PubMed

J Hazard Mater. 2024 Feb 12;468:133771. doi: 10.1016/j.jhazmat.2024.133771. Online ahead of print.ABSTRACTThe ubiquitous presence of microplastics (MPs) in aquatic environments poses a significant threat to crustaceans. Although exoskeleton quality is critical for crustacean survival, the impact of MPs on crustacean exoskeletons remains elusive. Our study represents a pioneering effort to characterize the effects of MPs exposure on crustacean exoskeletons. In this study, the mechanical properties of whiteleg shrimp Litopenaeus vannamei exoskeletons were analyzed after exposure to environmentally realistic levels of MPs. Nanoindentation data demonstrated that MPs exposure significantly increased the hardness and modulus of both the carapace and abdominal segments of L. vannamei. Moreover, fractures and embedded MPs were detected on the exoskeleton surface using SEM-EDS analysis. Further analysis demonstrated that the degree of chitin acetylation (DA) in the shrimp exoskeleton, as indicated by FTIR peaks, was reduced by MPs exposure. In addition, exposure to MPs significantly inhibited the muscle Ca2+-ATPase activity and hemolymph calcium levels. Transcriptome and metabolome analyses revealed that the expression levels of genes encoding key enzymes and metabolites in the chitin biosynthetic pathway were significantly affected by MPs exposure. In conclusion, MPs at environmentally relevant concentrations may affect the exoskeletal mechanical properties of L. vannamei through a comprehensive mechanism involving the disruption of the crystalline structure of chitin, assimilation into the exoskeleton, and dysregulation of exoskeleton biosynthesis-related pathways.PMID:38364581 | DOI:10.1016/j.jhazmat.2024.133771

Cancer Res. 2024 Feb 16. doi: 10.1158/0008-5472.CAN-24-0541. Online ahead of print.ABSTRACTSerine metabolism plays a pivotal role in cancer, making it an appealing therapeutic target. Two recent studies published in Nature Metabolism and Science Translational Medicine uncovered novel players and therapeutic opportunities within this crucial metabolic pathway. Papalazarou and colleagues employed genetic tools coupled with metabolomics and high-throughput imaging to identify and characterize membrane transporters involved in serine uptake and mitochondrial import in colorectal cancer. Notably, they showed that dual inhibition of these transporters in combination with impaired serine biosynthesis reduced tumor growth in xenograft models. In a parallel study, Zhang and colleagues identified isocitrate dehydrogenase I (IDH1) as a novel regulator of serine biosynthesis in non-small cell lung cancer (NSCLC). Through extensive mechanistic studies, they demonstrated that IDH1 enhances the expression of the key enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1) via a non-canonical function independent of its enzymatic activity. Strikingly, pharmacological disruption of this novel function of IDH1 not only diminished tumor growth but also enhanced the anticancer efficacy of dietary serine restriction in mouse models of lung cancer. Together, these studies advance our mechanistic understanding of how cancer cells fulfill their serine requirements and reveal innovative therapeutic avenues to deprive tumors of this vital nutrient.PMID:38364233 | DOI:10.1158/0008-5472.CAN-24-0541

mSystems. 2024 Feb 16:e0121423. doi: 10.1128/msystems.01214-23. Online ahead of print.ABSTRACTThe intestine plays a pivotal role in nutrient absorption and host defense against pathogens, orchestrated in part by antimicrobial peptides secreted by Paneth cells. Among these peptides, lysozyme has multifaceted functions beyond its bactericidal activity. Here, we uncover the intricate relationship between intestinal lysozyme, the gut microbiota, and host metabolism. Lysozyme deficiency in mice led to altered body weight, energy expenditure, and substrate utilization, particularly on a high-fat diet. Interestingly, these metabolic benefits were linked to changes in the gut microbiota composition. Cohousing experiments revealed that the metabolic effects of lysozyme deficiency were microbiota-dependent. 16S rDNA sequencing highlighted differences in microbial communities, with ASTB_g (OTU60) highly enriched in lysozyme knockout mice. Subsequently, a novel bacterium, ASTB Qing110, corresponding to ASTB_g (OTU60), was isolated. Metabolomic analysis revealed that ASTB Qing110 secreted high levels of NAD+, potentially influencing host metabolism. This study sheds light on the complex interplay between intestinal lysozyme, the gut microbiota, and host metabolism, uncovering the potential role of ASTB Qing110 as a key player in modulating metabolic outcomes.IMPORTANCEThe impact of intestinal lumen lysozyme on intestinal health is complex, arising from its multifaceted interactions with the gut microbiota. Lysozyme can both mitigate and worsen certain health conditions, varying with different scenarios. This underscores the necessity of identifying the specific bacterial responses elicited by lysozyme and understanding their molecular foundations. Our research reveals that a deficiency in intestinal lysozyme1 may offer protection against diet-induced obesity by altering bacterial populations. We discovered a strain of bacterium, ASTB Qing110, which secretes NAD+ and is predominantly found in lyz1-deficient mice. Qing110 demonstrates positive effects in both C. elegans and mouse models of ataxia telangiectasia. This study sheds light on the intricate role of lysozyme in influencing intestinal health.PMID:38364095 | DOI:10.1128/msystems.01214-23

Hepatology. 2024 Mar 1;79(3):E105. doi: 10.1097/HEP.0000000000000758. Epub 2024 Jan 19.NO ABSTRACTPMID:38363855 | DOI:10.1097/HEP.0000000000000758

Plant Biotechnol J. 2024 Feb 16. doi: 10.1111/pbi.14305. Online ahead of print.ABSTRACTHigh-quality genome of rosemary (Salvia rosmarinus) represents a valuable resource and tool for understanding genome evolution and environmental adaptation as well as its genetic improvement. However, the existing rosemary genome did not provide insights into the relationship between antioxidant components and environmental adaptability. In this study, by employing Nanopore sequencing and Hi-C technologies, a total of 1.17 Gb (97.96%) genome sequences were mapped to 12 chromosomes with 46 121 protein-coding genes and 1265 non-coding RNA genes. Comparative genome analysis reveals that rosemary had a closely genetic relationship with Salvia splendens and Salvia miltiorrhiza, and it diverged from them approximately 33.7 million years ago (MYA), and one whole-genome duplication occurred around 28.3 MYA in rosemary genome. Among all identified rosemary genes, 1918 gene families were expanded, 35 of which are involved in the biosynthesis of antioxidant components. These expanded gene families enhance the ability of rosemary adaptation to adverse environments. Multi-omics (integrated transcriptome and metabolome) analysis showed the tissue-specific distribution of antioxidant components related to environmental adaptation. During the drought, heat and salt stress treatments, 36 genes in the biosynthesis pathways of carnosic acid, rosmarinic acid and flavonoids were up-regulated, illustrating the important role of these antioxidant components in responding to abiotic stresses by adjusting ROS homeostasis. Moreover, cooperating with the photosynthesis, substance and energy metabolism, protein and ion balance, the collaborative system maintained cell stability and improved the ability of rosemary against harsh environment. This study provides a genomic data platform for gene discovery and precision breeding in rosemary. Our results also provide new insights into the adaptive evolution of rosemary and the contribution of antioxidant components in resistance to harsh environments.PMID:38363812 | DOI:10.1111/pbi.14305

Anal Chem. 2024 Feb 16. doi: 10.1021/acs.analchem.3c04131. Online ahead of print.ABSTRACTMetabolomics has emerged as a powerful tool in biomedical research to understand the pathophysiological processes and metabolic biomarkers of diseases. Nevertheless, it is a significant challenge in metabolomics to identify the reliable core metabolites that are closely associated with the occurrence or progression of diseases. Here, we proposed a new research framework by integrating detection-based metabolomics with computational network biology for function-guided and network-based identification of core metabolites, namely, FNICM. The proposed FNICM methodology is successfully utilized to uncover ulcerative colitis (UC)-related core metabolites based on the significantly perturbed metabolic subnetwork. First, seed metabolites were screened out using prior biological knowledge and targeted metabolomics. Second, by leveraging network topology, the perturbations of the detected seed metabolites were propagated to other undetected ones. Ultimately, 35 core metabolites were identified by controllability analysis and were further hierarchized into six levels based on confidence level and their potential significance. The specificity and generalizability of the discovered core metabolites, used as UC's diagnostic markers, were further validated using published data sets of UC patients. More importantly, we demonstrated the broad applicability and practicality of the FNICM framework in different contexts by applying it to multiple clinical data sets, including inflammatory bowel disease, colorectal cancer, and acute coronary syndrome. In addition, FNICM was also demonstrated as a practicality methodology to identify core metabolites correlated with the therapeutic effects of Clematis saponins. Overall, the FNICM methodology is a new framework for identifying reliable core metabolites for disease diagnosis and drug treatment from a systemic and a holistic perspective.PMID:38363654 | DOI:10.1021/acs.analchem.3c04131

Obes Surg. 2024 Feb 16. doi: 10.1007/s11695-024-07096-6. Online ahead of print.ABSTRACTINTRODUCTION: Bariatric surgery is an effective intervention to reduce obesity and improve associated comorbidities. However, its effects on cognitive function are still the subject of debate. Given that the bioavailability of circulating metabolites can influence brain metabolism and cognitive performance, we aimed to assess the effects of bariatric surgery on plasma metabolic profiles and cognitive performance.METHODS: We recruited 26 women undergoing gastric bypass surgery. We conducted anthropometric assessments and collected plasma samples for metabolomic analysis. A set of 4 cognitive tests were used to evaluate cognitive performance. Participants were reevaluated 1 year post-surgery.RESULTS: After surgery, attention capacity and executive function were improved, while immediate memory had deteriorated. Regarding metabolic profile, reduction of beta-tocopherol and increase of serine, glutamic acid, butanoic acid, and glycolic acid were observed. To better understand the relationship between cognitive function and metabolites, a cluster analysis was conducted to identify more homogeneous subgroups based on the cognitive performance. We identified cluster 1, which did not show changes in cognitive performance after surgery, and cluster 2, which showed improved attention and executive function, but reduced performance in the immediate memory test. Thus, cluster 2 was more homogeneous group that replicated the results of non-clustered subjects. Analysis of the metabolic profile of cluster 2 confirmed serine, glutamic acid, and glycolic acid as potential metabolites associated with cognitive performance.CONCLUSIONS: Metabolites identified in this study have potential for biomarkers and alternative therapeutic target to prevent obesity-related cognitive decline.KEY POINTS: • Attention capacity and executive function were improved 12 months post bariatric surgery. • Immediate memory was worsened 12 months post bariatric surgery. • Serine, glutamic acid, and glycolic acid are potential metabolites linked to the alteration of cognitive performance.PMID:38363496 | DOI:10.1007/s11695-024-07096-6

Stress Biol. 2024 Feb 16;4(1):13. doi: 10.1007/s44154-024-00153-1.ABSTRACTPollution by toxic heavy metals creates a significant impact on the biotic community of the ecosystem. Nowadays, a solution to this problem is an eco-friendly approach like phytoremediation, in which plants are used to ameliorate heavy metals. In addition, various amendments are used to enhance the potential of heavy metal phytoremediation. Symbiotic microorganisms such as phosphate-solubilizing bacteria (PSB), endophytes, mycorrhiza and plant growth-promoting rhizobacteria (PGPR) play a significant role in the improvement of heavy metal phytoremediation potential along with promoting the growth of plants that are grown in contaminated environments. Various chemical chelators (Indole 3-acetic acid, ethylene diamine tetra acetic acid, ethylene glycol tetra acetic acid, ethylenediamine-N, N-disuccinic acid and nitrilotri-acetic acid) and their combined action with other agents also contribute to heavy metal phytoremediation enhancement. With modern techniques, transgenic plants and microorganisms are developed to open up an alternative strategy for phytoremediation. Genomics, proteomics, transcriptomics and metabolomics are widely used novel approaches to develop competent phytoremediators. This review accounts for the synergistic interactions of the ameliorating agent's role in enhancing heavy metal phytoremediation, intending to highlight the importance of these various approaches in reducing heavy metal pollution.PMID:38363436 | DOI:10.1007/s44154-024-00153-1

Anal Bioanal Chem. 2024 Feb 16. doi: 10.1007/s00216-024-05179-y. Online ahead of print.ABSTRACTExposure to polyphenols is relevant throughout critical windows of infant development, including the breastfeeding phase. However, the quantitative assessment of polyphenols in human breast milk has received limited attention so far, though polyphenols may positively influence infant health. Therefore, a targeted LC-MS/MS assay was developed to investigate 86 analytes representing different polyphenol classes in human breast milk. The sample preparation consisted of liquid extraction, salting out, freeze-out, and a dilution step. Overall, nearly 70% of the chemically diverse polyphenols fulfilled all strict validation criteria for full quantitative assessment. The remaining analytes did not fulfill all criteria at every concentration level, but can still provide useful semi-quantitative insights into nutritional and biomedical research questions. The limits of detection for all analyzed polyphenols were in the range of 0.0041-87 ng*mL-1, with a median of 0.17 ng*mL-1. Moreover, the mean recovery was determined to be 82% and the mean signal suppression and enhancement effect was 117%. The developed assay was applied in a proof-of-principle study to investigate polyphenols in breast milk samples provided by twelve Nigerian mothers at three distinct time points post-delivery. In total, 50 polyphenol analytes were detected with almost half being phenolic acids. Phase II metabolites, including genistein-7-β-D-glucuronide, genistein-7-sulfate, and daidzein-7-β-D-glucuronide, were also detected in several samples. In conclusion, the developed method was demonstrated to be fit-for-purpose to simultaneously (semi-) quantify a wide variety of polyphenols in breast milk. It also demonstrated that various polyphenols including their biotransformation products were present in breast milk and therefore likely transferred to infants where they might impact microbiome development and infant health.PMID:38363307 | DOI:10.1007/s00216-024-05179-y

Clin Cancer Res. 2024 Feb 16. doi: 10.1158/1078-0432.CCR-23-3433. Online ahead of print.ABSTRACTINTRODUCTION: Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show altered fatty acid (FA) metabolism correlates with outcome. We hypothesized that pharmacologic and dietary modulation of FA catabolism will impact therapeutic efficacy.METHODS: We performed in vivo and in vitro experiments employing PPARα agonism with fenofibrate (FF) or high oleic acid diets (OAD) with radiotherapy, generating metabolomic, proteomic, stable isotope tracing, extracellular flux analysis, and flow cytometric data to investigate these alterations.RESULTS: FF improved anti-tumor efficacy of high dose per fraction radiotherapy in HNC murine models, while the OAD reversed this effect. FF treated mice on the control diet had evidence of increased FA catabolism. Stable isotope tracing showed less glycolytic utilization by ex vivo CD8+ T cells. Improved efficacy correlated with intratumoral alterations in eicosanoid metabolism and downregulated mTOR and CD36.CONCLUSION: Metabolic intervention with increased FA catabolism improves efficacy of HNC therapy and enhance anti-tumoral immune response.PMID:38363297 | DOI:10.1158/1078-0432.CCR-23-3433

J Agric Food Chem. 2024 Feb 16. doi: 10.1021/acs.jafc.3c08429. Online ahead of print.ABSTRACTCombining nanoselenium (nano-Se) and melatonin (MT) was more effective than treatment alone against abiotic stress. However, their combined application mitigated the toxic effects of bensulfuron methyl, and enhanced wheat growth and metabolism has not been studied. Metabolomics and proteomics revealed that combining nano-Se and MT markedly activated phenylpropanoid biosynthesis pathways, elevating the flavonoid (quercetin by 33.5 and 39.8%) and phenolic acid (vanillic acid by 38.8 and 48.7%) levels in leaves and roots of wheat plants. Interstingly, beneficial rhizosphere bacteria in their combination increased (Oxalobacteraceae, Nocardioidaceae, and Xanthomonadaceae), which positively correlated with the enhancement of soil urease and fluorescein diacetate enzyme activity (27.0 and 26.9%) and the allelopathic substance levels. To summarize, nano-Se and MT mitigate the adverse effects of bensulfuron methyl by facilitating interactions between the phenylpropane metabolism of the plant and the beneficial microbial community. The findings provide a theoretical basis for using nano-Se and MT to remediate herbicide-contaminated soil.PMID:38363203 | DOI:10.1021/acs.jafc.3c08429

Pediatr Allergy Immunol. 2024 Feb;35(2):e14084. doi: 10.1111/pai.14084.ABSTRACTThe increasing prevalence of IgE-mediated cow's milk allergy (CMA) in childhood is a worldwide health concern. There is a growing awareness that the gut microbiome (GM) might play an important role in CMA development. Therefore, treatment with probiotics and prebiotics has gained popularity. This systematic review provides an overview of the alterations of the GM, metabolome, and immune response in CMA children and animal models, including post-treatment modifications. MEDLINE, PubMed, Scopus, and Web of Science were searched for studies on GM in CMA-diagnosed children, published before 1 March 2023. A total of 21 articles (13 on children and 8 on animal models) were included. The studies suggest that the GM, characterized by an enrichment of the Clostridia class and reductions in the Lactobacillales order and Bifidobacterium genus, is associated with CMA in early life. Additionally, reduced levels of short-chain fatty acids (SCFAs) and altered amino acid metabolism were reported in CMA children. Commonly used probiotic strains belong to the Bifidobacterium and Lactobacillus genera. However, only Bifidobacterium levels were consistently upregulated after the intervention, while alterations of other bacteria taxa remain inconclusive. These interventions appear to contribute to the restoration of SCFAs and amino acid metabolism balance. Mouse models indicate that these interventions tend to restore the Th 2/Th 1 balance, increase the Treg response, and/or silence the overall pro- and anti-inflammatory cytokine response. Overall, this systematic review highlights the need for multi-omics-related research in CMA children to gain a mechanistic understanding of this disease and to develop effective treatments and preventive strategies.PMID:38363041 | DOI:10.1111/pai.14084

J Cell Biochem. 2024 Feb 16. doi: 10.1002/jcb.30542. Online ahead of print.ABSTRACTFerroptosis is a form of regulated cell death that is induced by inhibiting glutathione peroxidase 4 (GPX4), which eliminates lipid peroxidation. Ferroptosis induction is influenced by the cell environment. However, the cellular states altering ferroptosis susceptibility remain largely unknown. We found that melanoma cell lines became resistant to ferroptosis as cell density increased. Comparative transcriptome and metabolome analyses revealed that cell density-dependent ferroptosis resistance was coupled with a shift toward a lipogenic phenotype accompanied by strong induction of stearoyl-CoA desaturase (SCD). Database analysis of gene dependency across hundreds of cancer cell lines uncovered a negative correlation between GPX4 and SCD dependency. Importantly, SCD inhibition, either pharmacologically or through genetic knockout, sensitized melanoma cells to GPX4 inhibition, thereby attenuating ferroptosis resistance in cells at high density. Our findings indicate that transition to an SCD-inducing, lipogenic cell state produces density-dependent resistance to ferroptosis, which may provide a therapeutic strategy against melanoma.PMID:38362828 | DOI:10.1002/jcb.30542

FEBS J. 2024 Feb 16. doi: 10.1111/febs.17083. Online ahead of print.ABSTRACTNeuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time-lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion-fission-mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis.PMID:38362803 | DOI:10.1111/febs.17083

Expert Rev Proteomics. 2024 Feb 16. doi: 10.1080/14789450.2024.2320166. Online ahead of print.NO ABSTRACTPMID:38362700 | DOI:10.1080/14789450.2024.2320166

Front Cell Infect Microbiol. 2024 Feb 1;14:1258246. doi: 10.3389/fcimb.2024.1258246. eCollection 2024.ABSTRACTPulmonary fibrosis (PF) is a terminal change of a lung disease that is marked by damage to alveolar epithelial cells, abnormal proliferative transformation of fibroblasts, excessive deposition of extracellular matrix (ECM), and concomitant inflammatory damage. Its characteristics include short median survival, high mortality rate, and limited treatment effectiveness. More in-depth studies on the mechanisms of PF are needed to provide better treatment options. The idea of the gut-lung axis has emerged as a result of comprehensive investigations into the microbiome, metabolome, and immune system. This theory is based on the material basis of microorganisms and their metabolites, while the gut-lung circulatory system and the shared mucosal immune system act as the connectors that facilitate the interplay between the gastrointestinal and respiratory systems. The emergence of a new view of the gut-lung axis is complementary and cross-cutting to the study of the mechanisms involved in PF and provides new ideas for its treatment. This article reviews the mechanisms involved in PF, the gut-lung axis theory, and the correlation between the two. Exploring the gut-lung axis mechanism and treatments related to PF from the perspectives of microorganisms, microbial metabolites, and the immune system. The study of the gut-lung axis and PF is still in its early stages. This review systematically summarizes the mechanisms of PF related to the gut-lung axis, providing ideas for subsequent research and treatment of related mechanisms.PMID:38362497 | PMC:PMC10867257 | DOI:10.3389/fcimb.2024.1258246

iScience. 2024 Jan 26;27(2):108999. doi: 10.1016/j.isci.2024.108999. eCollection 2024 Feb 16.ABSTRACTExercise, an intervention with wide-ranging effects on the whole body, has been shown to delay aging. Due to aging and exercise as modulator of metabolism, a picture of how exercise delayed D-galactose (D-gal)-induced aging in a time-resolved manner was presented in this paper. The mapping of molecular changes in response to exercise has become increasingly accessible with the development of omics techniques. To explore the dynamic changes during exercise, the serum of rats and D-gal-induced aging rats before, during, and after exercise was analyzed by untargeted metabolomics. The variation of metabolites was monitored to reveal the specific response to D-gal-induced senescence and exercise in multiple pathways, especially the basal amino acid metabolism, including glycine serine and threonine metabolism, cysteine and methionine metabolism, and tryptophan metabolism. The homeostasis was disturbed by D-gal and maintained by exercise. The paper was expected to provide a theoretical basis for the study of anti-aging exercise.PMID:38362265 | PMC:PMC10867647 | DOI:10.1016/j.isci.2024.108999

Front Pharmacol. 2024 Feb 1;15:1257941. doi: 10.3389/fphar.2024.1257941. eCollection 2024.ABSTRACTBackground: Small extracellular vesicles (sEVs) mediate intercellular communication in the tumor microenvironment (TME) and contribute to the malignant transformation of tumors, including unrestricted growth, metastasis, or therapeutic resistance. However, there is a lack of agents targeting sEVs to overcome or reverse tumor chemotherapy resistance through sEVs-mediated TME reprogramming. Methods: The paclitaxel (PTX)-resistant A549T cell line was used to explore the inhibitory effect of alpha-hederin on impeding the transmission of chemoresistance in non-small cell lung cancer (NSCLC) through the small extracellular vesicles (sEVs) pathway. This investigation utilized the CCK-8 assay and flow cytometry. Transcriptomics, Western blot, oil red O staining, and targeted metabolomics were utilized to evaluate the impact of alpha-hederin on the expression of signaling pathways associated with chemoresistance transmission in NSCLC cells before and after treatment. In vivo molecular imaging and immunohistochemistry were conducted to assess how alpha-hederin influences the transmission of chemoresistance through the sEVs pathway. RT-PCR was employed to examine the expression of miRNA and lncRNA in response to alpha-hederin treatment. Results: The resistance to PTX chemotherapy in A549T cells was overcome by alpha-hederin through its dependence on sEV secretion. However, the effectiveness of alpha-hederin was compromised when vesicle secretion was blocked by the GW4869 inhibitor. Transcriptomic analysis for 463 upregulated genes in recipient cells exposed to A549T-derived sEVs revealed that these sEVs enhanced TGFβ signaling and unsaturated fatty acid synthesis pathways. Alpha-hederin inhibited 15 types of unsaturated fatty acid synthesis by reducing the signaling activity of the sEVs-mediated TGFβ/SMAD2 pathway. Further, we observed that alpha-hederin promoted the production of three microRNAs (miRNAs, including miR-21-5p, miR-23a-3p, and miR-125b-5p) and the sorting to sEVs in A549T cells. These miRNAs targeted the TGFβ/SMADs signaling activity in sEVs-recipient cells and sensitized them to the PTX therapy. Conclusion: Our finding demonstrated that alpha-hederin could sensitize PTX-resistant NSCLC cells by sEV-mediated multiple miRNAs accumulation, and inhibiting TGFβ/SMAD2 pathways in recipient cells.PMID:38362150 | PMC:PMC10867254 | DOI:10.3389/fphar.2024.1257941

Front Nutr. 2024 Feb 1;10:1358428. doi: 10.3389/fnut.2023.1358428. eCollection 2023.NO ABSTRACTPMID:38361955 | PMC:PMC10867326 | DOI:10.3389/fnut.2023.1358428

iScience. 2024 Jan 29;27(3):108959. doi: 10.1016/j.isci.2024.108959. eCollection 2024 Mar 15.ABSTRACTMucopolysaccharidoses (MPSs) are lysosomal disorders with neurological involvement for which no cure exists. Here, we show that recombinant NK1 fragment of hepatocyte growth factor rescues substrate accumulation and lysosomal defects in MPS I, IIIA and IIIB patient fibroblasts. We investigated PI3K/Akt pathway, which is of crucial importance for neuronal function and survival, and demonstrate that PI3K inhibition abolishes NK1 therapeutic effects. We identified that autophagy inhibition, by Beclin1 silencing, reduces MPS IIIB phenotype and that NK1 downregulates autophagic-lysosome (ALP) gene expression, suggesting a possible contribution of autophagosome biogenesis in MPS. Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs.PMID:38361619 | PMC:PMC10864807 | DOI:10.1016/j.isci.2024.108959