Metabolite regulation of epigenetics in cancer.

The catalytic activity of most epigenetic enzymes requires a metabolite produced by central carbon metabolism as a cofactor or (co-)substrate. The concentrations of these metabolites undergo dynamic changes in response to nutrient levels and environmental conditions, reprogramming metabolic processes and epigenetic landscapes. Abnormal accumulations of epigenetic modulatory metabolites resulting from mutations in metabolic enzymes contribute to tumorigenesis. In this review, we first present the concept that metabolite regulation of gene expression represents an evolutionarily conserved mechanism from prokaryotes to eukaryotes. We then review how individual metabolites affect epigenetic enzymes and cancer development. Lastly, we discuss the advancement of and opportunity for therapeutic targeting of metabolite-epigenetic regulation in cancer therapy.

TET2 promotes tumor antigen presentation and T cell IFN-γ which is enhanced by vitamin C.

Immune evasion by tumors is promoted by low T cell infiltration, ineffective T cell activity directed against the tumor and reduced tumor antigen presentation. The TET2 DNA dioxygenase gene is frequently mutated in hematopoietic malignancies and loss of TET enzymatic activity is found in a variety of solid tumors. We showed previously that vitamin C (VC), a co-factor of TET2, enhances tumor-associated T cell recruitment and checkpoint inhibitor therapy responses in a TET2-dependent manner. Using single-cell RNA sequencing (scRNA-seq) analysis performed on B16-OVA melanoma tumors, we have shown here that an additional function for TET2 in tumors is to promote expression of certain antigen presentation machinery genes, which is potently enhanced by VC. Consistently, VC promoted antigen presentation in cell-based and tumor assays in a TET2-dependent manner. Quantifying intercellular signaling from the scRNA-seq dataset showed that T cell-derived IFNγ-induced signaling within the tumor and tumor microenvironment requires tumor-associated TET2 expression which is enhanced by VC treatment. Analysis of patient tumor samples indicated that TET activity directly correlates with antigen-presentation gene expression and with patient outcomes. Our results demonstrate the importance of tumor-associated TET2 activity as a critical mediator of tumor immunity which is augmented by high-dose VC therapy.

Safety and Effectiveness of Drug-Eluting Embolic Bronchial Arterial Chemoembolization for Lung Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To assess the efficacy and safety of drug-eluting embolic bronchial arterial chemoembolization (DEE-BACE) in lung cancer, and to compare its outcomes with those of conventional bronchial arterial chemoembolization (cBACE). MATERIALS AND METHODS: A comprehensive search was conducted across PubMed, Embase, Cochrane Library, Web of Science, CNKI, VIP, and Wanfang databases. Random-effects model analysis was applied when I2 was ≥ 50%; otherwise, fixed-effects model analysis was used. Subgroup analysis was performed for I2 values ≥ 50%. Eighteen studies involving 681 patients were included, with 501 patients receiving DEE-BACE and 110 patients undergoing cBACE. RESULTS: Among lung cancer patients treated with DEE-BACE, the pooled objective response rates (ORRs) at 1, and 6 months were 64.4%, and 50.3%, respectively; the disease control rates (DCRs) were 93.4%, 74.4%, and 71.7%, respectively. The 1-year overall survival (OS) and progression-free survival (PFS) rate were 48.2%, and 22.5%, respectively. The incidence of adverse events was less than 50%. Compared with the cBACE group, the DEE-BACE group exhibited higher 1-month DCR [pooled relative risk (RR): 1.236, 95% confidence interval (CI): 1.028, 1.486), 6-month (pooled RR: 2.036, 95%CI: 1.226, 3.383) ORR and DCR (pooled RR: 1.824, 95%CI 1.249, 2.662). Both DEE-BACE and cBACE exhibited similar rates of adverse events. CONCLUSION: DEE-BACE presents a favorable efficacy and safety profile for lung cancer treatment compared with cBACE, particularly for nonresectable cases or when chemotherapy or radiation therapy options are limited. However, the lack of direct comparisons to standard treatments require cautious interpretation of these results.

Retrospective Analysis of Radiofrequency Ablation in Patients with Small Solitary Hepatocellular Carcinoma: Survival Outcomes and Development of a Machine Learning Prognostic Model.

BACKGROUND AND OBJECTIVE: The effectiveness of radiofrequency ablation (RFA) in improving long-term survival outcomes for patients with a solitary hepatocellular carcinoma (HCC) measuring 5 cm or less remains uncertain. This study was designed to elucidate the impact of RFA therapy on the survival outcomes of these patients and to construct a prognostic model for patients following RFA. METHODS: This study was performed using the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2017, focusing on patients diagnosed with a solitary HCC lesion ≤5 cm in size. We compared the overall survival (OS) and cancer-specific survival (CSS) rates of these patients with those of patients who received hepatectomy, radiotherapy, or chemotherapy or who were part of a blank control group. To enhance the reliability of our findings, we employed stabilized inverse probability treatment weighting (sIPTW) and stratified analyses. Additionally, we conducted a Cox regression analysis to identify prognostic factors. XGBoost models were developed to predict 1-, 3-, and 5-year CSS. The XGBoost models were evaluated via receiver operating characteristic (ROC) curves, calibration plots, decision curve analysis (DCA) curves and so on. RESULTS: Regardless of whether the data were unadjusted or adjusted for the use of sIPTWs, the 5-year OS (46.7%) and CSS (58.9%) rates were greater in the RFA group than in the radiotherapy (27.1%/35.8%), chemotherapy (32.9%/43.7%), and blank control (18.6%/30.7%) groups, but these rates were lower than those in the hepatectomy group (69.4%/78.9%). Stratified analysis based on age and cirrhosis status revealed that RFA and hepatectomy yielded similar OS and CSS outcomes for patients with cirrhosis aged over 65 years. Age, race, marital status, grade, cirrhosis status, tumor size, and AFP level were selected to construct the XGBoost models based on the training cohort. The areas under the curve (AUCs) for 1, 3, and 5 years in the validation cohort were 0.88, 0.81, and 0.79, respectively. Calibration plots further demonstrated the consistency between the predicted and actual values in both the training and validation cohorts. CONCLUSION: RFA can improve the survival of patients diagnosed with a solitary HCC lesion ≤5 cm. In certain clinical scenarios, RFA achieves survival outcomes comparable to those of hepatectomy. The XGBoost models developed in this study performed admirably in predicting the CSS of patients with solitary HCC tumors smaller than 5 cm following RFA.

Temsirolimus inhibits FSP1 enzyme activity to induce ferroptosis and restrain liver cancer progression.

Ferroptosis is a non-apoptotic mode of cell death characterized by iron-dependent accumulation of lipid peroxidation. While lipid radical elimination reaction catalyzed by glutathione peroxidase 4 (GPX4) is a major anti-ferroptosis mechanism, inhibiting this pathway pharmaceutically shows promise as an anti-tumor strategy. However, certain tumor cells exhibit redundancy in lipid radical elimination pathways, rendering them unresponsive to GPX4 inhibitors. In this study, we conducted screens across different cancer cell lines and FDA-approved drugs, leading to the identification of temsirolimus in combination with the GPX4 inhibitor RSL3 as a potent inducer of ferroptosis in liver cancer cells. Mechanistically, temsirolimus sensitized liver cancer cells to ferroptosis by directly binding to and inhibiting ferroptosis suppressor protein 1 (FSP1) enzyme. Notably, while temsirolimus is recognized as a potent mTOR inhibitor, its ferroptosis-inducing effect is primarily attributed to its inhibition of FSP1 rather than mTOR activity. By performing in vitro colony formation assays and in vivo tumor xenograft models, we demonstrated that the combination of temsirolimus and RSL3 effectively suppressed liver tumor progression. This tumoricidal effect was associated with increased lipid peroxidation and induction of ferroptosis. In conclusion, our findings underscore the potential of combining multi-target ferroptosis-inducing agents to circumvent resistance to ferroptosis in liver cancer cells and highlight temsirolimus as a promising FSP1 inhibitor and ferroptosis inducer, which also deserves further investigation in translational medicine.

US-based radiomics analysis of different machine learning models for differentiating benign and malignant BI-RADS 4A breast lesions.

RATIONALE AND OBJECTIVES: To investigate and authenticate the effectiveness of various radiomics models in distinguishing between benign and malignant BI-RADS 4A lesions. METHODS: A total of 936 patients with pathologically confirmed 4A lesions were included in the study (training cohort: n = 655; test cohort: n = 281). Radiomic features were derived from greyscale US images. Following dimensionality reduction and feature selection, radiomics models were developed using logistic regression (LR), support vector machine (SVM), random forest (RF), eXtreme gradient boosting (XGBoost) and multilayer perceptron (MLP) algorithms. Univariate and multivariable logistic regression analyses were employed to investigate clinical-radiological characteristics and determine variables for creating a clinical model. Five combined models integrating radiomic and clinical parameters were constructed by using each algorithm, and comparison with radiologists' performance was performed. SHapley Additive exPlanations (SHAP) approach was used to elucidate the radiomic model by ranking the significance of features based on their contribution to the evaluation. RESULTS: A total of 1561 radiomic features were extracted. Thirty-six features were deemed significant by dimensionality reduction and selection. The radiomic models showed good performance with AUCs of 0.829-0.945 in training cohort; and 0.805-0.857 in test cohort. The combined model developed by using LR showed the best performance (AUC, training cohort: 0.909; test cohort: 0.905), which is superior to radiologists' performance. Decision curve analysis (DCA) of this combined model indicated better clinical efficacy than clinical and radiomic models. CONCLUSIONS: The combined model integrating radiomic and clinical features demonstrated excellent performance in differentiating between benign and malignant 4A lesions. It may offer a non-invasive and efficient approach to aid in clinical decision-making.

Preparation of fibre-reinforced PLA-collagen@PLA-PCL@PCL-gelatin three-layer vascular graft by EDC/NHS cross-linking and its performance study.

In this study, a three-layer small diameter artificial vascular graft with a structure similar to that of natural blood vessels was first constructed by triple-step electrospinning technology, in which polylactic acid (PLA) and collagen (COL) were used for the inner layer, polylactic acid and polycaprolactone (PCL) was used for the middle layer and polycaprolactone and gelatin was used for the outer layer. The properties of the artificial vascular graft were adjusted by the EDC/NHS cross-linking agent through the reaction between the collagen or gelatine and EDC/NHS. The mechanical and hydrophilic properties of the cross-linked artificial vessels were substantially enhanced, with a maximum stress of 9.56 MPa in the axial direction and 9.31 MPa in the radial direction for the P/C (4:1) vascular graft, which exceeded that of many textile-based and natural vascular grafts. The increased hydrophilicity of the inner layer of the vessel before crosslinking was due to the addition of COL, and the inner layer of the artificial vessel after crosslinking had a substantial increase in hydrophilicity due to the production of a more hydrophilic urea derivative. The increased hydrophilicity led to easier cell adhesion to the inner layer of the artificial vessel, especially for the P/C (2:1) vascular graft, where the cell proliferation rate and adhesion were high due to COL incorporation and cross-linking. The three-layer vascular grafts studied did not lead to haemolysis. Therefore, the EDC/NHS cross-linked three-layer vascular graft had good mechanical properties, hydrophilicity, anticoagulation and could enhance cell adhesion and proliferation.

Corrigendum: Quercetin suppresses ovariectomy-induced osteoporosis in rat mandibles by regulating autophagy and the NLRP3 pathway.

[This corrects the article DOI: 10.1177/15353702231211977.].

PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress.

Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment.

Noncanonical assembly, neddylation and chimeric cullin-RING/RBR ubiquitylation by the 1.8 MDa CUL9 E3 ligase complex.

Ubiquitin ligation is typically executed by hallmark E3 catalytic domains. Two such domains, 'cullin-RING' and 'RBR', are individually found in several hundred human E3 ligases, and collaborate with E2 enzymes to catalyze ubiquitylation. However, the vertebrate-specific CUL9 complex with RBX1 (also called ROC1), of interest due to its tumor suppressive interaction with TP53, uniquely encompasses both cullin-RING and RBR domains. Here, cryo-EM, biochemistry and cellular assays elucidate a 1.8-MDa hexameric human CUL9-RBX1 assembly. Within one dimeric subcomplex, an E2-bound RBR domain is activated by neddylation of its own cullin domain and positioning from the adjacent CUL9-RBX1 in trans. Our data show CUL9 as unique among RBX1-bound cullins in dependence on the metazoan-specific UBE2F neddylation enzyme, while the RBR domain protects it from deneddylation. Substrates are recruited to various upstream domains, while ubiquitylation relies on both CUL9's neddylated cullin and RBR domains achieving self-assembled and chimeric cullin-RING/RBR E3 ligase activity.

Itaconate in host inflammation and defense.

Immune cells undergo rapid and extensive metabolic changes during inflammation. In addition to contributing to energetic and biosynthetic demands, metabolites can also function as signaling molecules. Itaconate (ITA) rapidly accumulates to high levels in myeloid cells under infectious and sterile inflammatory conditions. This metabolite binds to and regulates the function of diverse proteins intracellularly to influence metabolism, oxidative response, epigenetic modification, and gene expression and to signal extracellularly through binding the G protein-coupled receptor (GPCR). Administration of ITA protects against inflammatory diseases and blockade of ITA production enhances antitumor immunity in preclinical models. In this article, we review ITA metabolism and its regulation, discuss its target proteins and mechanisms, and conjecture a rationale for developing ITA-based therapeutics to treat inflammatory diseases and cancer.

Gestational Intermittent Hypoxia Enhances Mammary Stem Cells and Alters Tumor Phenotype in Adult Female Offspring.

An adverse perinatal environment can increase long-term cancer risk, although the precise nature of associated perinatal triggers remain unknown. Sleep apnea is a common condition during pregnancy, characterized by recurrent cessations in breathing during sleep, and the potential consequences of sleep apnea during pregnancy as it relates to breast cancer risk in offspring have not been explored. To model sleep apnea, Sprague-Dawley dams were exposed during gestation to nightly intermittent hypoxia (GIH) or normoxia (GNx), and the mammary glands of female offspring were examined. GIH offspring demonstrated increased epithelial stem and progenitor cell populations, which are associated with diminished transforming growth factor beta (TGFß) activity. Elevations in adipose tissue stem cells in the mammary gland were also identified in GIH offspring. In aging females, mammary tumors formed in GIH offspring. These tumors displayed a dramatic increase in stroma compared to tumors from GNx offspring, as well as distinct patterns of expression of stem cell-related pathways. Together, these results suggest that exposure to sleep apnea during pregnancy leads to lasting changes in the mammary glands of female offspring. Increased stem and progenitor cell populations as a result of GIH exposure could enhance long-term breast cancer risk, as well as alter the clinical behavior of resulting breast tumors.

Chemical shift assignments of the ACID domain of MED25, a subunit of the mediator complex in Arabidopsis thaliana.

Mediator complex is a key component that bridges various transcription activators and RNA polymerase during eukaryotic transcription initiation. The Arabidopsis thaliana Med25 (aMed25), a subunit of the Mediator complex, plays important roles in regulating hormone signaling, biotic and abiotic stress responses and plant development by interacting with a variety of transcription factors through its activator-interacting domain (ACID). However, the recognition mechanism of aMed25-ACID for various transcription factors remains unknown. Here, we report the nearly complete 1H, 13C, and 15N backbone and side chain resonance assignments of aMED25-ACID (residues 551-681). TALOS-N analysis revealed that aMED25-ACID structure is comprised of three α-helices and seven ß-strands, which lacks the C-terminal α-helix existing in the human MED25-ACID. This study lays a foundation for further research on the structure-function relationship of aMED25-ACID.

Predicting cancer-specific mortality in T1/2 hepatocellular carcinoma after radiofrequency ablation by competing risk nomogram: A population-based analysis.

BACKGROUND: Radiofrequency ablation (RFA) is one of the primary treatment methods for T1/2 hepatocellular carcinoma (HCC), but the risk factors after RFA remain controversial. This study aims to identify the key factors associated with cancer-specific mortality (CSM) in patients with T1/2 HCC after RFA using competing risk analysis and to establish a prognostic nomogram for improved clinical management. METHODS: A total of 2,135 T1/2 HCC patients treated with RFA were obtained from the Surveillance, Epidemiology, and End Results (SEER) database and randomly categorized into training and validation sets. Univariate and multivariable competing risk analyses were performed to identify risk factors associated with CSM and construct a competing risk nomogram. Receiver operating characteristic (ROC) curves, concordance indices (C-indexes), calibration plots, and decision curve analysis (DCA) were conducted to evaluate the predictive efficiency and clinical applicability of the nomogram in the training and validation sets. Patients were stratified according to their nomogram score, and the different risk groups were compared using cumulative incidence function (CIF) curves and Gray's validation . RESULTS: The 5-year CSM rate for HCC patients treated with RFA was 30.1 %. Grade, tumor size, tumor number, cirrhosis, and AFP level were identified as independent risk factors for CSM. A prognostic nomogram was developed based on these risk factors. The time-dependent C-indexes (0.65) were greater than those of the AJCC stage model (0.55) during the 12 to 60 months of follow-up. The calibration plots of the competing risk nomograms demonstrated excellent consistency between actual survival and nomogram predictions. ROC analyses showed that the 1-, 3-, and 5-year AUC values in both the training and validation cohorts were all greater than 0.63 and exceeded those of the AJCC stage model. DCA demonstrated the clinical usefulness of the nomogram. Patients were classified into low-, moderate-, and high-risk groups based on the nomogram scores, with the high-risk group showing significantly higher CSM rates after RFA compared to the other two groups. CONCLUSIONS: We identified Grade, AFP, cirrhosis, tumor size, and tumor number as independent risk factors associated with CSM. The competing risk nomogram exhibited high performance in predicting the probability of CSM for HCC patients undergoing RFA.

Using NMR to Monitor TET-Dependent Methylcytosine Dioxygenase Activity and Regulation.

The active removal of DNA methylation marks is governed by the ten-eleven translocation (TET) family of enzymes (TET1-3), which iteratively oxidize 5-methycytosine (5mC) into 5-hydroxymethycytosine (5hmC), and then 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). TET proteins are frequently mutated in myeloid malignancies or inactivated in solid tumors. These methylcytosine dioxygenases are α-ketoglutarate (αKG)-dependent and are, therefore, sensitive to metabolic homeostasis. For example, TET2 is activated by vitamin C (VC) and inhibited by specific oncometabolites. However, understanding the regulation of the TET2 enzyme by different metabolites and its activity remains challenging because of limitations in the methods used to simultaneously monitor TET2 substrates, products, and cofactors during catalysis. Here, we measure TET2-dependent activity in real time using NMR. Additionally, we demonstrate that in vitro activity of TET2 is highly dependent on the presence of VC in our system and is potently inhibited by an intermediate metabolite of the TCA cycle, oxaloacetate (OAA). Despite these opposing effects on TET2 activity, the binding sites of VC and OAA on TET2 are shared with αKG. Overall, our work suggests that NMR can be effectively used to monitor TET2 catalysis and illustrates how TET activity is regulated by metabolic and cellular conditions at each oxidation step.

mTOR hypoactivity leads to trophectoderm cell failure by enhancing lysosomal activation and disrupting the cytoskeleton in preimplantation embryo.

BACKGROUND: Metabolic homeostasis is closely related to early impairment of cell fate determination and embryo development. The protein kinase mechanistic target of rapamycin (mTOR) is a key regulator of cellular metabolism in the body. Inhibition of mTOR signaling in early embryo causes postimplantation development failure, yet the mechanisms are still poorly understood. METHODS: Pregnancy mice and preimplantation mouse embryo were treated with mTOR inhibitor in vivo and in vitro respectively, and subsequently examined the blastocyst formation, implantation, and post-implantation development. We used immunofluorescence staining, RNA-Seq smart2, and genome-wide bisulfite sequencing technologies to investigate the impact of mTOR inhibitors on the quality, cell fate determination, and molecular alterations in developing embryos. RESULTS: We showed mTOR suppression during preimplantation decreases the rate of blastocyst formation and the competency of implantation, impairs the post implantation embryonic development. We discovered that blocking mTOR signaling negatively affected the transformation of 8-cell embryos into blastocysts and caused various deficiencies in blastocyst quality. These included problems with compromised trophectoderm cell differentiation, as well as disruptions in cell fate specification. mTOR suppression significantly affected the transcription and DNA methylation of embryos. Treatment with mTOR inhibitors increase lysosomal activation and disrupts the organization and dynamics of the actin cytoskeleton in blastocysts. CONCLUSIONS: These results demonstrate that mTOR plays a crucial role in 8-cell to blastocyst transition and safeguards embryo quality during early embryo development.

Alterations in the mammary gland and tumor microenvironment of formerly obese mice.

BACKGROUND: Obesity is a risk factor for breast cancer, and women with obesity that develop breast cancer have a worsened prognosis. Within the mammary gland, obesity causes chronic, macrophage-driven inflammation and adipose tissue fibrosis. Weight loss is a recommended intervention to resolve obesity, but the impact of weight loss on the mammary gland microenvironment and in tumors has not been well identified. METHODS: To examine the effects of weight loss following obesity, mice were fed a high-fat diet for 16 weeks to induce obesity, then switched to a low-fat diet for 6 weeks. We examined changes in immune cells, including fibrocytes, which are myeloid lineage cells that have attributes of both macrophages and myofibroblasts, and collagen deposition within the mammary glands of non-tumor-bearing mice and within the tumors of mice that were transplanted with estrogen receptor alpha positive TC2 tumor cells. RESULTS: In formerly obese mice, we observed reduced numbers of crown-like structures and fibrocytes in mammary glands, while collagen deposition was not resolved with weight loss. Following transplant of TC2 tumor cells into the mammary glands of lean, obese, and formerly obese mice, diminished collagen deposition and cancer-associated fibroblasts were observed in tumors from formerly obese mice compared to obese mice. Within tumors of obese mice, increased myeloid-derived suppressor cells and diminished CD8+ T cells were identified, while the microenvironment of tumors of formerly obese mice were more similar to tumors from lean mice. When TC2 tumor cells were mixed with CD11b+CD34+ myeloid progenitor cells, which are the cells of origin for fibrocytes, and transplanted into mammary glands of lean and obese mice, collagen deposition within the tumors of both lean and obese was significantly greater than when tumor cells were mixed with CD11b+CD34- monocytes or total CD45+ immune cells. CONCLUSIONS: Overall, these studies demonstrate that weight loss resolved some of the microenvironmental conditions within the mammary gland that may contribute to tumor progression. Additionally, fibrocytes may contribute to early collagen deposition in mammary tumors of obese mice leading to the growth of desmoplastic tumors.

Efficient modulation of cellular phosphorus components in response to phosphorus deficiency in the dinoflagellate Karenia mikimotoi.

IMPORTANCE: Dinoflagellates are the most common phytoplankton group and account for more than 75% of harmful algal blooms in coastal waters. In recent decades, dinoflagellates seem to prevail in phosphate-depleted waters. However, the underlying acclimation mechanisms and competitive strategies of dinoflagellates in response to phosphorus deficiency are poorly understood, especially in terms of intracellular phosphorus modulation and recycling. Here, we focused on the response of intracellular phosphorus metabolism to phosphorus deficiency in the model dinoflagellate Karenia mikimotoi. Our work reveals the strong capability of K. mikimotoi to efficiently regulate intracellular phosphorus resources, particularly through membrane phospholipid remodeling and miRNA regulation of energy metabolism. Our research improved the understanding of intracellular phosphorus metabolism in marine phytoplankton and underscored the advantageous strategies of dinoflagellates in the efficient modulation of internal phosphorus resources to maintain active physiological activity and growth under unsuitable phosphorus conditions, which help them outcompete other species in coastal phosphate-depleted environments.

Melatonin ameliorates simulated-microgravity-induced mitochondrial dysfunction and lipid metabolism dysregulation in hepatocytes.

The liver is an essential multifunctional organ, which constantly communicates with nearly all tissues. It has raised the concern that microgravity exposure can lead to liver dysfunction and metabolic syndromes. However, molecular mechanisms and intervention measures of the adverse effects of microgravity on hepatocytes are limited. In this study, we utilized the random positioning machine culture system to investigate the adverse effects on hepatocytes under simulated microgravity (SMG). Our results showed that SMG impaired hepatocyte viability, causing cell cycle arrest and apoptosis. Compared to normal gravity, it also triggered lipid accumulation, elevated triglyceride (TG) and ROS levels, and impaired mitochondria function in hepatocytes. Furthermore, RNA sequencing results showed that SMG upregulated genes implicated in lipid metabolisms, including PPARγ, PLIN2, CD36, FABPs, etc. Importantly, all these defects can be suppressed by melatonin, a potent antioxidant secreted by the pineal gland, suggesting its potential use of therapeutic intervention.