Regulation Of Metabolism Research Articles

Evolutionary conservation and metabolic significance of autophagy in algae.

Autophagy is a highly conserved 'self-digesting' mechanism used in eukaryotes to degrade and recycle cellular components by enclosing them in a double membrane compartment and delivering them to lytic organelles (lysosomes or vacuoles). Extensive studies in plants have revealed how autophagy is intricately linked to essential aspects of metabolism and growth, in both normal and stress conditions, including cellular and organelle homeostasis, nutrient recycling, development, responses to biotic and abiotic stresses, senescence and cell death. However, knowledge regarding autophagic processes in other photosynthetic organisms remains limited. In this review, we attempt to summarize the current understanding of autophagy in algae from a metabolic, molecular and evolutionary perspective. We focus on the composition and conservation of the autophagy molecular machinery in eukaryotes and discuss the role of autophagy in metabolic regulation, cellular homeostasis and stress adaptation in algae. This article is part of the theme issue 'The evolution of plant metabolism'.

Spatiotemporal characterization of extracellular matrix maturation in human artificial stromal-epithelial tissue substitutes

Abstract Background Tissue engineering techniques offer new strategies to understand complex processes in a controlled and reproducible system. In this study, we generated bilayered human tissue substitutes consisting of a cellular connective tissue with a suprajacent epithelium (full-thickness stromal-epithelial substitutes or SESS) and human tissue substitutes with an epithelial layer generated on top of an acellular biomaterial (epithelial substitutes or ESS). Both types of artificial tissues were studied at sequential time periods to analyze the maturation process of the extracellular matrix. Results Regarding epithelial layer, ESS cells showed active proliferation, positive expression of cytokeratin 5, and low expression of differentiation markers, whereas SESS epithelium showed higher differentiation levels, with a progressive positive expression of cytokeratin 10 and claudin. Stromal cells in SESS tended to accumulate and actively synthetize extracellular matrix components such as collagens and proteoglycans in the stromal area in direct contact with the epithelium (zone 1), whereas these components were very scarce in ESS. Regarding the basement membrane, ESS showed a partially differentiated structure containing fibronectin-1 and perlecan. However, SESS showed higher basement membrane differentiation, with positive expression of fibronectin 1, perlecan, nidogen 1, chondroitin-6-sulfate proteoglycans, agrin, and collagens types IV and VII, although this structure was negative for lumican. Finally, both ESS and SESS proved to be useful tools for studying metabolic pathway regulation, revealing differential activation and upregulation of the transforming growth factor-β pathway in ESS and SESS. Conclusions These results confirm the relevance of epithelial-stromal interaction for extracellular matrix development and differentiation, especially regarding basement membrane components, and suggest the usefulness of bilayered artificial tissue substitutes to reproduce ex vivo the extracellular matrix maturation and development process of human tissues. Graphical Abstract

Synthetic Biology-Enabled Engineering of Probiotics for Precision and Targeted Therapeutic Delivery Applications

Probiotics, defined as live microorganisms that offer health benefits when consumed in adequate amounts, have traditionally been used to maintain gastrointestinal (GI) health. They are effective in managing conditions such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and antibiotic-associated diarrhea. Recent research, however, has expanded their potential applications beyond the GI tract to include immune modulation, metabolic regulation, and mental health support. Despite these advances, conventional probiotics face limitations such as instability in harsh environments, lack of precise targeting, and ineffective control over drug release. This review explores the application of synthetic biology in addressing these limitations, emphasizing how tools such as CRISPR-Cas systems, synthetic gene circuits, and plasmid-based mechanisms enhance the stability, functionality, and specificity of engineered probiotics for therapeutic delivery. Applications of synthetic biology-enabled probiotics are examined across a range of health contexts, including GI health, cancer therapy, metabolic disorders, immune modulation, and mental well-being. Synthetic biology tools provide precise genetic modifications that improve the stability, viability, and functionality of engineered probiotics, enabling more targeted therapeutic delivery. Additionally, technologies such as encapsulation support probiotic survival, while gene circuits allow programmable, stimulus-responsive therapeutic release. As synthetic biology continues to advance, the development of programmable probiotics holds promise for personalized, targeted medicine, positioning probiotics as living therapeutics and patient-friendly alternatives to conventional therapeutic delivery systems.

CORRELATION OF LEPTIN AND ADIPONECTIN LEVELS WITH METABOLIC AND HORMONAL PROFILES IN PCOS PATIENTS: A COMPARATIVE STUDY WITH NORMAL CONTROLS

Objective: Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder characterized by metabolic and reproductive abnormalities, including insulin resistance and hyperandrogenism. Leptin and adiponectin, two adipokines involved in metabolic regulation, are known to be dysregulated in PCOS. This study aims to investigate the correlation between leptin and adiponectin levels and their association with metabolic and hormonal profiles in PCOS patients compared to healthy controls. Methods: A prospective, observational study was conducted involving 120 women diagnosed with PCOS and 50 healthy controls. Leptin and adiponectin levels were measured using enzyme-linked immunosorbent assay (ELISA). The adiponectin-to-leptin ratio (ALR) was calculated, and correlations with BMI, LH/FSH ratio, and other metabolic parameters were analyzed. Data were analyzed using appropriate statistical methods. Results: Leptin levels were significantly higher in the PCOS group compared to controls (25.34 ng/ml vs. 11.16 ng/ml, p<0.0001), while adiponectin levels were significantly lower (2.93 mcg/ml vs. 21.44 mcg/ml, p<0.0001). The adiponectin-to-leptin ratio was markedly reduced in PCOS patients (0.13 vs. 2.05, p<0.0001). A significant correlation was observed between the adiponectin/leptin ratio and the LH/FSH ratio (r = 0.2138, p = 0.019). Conclusion: This study highlights the dysregulation of leptin and adiponectin in PCOS, suggesting their potential role in metabolic and reproductive dysfunction. The adiponectin-to-leptin ratio emerges as a promising biomarker for insulin resistance and metabolic risk in PCOS patients.

Multi-Omics and Physiological Analysis Reveal Crosstalk Between Aphid Resistance and Nitrogen Fertilization in Wheat.

The availability of nitrogen (N) can dramatically influence crops resistance to herbivorous insects. However, the interaction between N fertilization and crop resistance to insects is not well understood. In this study, the effects of N fertilization on the grain aphid (Sitobion miscanthi) were investigated using three wheat (Triticum aestivum) cultivars with different aphid resistances. We measured aphid life cycle parameters, fecundity, survival rate, weight and feeding behavior, in conjunction with wheat metabolomics, transcriptomics and alien introgression analysis. Our results demonstrated that higher N application benefits aphid feeding across all three wheat cultivars. We also reveal that the highly resistant cultivar (ZM9) can only exert its resistance-advantage under low N fertilization, losing its advantage compared to moderately resistant cultivar YN19 and susceptible cultivar YN23 under higher N fertilization. The effects of N fertilization on wheat-aphid interactions were due to changes in the regulation of carbon and nitrogen metabolism. Integration of multi-omics highlighted specific aphid-induced differentially expressed genes (DEGs, e.g., TUB6, Tubulin 6; ENODL20, Early nodulin-like protein 20; ACT7 Actin 7; Prx47, Peroxidase 47) and significantly different metabolites (SDMs, e.g., crotonoside, guanine, 2'-O-methyladenosine, ferulic acid) in ZM9. Additionally, we report the unique SDMs-DEGs interactions, associated with introgression during wheat domestication, may help infer aphid resistance. In summary, this study provides new insights into the relationships between N fertilization practices, defense responses and integrated pest management for sustainable wheat production.

The effects of PstR, a PadR family transcriptional regulatory factor, in Plesiomonas shigelloides are revealed by transcriptomics.

Plesiomonas shigelloides is a gram-negative opportunistic pathogen associated with gastrointestinal and extraintestinal diseases in humans. There have been reports of specific functional genes in the study of P. shigelloides, but there are also many unknown genes that may play a role in P. shigelloides pathogenesis as global regulatory proteins or virulence factors. In this study, we found a transcriptional regulator of the PadR family in P. shigelloides and named it PstR (GenBank accession number: EON87311.1), which is present in various pathogenic bacteria but whose function has rarely been reported. RNA sequencing (RNA-Seq) was used to analyze the effects of PstR on P. shigelloides, and the results indicated that PstR regulates approximately 9.83% of the transcriptome, which includes impacts on motility, virulence, and physiological metabolism. RNA-seq results showed that PstR positively regulated the expression of the flagella gene cluster, which was also confirmed by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Luminescence screening assay. Meanwhile, the ΔpstR mutant strains lacked flagella and were non-motile, as confirmed by motility assays and transmission electron microscopy (TEM). Additionally, PstR also positively regulates T3SS expression, which aids in P. shigelloides' capacity to infect Caco-2 cells. Meanwhile, we also revealed that PstR negatively regulates fatty acid degradation and metabolism, as well as the regulatory relationship between PsrA, a regulator of fatty acid degradation and metabolism, and its downstream genes in P. shigelloides. Overall, we revealed the effects of PstR on motility, virulence, and physiological metabolism in P. shigelloides, which will serve as a foundation for future research into the intricate regulatory network of PstR in bacteria.

CDH2 and CDH13 as potential prognostic and therapeutic targets for adrenocortical carcinoma

ABSTRACT Cadherin 2 (CDH2, N-cadherin) and cadherin 13 (CDH13, T-cadherin, H-cadherin) affect the progress and prognoses of many cancers. However, their roles in adrenocortical carcinoma (ACC), a rare endocrine cancer, remain unclear. To decipher the roles of these proteins in ACC and to identify their regulatory targets, we analyzed their expression levels, gene regulatory networks, prognostic value, and targets in ACC, using various bioinformatic analyses. CDH2 was strongly downregulated and CDH13 was strongly upregulated in patients with ACC; the expression levels of these genes affected the prognosis. In 75 patients, the expression of CDH2 and CDH13 was altered by 8% and 5%, respectively. CDH2 and CDH13, as well as their neighboring genes, were predicted to form a complex network of interactions, mainly through coexpression and physical and genetic interactions. CDH2 and its altered neighboring genes (ANGs) mainly affect tumor-related gene expression, cell cycle, and energy metabolism. The regulation of tumor-related integrin function, gene transcription, metabolism, and amide and phospholipid metabolism are the main functions of CDH13 and its ANGs. MiRNA and kinase targets of CDH2 and CDH13 in ACC were identified. CDH13 expression in patients with ACC was positively associated with immune cell infiltration. Anti-PD1/CTLA-4/PD-L1 immunotherapy significantly downregulated the expression of CDH13 in patients with ACC. Foretinib and elesclomol were predicted to exert strong inhibitory effects on SW13 cells by inhibiting the expression of CDH2 and CDH13. These data indicate that CDH2 and CDH13 are promising targets for precise treatment of ACC and may serve as new biomarkers for ACC prognosis.

Tetramethylpyrazine inhibits ferroptosis in spinal cord injury by regulating iron metabolism through the NRF2/ARE pathway

BackgroundTetramethylpyrazine (TMP) is a natural alkaloid compound with antioxidant and neuroprotective effects. We hypothesized that TMP could exert neuroprotective effects by inhibiting ferroptosis through modulating iron metabolism, but its mechanism is unclear. Through in vivo and in vitro experiments, we have explored how TMP can regulate neurons’ iron metabolism through the NRF2/ARE pathway to Inhibit ferroptosis.MethodsIn the in vivo experiment, the effects of TMP on nerve function and secondary spinal cord injury were observed through behavioral tests and morphology staining. Transmission electron microscopy, molecular biology tests and immunofluorescence staining were used to investigate the role of TMP in the regulation of iron metabolism and ferroptosis through the Nrf2/ARE pathway. Using in vitro experiments to investigate the mechanism of TMP in inhibiting ferroptosis through the Nrf2/ARE pathway.ResultsFirstly, through in vivo experiments, we found that TMP improves motor function of rats with spinal cord injury, reduces spinal cord tissue damage and nerve cell death caused by secondary injury. Moreover, neuronal death and the formation of spinal cord cavities are inhibited by TMP. By regulating lipid peroxidation, TMP can inhibit mitochondrial damage and reduce ROS accumulation. Our study also demonstrated that TMP regulates iron metabolism through the NRF2/ARE pathway to inhibit ferroptosis and repair spinal cord injury. To further explore the regulatory mechanisms of TMP we down-regulating Nrf2 expression in subsequent in vitro experiments. We find that a key ferroptosis pathway, lipid peroxidation, can be regulated by TMP. Additionally, TMP inhibits iron overload-mediated ferroptosis by increasing Nrf2 transcriptional activity.ConclusionA regulatory effect of TMP on the NRF2/ARE pathway was found in both in vitro and in vivo experiments. It promotes the transcription and translation of iron metabolizing and antioxidant molecules. Our study explored the inhibitory effect of TMP on ferroptosis from the iron metabolism pathway and provided new ideas for the treatment of SCI.

Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms

Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that exerts cytoprotective effects in response to oxidative stressors and is associated with longevity. Using a mouse model of hemorrhagic shock that mimics the clinical condition of adult patients, we investigated whether treatment with a humanin analog, humanin-G, mitigates lung injury and whether its mechanisms of action are dependent on the catalytic AMPKα1 subunit activation. Methods: Male and female AMPKα1 wild-type (WT) and knock-out (KO) mice (8–13 months old) were subjected to hemorrhagic shock by blood withdrawal, followed by resuscitation with shed blood and lactated Ringer’s solution. The mice were treated with PEGylated humanin-G or vehicle and euthanized 3 h post-resuscitation. Results: Sex- and genotype-related differences were observed after hemorrhagic shock as lung neutrophil infiltration was more pronounced in the male AMPKα1 WT mice than the female WT mice; also, the male AMPKα1 KO mice experienced a significant decline in mean arterial blood pressure when compared to the male WT mice after resuscitation. The scores of histological lung injury were similarly elevated in all the male and female AMPKα1 WT and KO mice when compared to the control mice. At molecular analysis, acute lung injury was associated with the downregulation of AMPKα1/α2 catalytic subunits in the WT mice, whereas an increased activation of the signal transducer and activator of transcription-3 (STAT3) was observed in all the vehicle-treated groups. The in vivo administration of humanin-G ameliorated histological lung damage in all the groups of animals and ameliorated mean arterial blood pressure in the male AMPKα1 KO mice. The in vivo administration of humanin-G lowered lung neutrophil infiltration in the male and female AMPKα1 WT mice only but not in the KO mice. The beneficial results of humanin-G correlated with the lung cytosolic and nuclear activation of AMPKα in the male and female AMPKα1 WT groups, whereas STAT3 activation was not modified. Conclusions: In adult age, hemorrhage-induced acute lung injury manifests with sex-dependent characteristics. Humanin-G has therapeutic potential and the AMPKα1subunit is an important requisite for its inhibitory effects on lung leucosequestration, but not for the amelioration of lung alveolar structure or the hemodynamic effects of the peptide.

Transcriptional Responses of Lacticaseibacillus rhamnosus to TNFα, IL-6, IL-8, and IL-10 Cytokines

The interaction between gut microbiota and the host immune system is a complex and understudied field, with cytokines like TNFα, IL-6, IL-8, and IL-10 playing pivotal roles. Commensal bacteria, including lactobacilli, respond to these cytokines through adaptive mechanisms that support their survival and function within the gut. While the influence of cytokines on pathogenic bacteria is well documented, their impact on commensal bacteria, particularly lactobacilli, remains underexplored. This study investigates the transcriptional responses of Lacticaseibacillus rhamnosus strains K32 and R19-3 to various cytokines using next-generation RNA sequencing (RNA-seq). Our findings reveal that cytokines, especially IL-8 and IL-10, significantly alter the L. rhamnosus transcriptome, affecting genes involved in carbohydrate metabolism, stress response, and transcriptional regulation. Notably, IL-8 and IL-10 induce a significant downregulation of genes related to the phosphotransferase system, suggesting a reduction in metabolic activity in response to inflammatory signals. This study unveils a previously unexplored aspect of L. rhamnosus adaptation, highlighting its intricate response to cytokine signals. By modulating gene expression, L. rhamnosus may mitigate the adverse effects of inflammation and promote gut health. These insights could inform the development of targeted probiotic therapies for inflammatory bowel disease (IBD) and other conditions with altered cytokine levels. Our results suggest that co-evolution between a host and gut microbiota enables bacteria to respond to specific cytokines through gene expression changes, revealing a unique and underexplored facet of the interaction between commensal bacteria and the host organism.

Succinate exacerbates mastitis in mice via extracellular vesicles derived from the gut microbiota: a potential new mechanism for mastitis.

A high grain diet causes an ecological imbalance in the gut microbiota and serves as an important endogenous trigger of mastitis in dairy cows, but the underlying mechanisms are unclear. Our previous study revealed that subacute rumen acidosis (SARA)-associated mastitis has distinct metabolic profiles in the rumen, especially a significant increase in succinate, but the role of succinate in the pathogenesis of mastitis remains unclear. Succinate treatment exacerbates low-grade endotoxemia-induced mastitis in mice. Specifically, succinate increased the production of gut microbiota-extracellular vehicles (mEVs) containing lipopolysaccharides, which can diffuse across the damaged intestinal barrier into the mammary glands. Administration of mEVs promotes mammary inflammation via activation of the TLR4/NF-κB pathway. Our findings suggest that succinate promotes mastitis through the proliferation of enteric pathogens and mEVs production, suggesting a potential strategy for mastitis intervention on the basis of intestinal metabolic regulation and pathogen inhibition. The role of mEVs in interspecific communication has also been elucidated.

Interfacing Complex Coacervates with Natural Cells

Coacervates have been investigated as protocells or synthetic cells, as well as subcellular compartments for the creation of new materials, thus bridging the gap between living and non‐living systems in materials science, synthetic biology, and bioengineering. Given the design flexibility and simplicity of coacervates, along with the functionality and complexity of natural cells, the interfacing of complex coacervates with natural cells is considered significant for various biotechnological and biomedical applications. In this review, the fundamental mechanisms and underlying theories of coacervate systems are introduced. Recent efforts to interface coacervates with natural cells are summarized in three key scenarios: (i) the integration of coacervates with natural cell components for the living material assembly into protocells; (ii) communication between therapeutic synthetic cells and natural cells for drug delivery and cell repair; and (iii) the formation of intracellular condensates for metabolic regulation, followed by the regulation of their phase transitions for pathological elucidation. Finally, the potential of coacervate‐natural cell interfaces is discussed in the context of developing living/synthetic cell constructs, creating precise disease therapy strategies, and advancing programmable metabolic engineering networks.

Critical radicle length window governing loss of dehydration tolerance in germinated Perilla seeds: insights from physiological and transcriptomic analyses.

Perilla (Perilla frutescens L. Britt.) is an important oilseed and medicinal crop that frequently faces seasonal drought stress during seed germination, leading to a loss of dehydration tolerance (DT), which affects seed emergence and significantly reduces yield. DT has been successfully re-established for many species seeds. However, the physiological mechanisms and gene networks that regulate Perilla's response to DT loss remain unclear. Phenotypic analysis determined that the window for DT in Perilla seeds occurs at radicle lengths of 0-4mm. Integrating physiological and transcriptomic analyses revealed that the loss of DT promotes the production of reactive oxygen species (ROS) and regulates oxidase activity and gene expression. This implies that DT may influence seed germination by modulating ROS activity. Four radicle length (i.e., 0, 1, 3, and 4mm) stages were analyzed, and 262 differentially expressed genes (DEGs) were identified that responded to DT. The majority of these genes were associated with epigenetics, cell function, and transport mechanisms. Analysis of expression data shows that desiccation inhibits the signaling network of genes encoding small secreted peptides (SSPs) and receptor-like protein kinases (RLKs). Finally, a relevant network diagram of DT response was proposed. Based on this information, we have revealed the metabolism regulation maps of the four main pathways involving these DEGs (i.e., metabolic pathways, cell cycle, plant hormone signal transduction, and motor proteins). In conclusion, these findings deepen our understanding of gene network responses to DT during Perilla seed germination and provide potential target genes for the genetic improvement of drought resistance in this crop.

Lactylation and Ischemic Stroke: Research Progress and Potential Relationship.

Ischemic stroke is caused by interrupted cerebral blood flow and is a leading cause of mortality and disability worldwide. Significant advancements have been achieved in comprehending the pathophysiology of stroke and the fundamental mechanisms responsible for ischemic damage. Lactylation, as a newly discovered post-translational modification, has been reported to participate in several physiological and pathological processes. However, research on lactylation and ischemic stroke is scarce. This review summarized the current function of protein lactylation in other diseases or normal physiological processes and explored their potential link with the pathophysiological process and the reparative mechanism of ischemic stroke. We proposed that neuroinflammation, regulation of metabolism, regulation of messenger RNA translation, angiogenesis, and neurogenesis might be the bridge linking lactylation and ischemic stroke. Our study provided a novel perspective for comprehending the role of protein lactylation in the pathophysiological processes underlying ischemic stroke. Lactylation might be a promising target in drug development of ischemic stroke.

Therapeutic Modulation of the Microbiome in Oncology: Current Trends and Future Directions.

Cancer is a predominant cause of mortality worldwide, necessitating the development of innovative therapeutic techniques. The human microbiome, particularly the gut microbiota, has become a significant element in cancer research owing to its essential role in sustaining health and influencing disease progression. This review examines the microbiome's makeup and essential functions, including immunological modulation and metabolic regulation, which may be evaluated using sophisticated methodologies such as metagenomics and 16S rRNA sequencing. The microbiome influences cancer development by promoting inflammation, modulating the immune system, and producing carcinogenic compounds. Dysbiosis, or microbial imbalance, can undermine the epithelial barrier and facilitate cancer. The microbiome influences chemotherapy and radiation results by modifying drug metabolism, either enhancing or reducing therapeutic efficacy and contributing to side effects and toxicity. Comprehending these intricate relationships emphasises the microbiome's significance in oncology and accentuates the possibility for microbiome-targeted therapeutics. Contemporary therapeutic approaches encompass the utilisation of probiotics and dietary components to regulate the microbiome, enhance treatment efficacy, and minimise unwanted effects. Advancements in research indicate that personalised microbiome-based interventions, have the potential to transform cancer therapy, by providing more effective and customised treatment alternatives. This study aims to provide a comprehensive analysis of the microbiome's influence on the onset and treatment of cancer, while emphasising current trends and future possibilities for therapeutic intervention.

Chronobiological disruptions: unravelling the interplay of shift work, circadian rhythms, and vascular health in the context of stroke risk.

Shift work, particularly night shifts, disrupts circadian rhythms and increases stroke risk. This manuscript explores the mechanisms connecting shift work with stroke, focusing on circadian rhythms, hypertension, and diabetes. The circadian system, controlled by different mechanisms including central and peripheral clock genes, suprachiasmatic nuclei (SCN), and pineal gland (through melatonin production), regulates body functions and responds to environmental signals. Disruptions in this system affect endothelial cells, leading to blood pressure issues. Type 2 diabetes mellitus (T2DM) is significantly associated with night shifts, with circadian disturbances affecting glucose metabolism, insulin sensitivity, and hormone regulation. The manuscript examines the relationship between melatonin, insulin, and glucose balance, highlighting pathways that link T2DM to stroke risk. Additionally, dyslipidemia, particularly reduced HDL-c levels, results from shift work and contributes to stroke development. High lipid levels cause oxidative stress, inflammation, and endothelial dysfunction, increasing cerebrovascular risks. The manuscript details the effects of dyslipidemia on brain functions, including disruptions in blood flow, blood-brain barrier integrity, and neural cell death. This comprehensive analysis emphasizes the complex interplay of circadian disruption, hypertension, diabetes, and dyslipidemia in increasing stroke risk among shift workers. Understanding these mechanisms is essential for developing targeted interventions to reduce stroke susceptibility and improve cerebrovascular health in this vulnerable population.

Metabolic Regulation of Inflammation: Exploring the Potential Benefits of Itaconate in Autoimmune Disorders.

Itaconic acid and its metabolites have demonstrated significant therapeutic potential in various immune diseases. Originating from the tricarboxylic acid cycle in immune cells, itaconic acid can modulate immune responses, diminish inflammation, and combat oxidative stress. Recent research has uncovered multiple mechanisms through which itaconic acid exerts its effects, including the inhibition of inflammatory cytokine production, activation of anti-inflammatory pathways, and modulation of immune cell function by regulating cellular metabolism. Cellular actions are influenced by the modulation of metabolic pathways, such as inhibiting succinate dehydrogenase (SDH) activity or glycolysis, activation of nuclear-factor-E2-related factor 2 (Nrf2), boosting cellular defences against oxidative stress, and suppression of immune cell inflammation through the NF-κB pathway. This comprehensive review discusses the initiation, progression, and mechanisms of action of itaconic acid and its metabolites, highlighting their modulatory effects on various immune cell types. Additionally, it examines their involvement in immune disease like rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and autoimmune hepatitis, offering greater understanding for creating new therapies for these ailments.

Unveiling tryptophan dynamics and functions across model organisms via quantitative imaging.

Tryptophan is an essential amino acid involved in critical cellular processes in vertebrates, serving as a precursor for serotonin and kynurenine, which are key neuromodulators to influence neural and immune functions. Systematic and quantitative measurement of tryptophan is vital to understanding these processes. Here, we utilized a robust and highly responsive green ratiometric indicator for tryptophan (GRIT) to quantitatively measure tryptophan dynamics in bacteria, mitochondria of mammalian cell cultures, human serum, and intact zebrafish. At the cellular scale, these quantitative analyses uncovered differences in tryptophan dynamics across cell types and organelles. At the whole-organism scale, we revealed that inflammation-induced tryptophan concentration increases in zebrafish brain led to elevated serotonin and kynurenine levels, prolonged sleep duration, suggesting a novel metabolic connection between immune response and behavior. Moreover, GRIT's application in detecting reduced serum tryptophan levels in patients with inflammation symptoms suggests its potential as a high-throughput diagnostic tool. In summary, this study introduces GRIT as a powerful method for studying tryptophan metabolism and its broader physiological implications, paving the way for new insights into the metabolic regulation of health and disease across multiple biological scales.

BS O02 - Impact of Bariatric surgery on Obesity Indices and Reproductive Hormones: A Prospective Study in Morbidly Obese Women

Abstract Background Obesity, defined by a BMI of 30 kg/m² or higher, is influenced by genetics, socio-economic, and cultural factors. Genetic predispositions affect metabolism and energy regulation, while environmental factors like sedentary lifestyles and poor food environments worsen obesity. Obesity disrupts hormonal balances, impacting sex hormone levels and menstrual cycles, leading to infertility in women. This hormonal imbalance affects oocyte quality and ovulation. Bariatric surgery offers significant weight loss and metabolic improvements, enhancing reproductive hormone profiles and insulin sensitivity. Our study explores how sleeve gastrectomy affects BMI and hormone levels, aiming to understand its impact on obesity management and reproductive health. Method This prospective observational study examines the effects of laparoscopic sleeve gastrectomy on reproductive hormones and ovarian function in 32 morbidly obese women, adhering to Helsinki Declaration ethics. Participants, aged 18-50 with no menopause or chronic illness, consented to the study. Exclusions included those with polycystic ovary syndrome, recent reproductive organ surgery, or recent infertility medications. The study assessed changes in BMI, antral follicles, anti-Müllerian hormone, and reproductive hormones before surgery and at 6 and 12 months post-surgery. Blood samples and transvaginal ultrasounds were conducted preoperatively and at 6 and 12 months postoperatively to monitor outcomes. Results The study involved participants with an average age of 33 and a mean BMI of 42.12. Significant changes were observed post-sleeve gastrectomy at 6 and 12 months (p < 0.001). At 6 months, BMI decreased by 9.24 units, AMH levels dropped from 3 to 2.5 ng/mL, and antral follicle counts in both ovaries declined. By 12 months, BMI decreased by 16.47 units, AMH levels fell to 2 ng/mL, and antral follicle counts further reduced. Hormonal changes included increases in FSH, LH, and estradiol, while SHBG levels rose, and free testosterone levels decreased significantly. Conclusion Individual hormone responses to weight loss and surgery necessitate personalized obesity treatments. Tailoring surgical approaches and care to hormonal profiles can optimize outcomes and reduce complications. Monitoring AMH levels post-surgery can offer insights into reproductive effects, aiding clinical management and counseling for women with obesity-related infertility. We highlight the significant impact of sleeve gastrectomy on physiological parameters in obese individuals, especially regarding reproductive health and metabolic regulation. The findings enhance understanding of the changes associated with bariatric surgery and its potential benefits for metabolic and reproductive health.

Lactylation of Hdac1 regulated by Ldh prevents the pluripotent-to-2C state conversion.

Cellular metabolism regulates the pluripotency of embryonic stem cells (ESCs). Yet, how metabolism regulates the transition among different pluripotent states remains elusive. It has been shown that protein lactylation, which uses lactate, a metabolic product of glycolysis, as a substrate, plays a critical role in various biological events. Here we focused on that glycolysis regulates the conversion between ESCs and 2-cell-like cells (2CLCs) through protein lactylation. RNA-seq revealed the activation of 2-cell (2C) genes by suppression of Ldh. Stable isotope labeling by amino acids in cell culture (SILAC) coupled with lactylated peptide enrichment and quantitative mass spectrometric analysis was carried out to investigate the mechanism how protein lactylation regulates the pluripotent-to-2C transition. And we focused on Hdac1. Lactylation of Hdac1 required for silencing 2C genes was proved by quantitative reverse-transcription PCR (qRT-PCR), immunofluorescence (IF), Western blot and chimeric embryos. Chromatin immunoprecipitation coupled with sequencing (ChIP-seq) and in vitro deacetylation assay confirmed lactylation of Hdac1 promoting its binding at 2C genes and enhancing its deacetylase activity, thereby facilitating the removal of H3K27ac and the silencing of 2C genes. We found that inhibition or depletion of Ldha, the enzyme converting pyruvate to lactate, leads to the activation of 2C genes, as well as reduced global lactylation in ESCs. To investigate the mechanism how protein lactylation regulates the pluripotent-to-2C transition, quantitative lactylome analysis was performed, and 1716 lactylated proteins were identified. We then focused on Hdac1, a histone deacetylase involved in the silencing of 2C genes. Lactylation of Hdac1 promotes its binding at 2C genes and enhances its deacetylase activity, thus facilitating the removal of H3K27ac and the silencing of 2C genes. In summary, our study reveals a mechanistic link between cellular metabolism and pluripotency regulation through protein lactylation. Our research is the first time to reveal that quantitative lactylome analysis in mouse ESCs. We found that lactylated Hdac1 promotes its binding at 2C genes and enhances its deacetylase activity, thus facilitating the removal of H3K27ac and the silencing of 2C genes.