proposed to facilitate physiological recovery post-contest while bearing in mind body composition and future athlete outcomes; (1) a gradual increase in energy intake to maintenance requirements, (2) ad libitum eating, (3) an immediate return to maintenance energy requirements. Future research is required to determine the timeline in which full physiological recovery occurs post-contest and which strategies best support athlete health and performance during post-contest recovery.

Emerging research shows that innate immunity can also keep the memory of prior experiences, challenging the long-held notion that immunological memory is only the domain of the adaptive immune cells. However, the absence of immunological memory in innate immune responses has recently been brought into question. Now it is known that after a few transient activations, innate immune cells may acquire immunological memory phenotype, resulting in a stronger response to a subsequent secondary challenge. When exposed to particular microbial and/or inflammatory stimuli, trained innate immunity is characterized by the enhanced non-specific response, which is regulated by substantial metabolic alterations and epigenetic reprogramming. Trained immunity is acquired by two main reprogramming, namely, epigenetic reprogramming and metabolic adaptation/reprogramming. Epigenetic reprogramming causes changes in gene expression and cell physiology, resulting in internal cell signaling and/or accelerated and amplified cytokine release. Metabolic changes due to trained immunity induce accelerated glycolysis and glutaminolysis. As a result, trained immunity can have unfavorable outcomes, such as hyper inflammation and the development of cardiovascular diseases, autoinflammatory diseases, and neuroinflammation. In this review, the current scenario in the area of trained innate immunity, its mechanisms, and its involvement in immunological disorders are briefly outlined.

Abstract Background Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed. Methods Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness. Results Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC-3_DCX20 reacted to metformin with the Warburg effect; however, PC-3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial–mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress. Conclusions Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.