Metabolic Balance Research Articles

Investigation of Bottleneck Enzyme Through Flux Balance Analysis to Improve Glycolic Acid Production in Escherichia coli.

Amid rising environmental concerns, attempts have been made to produce glycolic acid (GA) using microbial processes with renewable carbon resources instead of using chemicals. The Dahms pathway for GA production uses xylose as a substrate and consists of relatively simple enzymatic steps. However, employing it leads to a decrease in cell growth and GA productivity. Systematically identifying and addressing metabolic bottlenecks in the Dahms pathway are essential for efficient glycolic acid (GA) production have not yet been performed. Through metabolic flux balance analysis, we found that insufficient aldehyde dehydrogenase (AldA) activity lowers GA production and negatively affects cell growth due to reduced energy production. Thus, we discovered a novel AldA isolated from Buttiauxella agrestis (BaAldA) demonstrated a 1.69-fold lower KM and a 1.49-fold higher turnover rate (kcat/KM) than AldA from Escherichia coli (EcAldA). GA production in E. coli harboring BaAldA was 1.59 times higher than in the original strain. Fed-batch fermentation of E. coli harboring BaAldA produced 22.70g/L GA with a yield of 0.497g/gxylose (98.2% of the theoretical maximum yield in the Dahms pathway), showing a higher final yield for GA than previously reported in E. coli. Our novel BaAldA enzyme shows great potential for the production of GA using microorganisms or enzymes. Furthermore, our approach to identifying metabolic bottlenecks using flux balance analysis could be utilized to enhance the microbial production of various desirable products in future studies.

Ranolazine therapy is associated with a reduced new diagnosis of diabetes mellitus in chronic coronary syndrome patients: the results of a real-world analysis of an Italian population

Abstract Background Ranolazine (Ran) is an anti-anginal drug acting as a late sodium current inhibitor at a cell membrane level. Some experimental and clinical studies showed an antihyperglycemic effect of the drug, possibly mediated by the increase of insulin secretion, the inhibition of glucagon release, and the protective action on beta-cell function. These effects, additive to the anti-anginal properties of Ran in patients with chronic coronary syndrome (CCS), could modulate and improve glucose metabolic balance. Indeed, data exploring at a population level the association of the drug with diabetes mellitus (DM) incidence are effectively lacking. Aims Aim of this study was to evaluate in CCS patients if the use of Ran, compared with other treatments (No-Ran), was associated with a lower incidence of DM in an Italian real-world clinical setting. Methods Patients included in the database of the National Health System were evaluated (N=6.1 million; about 10% of the Italian population); the recorded information concerned hospitalizations with the related diseases, clinical events, outpatient visits and drug therapy. Patients hospitalized for any cause and discharged with a diagnosis of angina between 2011 and 2020 (ICD-9-CM codes: 413-414) were included in the study after having proved the absence of DM in their medical history. Study population was divided into the Ran (at least one drug prescription) and in the No-Ran cohorts. The mean follow up was 4.3 years for the Ran and 5.0 years for the No-Ran cohorts, respectively. Results The study population included N=171,015 patients (mean age: 72 years, men: 66%). Among them, N=148,808 (No-Ran cohort) were treated with other therapies while N=22,207 (Ran cohort) received Ran. After propensity score matching, Ran (N=6,384) and No-Ran (N=25,536) cohorts did not differ for age, Charlson comorbidity index, use of aspirin and other antithrombotic agents, statins, beta-blockers, Ca-antagonists and nitrates. The incidence of a new diagnosis of DM during the follow-up period was 10.5 and 15.8% in the Ran and in the No-Ran cohorts, respectively (p<0.001). The Cox-regression analysis showed that Ran therapy was associated with a 30% risk reduction to present a new diagnosis of DM (HR=0.70, 95%CI: 0.64-0.76, p<0.001), independently of age, Charlson comorbidity index, heart failure, previous stroke, use of ivabradine, Ca-antagonists and nitrates. Conclusions This real-world study, performed in a whole subset of the Italian population, showed that, in the long-term, the incidence of a new DM diagnosis was lower in Ran users. This association could contribute to explain the benefits of the drug in patients with CCS.

Downregulation of CPEB3 exacerbates cardiac injury by inhibiting cardiomyocyte adaptive metabolic reprogramming after myocardial infarction

Abstract Background Adaptive metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis in hypoxia plays a protective role in cardiomyocyte survival by reducing reactive oxygen species (ROS) and increasing ATP. Cytoplasmic polyadenylation element binding protein 3 (CPEB3) influences protein translation by modulating 3' untranslated region (3'UTR) lengths through alternative polyadenylation (APA). However, the role of CPEB3 in cardiomyocyte after myocardial infarction (MI) remains unknown. Purpose This study aims to explore the function of CPEB3 in cardiomyocyte after MI. Methods Three GEO databases of mice MI (GSE110209, GSE114695 and GSE236374) were analyzed to identify CPEB3 dysregulation. Cardiomyocyte-specific CPEB3 knockout mice and CPEB3-knockdown neonatal mouse cardiomyocytes (NMCMs), RNA sequencing, flow cytometry, TUNEL staining, Seahorse, ROS and ATP measurements were used to investigate the impact of CPEB3. APA events analysis, RIP sequencing, CUT-TAG, 3’RACE, polysome profiling and dual luciferase report were performed to elucidate the mechanisms of CPEB3. Recombinant adeno-associated virus carrying cardiac troponin T promoter was used to evaluate the therapeutic efficacy of CPEB3 in mice with MI. Results CPEB3 expression was markedly reduced in the heart tissue after MI and in NMCMs after hypoxia. Cardiomyocyte-specific CPEB3 deletion aggravated cardiomyocyte apoptosis, enlarged infarct size, and exacerbated cardiac injury after MI. RNA sequencing revealed that CPEB3 deficiency predominantly inhibited glycolysis-related pathway, with a notable decrease in pyruvate dehydrogenase kinase 1 (PDK1) expression. In CPEB3-knockdown NMCMs, adaptive metabolic reprogramming from OXPHOS to glycolysis and ATP level were decreased in hypoxia, whereas ROS production was significantly enhanced, all of which resulted in apoptosis and were regulated by PDK1. Besides, PDK1 overexpression counteracted the effects of CPEB3 knockdown on metabolic pattern, ROS, ATP and apoptosis. Mechanistically, CPEB3 deficiency led to a shortened 3’UTR of the transcription factor forkhead box O3 (FOXO3), and a decline of FOXO3 protein level. CPEB3 protein was confirmed to directly bind to FOXO3 mRNA, and the translation efficiency of FOXO3 was decreased with CPEB3 knockdown. Furthermore, FOXO3 was found to activate the transcription of PDK1, and FOXO3 overexpression alleviated the decline of PDK1 and attenuated CPEB3 knockdown-induced apoptosis in hypoxia. Finally, cardiomyocyte-specific CPEB3 overexpression reduced cardiomyocyte apoptosis, suppressed myocardial fibrosis, and improved cardiac function by upregulating FOXO3 and PDK1 levels after MI. Conclusion CPEB3 could promote FOXO3 protein expression via APA of FOXO3 3’UTR, activate transcription of PDK1 and ultimately protect cardiomyocyte from apoptosis by restoring metabolic balance in hypoxia. CPEB3 may serve as a promising therapeutic target for cardiomyocyte apoptosis after MI.Schematic diagram

Bergamot (Citrus bergamia), a (Poly)Phenol-Rich Source for Improving Osteosarcopenic Obesity: A Systematic Review

This systematic review investigates the potential of bergamot, a polyphenol-rich citrus fruit, in improving osteosarcopenic obesity, a condition characterized by the simultaneous presence of osteoporosis, obesity, and sarcopenia. Bergamot extracts have been suggested to possess several pharmacological properties, including anti-inflammatory and antioxidant effects, which could be useful in the management of age-related diseases and neuromuscular health. The review highlights the promising effects of bergamot extracts on skeletal muscle mass and function, particularly in the context of obesity, metabolic syndrome, osteosarcopenic obesity, and osteoporosis. Furthermore, some studies have shown that bergamot extracts can improve the metabolic balance, endothelial function, and maximal oxygen uptake in athletes, highlighting their potential benefits for skeletal muscle health. Taken together, these results suggest that bergamot extracts, especially those rich in polyphenols, may be a valuable adjunct in the management of osteosarcopenic obesity and other associated clinical conditions involving pro-inflammatory effects on organs and tissues.

Exploring the Dynamic Changes of Brain Lipids, Lipid Rafts, and Lipid Droplets in Aging and Alzheimer’s Disease

Aging induces complex changes in the lipid profiles across different areas of the brain. These changes can affect the function of brain cells and may contribute to neurodegenerative diseases such as Alzheimer’s disease. Research shows that while the overall lipid profile in the human brain remains quite steady throughout adulthood, specific changes occur with age, especially after the age of 50. These changes include a slow decline in total lipid content and shifts in the composition of fatty acids, particularly in glycerophospholipids and cholesterol levels, which can vary depending on the brain region. Lipid rafts play a crucial role in maintaining membrane integrity and facilitating cellular signaling. In the context of Alzheimer’s disease, changes in the composition of lipid rafts have been associated with the development of the disease. For example, alterations in lipid raft composition can lead to increased accumulation of amyloid β (Aβ) peptides, contributing to neurotoxic effects. Lipid droplets store neutral lipids and are key for cellular energy metabolism. As organisms age, the dynamics of lipid droplets in the brain change, with evidence suggesting a decline in metabolic activity over time. This reduced activity may lead to an imbalance in lipid synthesis and mobilization, contributing to neurodegenerative processes. In model organisms like Drosophila, studies have shown that lipid metabolism in the brain can be influenced by diet and insulin signaling pathways, crucial for maintaining metabolic balance. The interplay between lipid metabolism, oxidative stress, and inflammation is critical in the context of aging and Alzheimer’s disease. Lipid peroxidation, a consequence of oxidative stress, can lead to the formation of reactive aldehydes that further damage neurons. Inflammatory processes can also disrupt lipid metabolism, contributing to the pathology of AD. Consequently, the accumulation of oxidized lipids can affect lipid raft integrity, influencing signaling pathways involved in neuronal survival and function.

Unleashing the Power of Cold Atmospheric Plasma: Inducing Mitochondria Damage-Mediated Mitotic Catastrophe.

Despite the promise of cold atmospheric plasma (CAP) for cancer treatment, the challenges associated with the treatment of solid tumors and penetration depth limitations remain, restricting its clinical application. Here, biological evidence is provided that the killing effect of CAP treatment is confined to less than 500µm subcutaneously and the actual biological dose decreased gradually with depth for the first time, indicating that the limited penetration depth has become an urgent problem that demands immediate solutions. Significantly, it is showed that different from high-dose treatments, CAP decreased the doses to the low-dose range but still exhibited anti-tumor effects via mitotic catastrophe. Unlike radiotherapy or chemotherapy, low-dose CAP treatment induces mitochondrial structural damage and dysfunction, disrupts energy metabolism and redox balance, and results in mitotic catastrophe. Collectively, these findings suggest that better understanding and taking full advantage of the dose-response gradient effect of CAP is a potential strategy to prompt its clinical application beyond improving CAP penetration.

Synergistic role of prebiotics and probiotics in gut microbiome health: Mechanisms and clinical applications

AbstractPrebiotic and probiotic usage has exploded, with most formulations promoting gastrointestinal and immunological benefits. Prebiotics modulate the gut microbiota, as a result, short‐chain fatty acids are released into the bloodstream. Prebiotics have immunomodulatory properties that reduce inflammation while enhancing immune responses and boosting gut health. The potential of probiotics has shown steady expansion in the digestive system, metabolic balance, and vaginal health. Probiotics offer therapeutic and preventative strategies for a range of human diseases. The in vitro studies suggested the delivery matrix might influence their effects through physicochemical interactions with molecular and cellular structures as well as modifications in cellular expression. Dietary fibers and polyphenols both contribute significantly to human health protection and can ferment in the gut microbiota to create butyrate. This comprehensive review aims to highlight the probiotics and prebiotics, and provide evidence to support their use in preventive and therapeutic medicine. It is anticipated that it will help the clinical and preclinical research to look into the effects of inclusion and processing on their activity in different food delivery formulations. There are potential opportunities needed to enhance immunological and digestive health by comprehending and using the interaction between the gut microbiota and the immune system in our diet.

Pancreatic β-Cells, Diabetes and Autophagy.

Pancreatic β-cells play a critical role in regulating plasma insulin levels and glucose metabolism balance, with their dysfunction being a key factor in the progression of diabetes. This review aims to explore the role of autophagy, a vital cellular self-maintenance process, in preserving pancreatic β-cell functionality and its implications in diabetes pathogenesis. We examine the current literature on the role of autophagy in β-cells, highlighting its function in maintaining cell structure, quantity, and function. The review also discusses the effects of both excessive and insufficient autophagy on β-cell dysfunction and glucose metabolism imbalance. Furthermore, we discuss potential therapeutic agents that modulate the autophagy pathway to influence β-cell function, providing insights into therapeutic strategies for diabetes management. Autophagy acts as a self-protective mechanism within pancreatic β-cells, clearing damaged organelles and proteins to maintain cellular stability. Abnormal autophagy activity, either overactive or deficient, can disrupt β-cell function and glucose regulation, contributing to diabetes progression. Autophagy plays a pivotal role in maintaining pancreatic β-cell function, and its dysregulation is implicated in the development of diabetes. Targeting the autophagy pathway offers potential therapeutic strategies for diabetes management, with agents that modulate autophagy showing promise in preserving β-cell function.

Regulation of Mitochondrial and Peroxisomal Metabolism in Female Obesity and Type 2 Diabetes.

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role. Mitochondria and peroxisomes are vital organelles responsible for lipid and energy regulation, including the β-oxidation and oxidation of very long-chain fatty acids (VLCFAs), cholesterol biosynthesis, and bile acid metabolism. These processes are significantly influenced by estrogens, highlighting the interplay between these organelles' function and hormonal regulation in the development and progression of metabolic diseases, such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and T2D. Estrogens modulate lipid metabolism through interactions with nuclear receptors, like peroxisome proliferator-activated receptors (PPARs), which are crucial for maintaining metabolic balance. Estrogen deficiency, such as in postmenopausal women, impairs PPAR regulation, leading to lipid accumulation and increased risk of metabolic disorders. The disruption of peroxisomal-mitochondrial function and estrogen regulation exacerbates lipid imbalances, contributing to insulin resistance and ROS accumulation. This review emphasizes the critical role of these organelles and estrogens in lipid metabolism and their implications for metabolic health, suggesting that therapeutic strategies, including hormone replacement therapy, may offer potential benefits in treating and preventing metabolic diseases.

Actions of thyroid hormones and thyromimetics on the liver.

Thyroid hormones (triiodothyronine and thyroxine) are pivotal for metabolic balance in the liver and entire body. Dysregulation of the hypothalamus-pituitary-thyroid axis can contribute to hepatic metabolic disturbances, affecting lipid metabolism, glucose regulation and protein synthesis. In addition, reductions in circulating and intrahepatic thyroid hormone concentrations increase the risk of metabolic dysfunction-associated steatotic liver disease by inducing lipotoxicity, inflammation and fibrosis. Amelioration of hepatic metabolic disease by thyroid hormones in preclinical and clinical studies has spurred the development of thyromimetics that target THRB (the predominant thyroid hormone receptor isoform in the liver) and/or the liver itself to provide more selective activation of hepatic thyroid hormone-regulated metabolic pathways while reducing thyrotoxic side effects in tissues that predominantly express THRA such as the heart and bone. Resmetirom, a liver and THRB-selective thyromimetic, recently became the first FDA-approved drug for metabolic dysfunction-associated steatohepatitis (MASH). Thus, a better understanding of the metabolic actions of thyroid hormones and thyromimetics in the liver is timely and clinically relevant. Here, we describe the roles of thyroid hormones in normal liver function and pathogenesis of MASH, as well as some potential clinical issues that might arise when treating patients with MASH with thyroid hormone supplementation or thyromimetics.

Assessing Human Iron Kinetics Using Stable Iron Isotopic Techniques.

Stable iron isotope techniques are critical for developing strategies to combat iron deficiency anemia, a leading cause of global disability. There are four primary stable iron isotope methods to assess ferrokinetics in humans. (i) The fecal recovery method applies the principles of a metabolic balance study but offers enhanced accuracy because the amount of iron isotope present in feces can be directly traced back to the labeled dose, distinguishing it from endogenous iron lost in stool from shed intestinal cells. (ii) In the plasma isotope appearance method, plasma samples are collected for several hours after oral dosing to evaluate the rate, quantity, and pattern of iron absorption. Key metrics include the time of peak isotope concentration and the area under the curve. (iii) The erythrocyte iron incorporation method measures iron bioavailability (absorption and erythrocyte iron utilization) from a whole blood sample collected 2 weeks after oral dosing. Simultaneous administration of oral and intravenous tracers allows for separate measurements of iron absorption and iron utilization. These threemethods determine iron absorption by measuring tracer concentrations in feces, serum, or erythrocytes after administration of a tracer. In contrast, (iv) in iron isotope dilution, an innovative new approach, iron of natural composition acts as the tracer, diluting an ad hoc modified isotopic signature obtained via prior isotope administration and equilibration with body iron. This technique enables highly accurate long-term studies of iron absorption, loss, and gain. This review discusses the application of these kinetic methods and their potential to address important questions in hematology andiron biology.

Tracing links between micronutrients and type 2 diabetes risk: the singular role of selenium.

Type 2 diabetes (T2D) is a growing global health concern. While micronutrients are crucial for physiological functions and metabolic balance, their precise links to T2D are not fully understood. We investigated the causal relationships between 15 key micronutrients and T2D risk using both univariate and multivariate Mendelian randomization (MR) methods. Our analysis leveraged data from a large prospective cohort genome-wide association study (GWAS) on these micronutrients and T2D. We employed MR techniques such as inverse variance weighting (IVW), MR Egger, weighted median, and simple models. Multivariate analysis adjusted for diabetes-related factors like body mass index (BMI) and hypertension to assess the independent effects of micronutrients, particularly selenium, on T2D risk. Selenium intake was associated with an increased risk of T2D, with an odds ratio (OR) of 1.045, a 95% confidence interval (CI) ranging from 1.009 to 1.082, and a P-value of 0.015. This association was consistent in multivariate analyses, suggesting an independent effect of selenium on T2D risk after adjusting for confounders. Our study presents novel evidence of a positive correlation between selenium intake and T2D risk, underscoring the importance of micronutrients in diabetes prevention and treatment strategies. Further research is necessary to confirm these findings and to clarify the specific biological mechanisms through which selenium influences diabetes risk.

The Gut Microbiome in Sepsis: From Dysbiosis to Personalized Therapy

Sepsis is a complex clinical syndrome characterized by an uncontrolled inflammatory response to an infection that may result in septic shock and death. Recent research has revealed a crucial link between sepsis and alterations in the gut microbiota, showing that the microbiome could serve an essential function in its pathogenesis and prognosis. In sepsis, the gut microbiota undergoes significant dysbiosis, transitioning from a beneficial commensal flora to a predominance of pathobionts. This transformation can lead to a dysfunction of the intestinal barrier, compromising the host’s immune response, which contributes to the severity of the disease. The gut microbiota is an intricate system of protozoa, fungi, bacteria, and viruses that are essential for maintaining immunity and metabolic balance. In sepsis, there is a reduction in microbial heterogeneity and a predominance of pathogenic bacteria, such as proteobacteria, which can exacerbate inflammation and negatively influence clinical outcomes. Microbial compounds, such as short-chain fatty acids (SCFAs), perform a crucial task in modulating the inflammatory response and maintaining intestinal barrier function. However, the role of other microbiota components, such as viruses and fungi, in sepsis remains unclear. Innovative therapeutic strategies aim to modulate the gut microbiota to improve the management of sepsis. These include selective digestive decontamination (SDD), probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT), all of which have shown potential, although variable, results. The future of sepsis management could benefit greatly from personalized treatment based on the microbiota. Rapid and easy-to-implement tests to assess microbiome profiles and metabolites associated with sepsis could revolutionize the disease’s diagnosis and management. These approaches could not only improve patient prognosis but also reduce dependence on antibiotic therapies and promote more targeted and sustainable treatment strategies. Nevertheless, there is still limited clarity regarding the ideal composition of the microbiota, which should be further characterized in the near future. Similarly, the benefits of therapeutic approaches should be validated through additional studies.

Gene Enrichment and Pathway Analysis for Ketosis Resistance in Dairy Cattle: A GWAS-Based Approach

Ketosis in dairy cattle is a common metabolic disorder that arises during the transition period from late gestation to early lactation. It is primarily caused by an imbalance between energy intake and expenditure, leading to an excessive accumulation of ketone bodies. This condition can significantly affect cattle health and productivity. Recent advances in genomic research, especially genome-wide association studies (GWAS), offer an opportunity to explore the genetic factors that contribute to ketosis resistance. The aim of this study is to comprehensively review and analyze existing GWAS data using gene enrichment analysis to identify potential functional candidate gene pathways associated with ketosis resistance in dairy cattle. In this study, data obtained from seven different studies were examined and 640 non-repetitive genes were obtained after filtering. Using Enrichr, an online tool for gene annotation, pathway analysis was performed with human homologs of the identified genes. Our findings highlight the acylglycerol homeostasis pathway, the regulation of triglyceride metabolism, and the role of chylomicrons in maintaining metabolic balance during ketosis. Additionally, immune response pathways were found to be linked to the genes associated with ketosis, offering insights into the intricate interplay between metabolic and immune pathways in ketosis. This study emphasizes the importance of understanding genetic factors in developing breeding strategies aimed at enhancing metabolic health and productivity in dairy cattle. Future research should focus on validating these candidate genes and exploring their mechanistic roles to facilitate targeted interventions and improve resistance to ketosis in dairy herds.

Application Evaluation and Performance-Directed Improvement of the Native and Engineered Biosensors.

Transcription factor (TF)-based biosensors (TFBs) have received considerable attention in various fields due to their capability of converting biosignals, such as molecule concentrations, into analyzable signals, thereby bypassing the dependence on time-consuming and laborious detection techniques. Natural TFs are evolutionarily optimized to maintain microbial survival and metabolic balance rather than for laboratory scenarios. As a result, native TFBs often exhibit poor performance, such as low specificity, narrow dynamic range, and limited sensitivity, hindering their application in laboratory and industrial settings. This work analyzes four types of regulatory mechanisms underlying TFBs and outlines strategies for constructing efficient sensing systems. Recent advances in TFBs across various usage scenarios are reviewed with a particular focus on the challenges of commercialization. The systematic improvement of TFB performance by modifying the constituent elements is thoroughly discussed. Additionally, we propose future directions of TFBs for developing rapid-responsive biosensors and addressing the challenge of application isolation. Furthermore, we look to the potential of artificial intelligence (AI) technologies and various models for programming TFB genetic circuits. This review sheds light on technical suggestions and fundamental instructions for constructing and engineering TFBs to promote their broader applications in Industry 4.0, including smart biomanufacturing, environmental and food contaminants detection, and medical science.

CISD3 is a prognostic biomarker and therapeutic target in pan-cancer.

Recent studies indicate that CISD3 is crucial in mitochondrial function and tumorigenesis. Using various databases, we systematically analyzed its expression, prognostic value, and immune activity. Our findings show CISD3 is mainly expressed in tumor cells across cancers, with higher mRNA but lower protein levels, degraded post-translationally via the lysosomal pathway. In certain cancers, CISD3 expression is positively correlated with tumor-infiltrating immune cells. Prognostic analysis suggests dual roles as both protective and risk factors, notably an independent prognostic predictor in renal cell carcinoma (RCC). CISD3 copy number variations are linked to homologous recombination defects and tumor-specific neoantigens, negatively correlated with methylation levels. Pathway analysis reveals CISD3 involvement in oncogenic processes, such as proliferation inhibition and epithelial-mesenchymal transition. Protein interactions underline its role in mitochondrial metabolism and redox balance. Experiments confirm low CISD3 expression in cancers, with overexpression reducing proliferation, migration, invasion, and tumor growth in mice. Mechanistic studies indicate CISD3 overexpression disrupts mitochondrial function, increases ROS levels, decreases GSH/GSSG ratios and mitochondrial membrane potential, inhibiting antioxidant activity and promoting cell damage and ferroptosis, thus impeding cancer progression. This study highlights CISD3's potential as a prognostic biomarker and therapeutic target.

Bioorthogonal Regulated Metabolic Balance for Promotion of Ferroptosis and Mild Photothermal Therapy.

The nanozyme with NADPH oxidase (NOX)-like activity can promote the consumption of NADPH and the generation of free radicals. In consideration of that the upregulation of glucose-6-phosphate dehydrogenase (G6PD) would accelerate the compensation production of NADPH, for inhibition of G6PD activity, our designed bioorthogonal nanozyme can in situ catalyze pro-DHEA to produce G6PD inhibitor and dehydroepiandrosterone (DHEA) drugs to inhibit G6PD activity. Therefore, the well-defined platform can disrupt NADPH homeostasis, leading to the collapse of the antioxidant defense system in the tumor cells. The enzyme-like activity of PdCuFe is further enhanced when irradiated by NIR-II light. The destruction of NADPH homeostasis can promote ferroptosis and, in turn, facilitate mild photothermal therapy. Our design can realize NADPH depletion and greatly improve the therapeutic effect through metabolic regulation, which may provide inspiration for the design of bioorthogonal catalysis.

Ozone-Induced Lung Injury are Mediated Via PPAR-Mediated Ferroptosis in Mice.

In recent years, the concentration of PM2.5 in China has decreased, while the concentration of ozone remains rising. Exposure to ozone contributes to respiratory illnesses; however, little is known about the underlying molecular mechanisms. The present study established an ozone-induced lung injury mice model to investigate potential molecular biomarkers and toxic mechanisms. Collected and analyzed the ozone pollution data in Xinxiang city from 2015 to 2022. At the same time, 24 male C57BL/6 mice were randomly assigned to control group and ozone exposure group. The ozone exposure concentration is 1ppm, with 4h of daily exposure for 33 consecutive days. HE staining was used to assess lung histological alterations and lung injury. High-throughput sequencing performed on the lung tissues of mice was used to analyze the differential expressed genes and signal transduction pathways. Xinxiang city is suffering from ozone pollution, especially in summer. HE staining showed that the ozone exposure could induce obvious inflammatory cell infiltration, alveolar wall thickening, or fracture. Transcriptome data revealed that there is a 145 differentially expressed genes between two groups and the genes enriched in PPAR signaling pathway, ferroptosis. The pivotal genes in the PPAR pathway including Adipoq, Lpl, Pck1, and Plin1 expression were significantly reduced. Additionally, the expression of Acsl6 and Scl7a11, which are close to PPAR pathway and ferroptosis has decreased. Ozone exposure could disrupt the lipid metabolism balance via downregulating lipid peroxidation-related genes through the PPAR signaling pathway, which further induced lung cell ferroptosis and aggravated lung injury in mice.

Sustainable ferritin from bovine by-product liver as a potential resource: Ultrasound assisted extraction and physicochemical, structural, functional, and stable analysis

Ferritin is an iron-containing protein that is widely present in all organisms and has the function of regulating the metabolic balance of iron in organisms. It can be separated from animal by-product tissues and converted into value-added components to promote the development of a circular economy. This study established a method for extracting bovine liver ferritin (BLFer) using ultrasound-assisted buffer system. The optimal extraction conditions were determined through single factor and response surface optimization experiments as follows: ultrasound temperature of 70 °C, extraction time of 25 min, ultrasonic power of 400 W and solvent-to-solid ratio of 2 mL/g, the experimental value of the ferritin yield was 32.18 ± 0.12 g/kg. Compared with traditional methods, Ultrasound-assisted extraction improved the ferritin yield and enhanced its structural stability. Bioinformatics analysis revealed that BLFer is a hydrophilic protein with strong thermal stability. The BLFer has a ferrous oxidase active center, which plays an important role in the oxidative precipitation and reductive release of iron. It can dissociate under strong acids or bases but maintains good stability after heat treatment. These findings will help improve the comprehensive utilization of animal by-products, and promote the potential application of animal by-product ferritin in food and other industries.

Engineering Halomonas bluephagenesis for Synthesis of Polyhydroxybutyrate (PHB) in the Presence of High Nitrogen Containing Media

The trade-offs exist between microbial growth and bioproduct synthesis including intracellular polyester polyhydroxybutyrate (PHB). Under nitrogen limitation, more carbon flux is directed to PHB synthesis while growth is inhibited with diminishing overall carbon utilization, similar to the suboptimal carbon utilization during glycolysis-derived pyruvate decarboxylation. This study reconfigured the central carbon network of Halomonas bluphagenesis to improve PHB yield theoretically and practically. It was found that the downregulation of glutamine synthetase (GS) activity led to a synchronous improvement on PHB accumulation and cell growth under nitrogen non-limitation condition, increasing the PHB yield from glucose (g/g) to 85% of theoretical yield, PHB titer from 7.6 g/L to 12.9 g/L, and from 51 g/L to 65 g/L when grown in shake flasks containing a rich N-source, and grown in a fed-batch cultivation conducted in a 7-L bioreactor also containing a rich N-source, respectively. Results offer better metabolic balance between glucose conversion efficiency and microbial growth for economic PHB production.