PubMed

Trans R Soc Trop Med Hyg. 2025 Jan 3:trae073. doi: 10.1093/trstmh/trae073. Online ahead of print.ABSTRACTSnake venom proteins have long been recognized for their therapeutic potential. Proteogenomic strategies, integrating transcriptomics and proteomics, have emerged as powerful tools for identifying and characterizing venom proteins for the development of novel therapeutic agents. Analytical techniques like mass spectrometry and next-generation sequencing enable comprehensive analysis, identifying key venom components and their variants. Recent studies unveil the diversity and complexity of snake venom, highlighting species-specific variations in toxin composition. Structural biology techniques, including x-ray crystallography and cryo-electron microscopy, provide insights into venom enzyme structures and mechanisms of action, facilitating drug design. Bioinformatics tools aid in data analysis and prediction of venom protein functions, enhancing drug discovery efforts. Despite advancements, challenges persist, including toxicity, formulation stability and clinical validation. This review describes the current as well as future options for research and development and emphasizes the critical role of proteogenomic techniques in developing snake venom protein-based drugs.PMID:39749538 | DOI:10.1093/trstmh/trae073

Front Microbiol. 2024 Dec 19;15:1477187. doi: 10.3389/fmicb.2024.1477187. eCollection 2024.ABSTRACTGut microbiota regulates the immune system, the development and progression of autoimmune diseases (AIDs) and overall health. Recent studies have played a crucial part in understanding the specific role of different gut bacterial strains and their metabolites in different AIDs. Microbial signatures in AIDs are revealed by advanced sequencing and metabolomics studies. Microbes such as Faecalibacterium prausnitzii, Akkermansia muciniphila, Anaerostipes caccae, Bacteroides sp., Roseburia sp., Blautia sp., Blautia faecis, Clostridium lavalense, Christensenellaceae sp., Coprococcus sp., Firmicutes sp., Ruminococcaceae sp., Lachnospiraceae sp., Megamonas sp., Monoglobus sp., Streptococcus pneumoniae and Bifidobacterium sp. help maintain immune homeostasis; whereas, Prevotella copri, Ruminococcus gnavus, Lactobacillus salivarius, Enterococcus gallinarum, Elizabeth menigoseptica, Collinsella sp., Escherichia sp., Fusobacterium sp., Enterobacter ludwigii, Enterobacteriaceae sp., Proteobacteria, Porphyromonas gingivalis, Porphyromonas nigrescens, Dorea sp., and Clostridium sp. cause immuno-pathogenesis. A complex web of interactions is revealed by understanding the influence of gut microbiota on immune cells and various T cell subsets such as CD4+ T cells, CD8+ T cells, natural killer T cells, γδ T cells, etc. Certain AIDs, including rheumatoid arthritis, diabetes mellitus, atopic asthma, inflammatory bowel disease and non-alcoholic fatty liver disease exhibit a state of dysbiosis, characterized by alterations in microbial diversity and relative abundance of specific taxa. This review summarizes recent developments in understanding the role of certain microbiota composition in specific AIDs, and the factors affecting specific regulatory T cells through certain microbial metabolites and also focuses the potential application and therapeutic significance of gut microbiota-based interventions as novel adjunctive therapies for AIDs. Further research to determine the precise association of each gut bacterial strain in specific diseases is required.PMID:39749132 | PMC:PMC11694513 | DOI:10.3389/fmicb.2024.1477187

Pulm Circ. 2025 Jan 2;15(1):e70027. doi: 10.1002/pul2.70027. eCollection 2025 Jan.ABSTRACTPulmonary vascular disease is not a single condition; rather it can accompany a variety of pathologies that impact the pulmonary vasculature. Applying precision medicine strategies to better phenotype, diagnose, monitor, and treat pulmonary vascular disease is increasingly possible with the growing accessibility of powerful clinical and research tools. Nevertheless, challenges exist in implementing these tools to optimal effect. The 2023 Grover Conference Series reviewed the research landscape to summarize the current state of the art and provide a better understanding of the application of precision medicine to managing pulmonary vascular disease. In particular, the following aspects were discussed: (1) Clinical phenotypes, (2) genetics, (3) epigenetics, (4) biomarker discovery, (5) application of precision biology to clinical trials, (6) the right ventricle (RV), and (7) integrating precision medicine to clinical care. The present review summarizes the content of these discussions and the prospects for the future.PMID:39749110 | PMC:PMC11693987 | DOI:10.1002/pul2.70027

J Inflamm Res. 2024 Dec 27;17:11753-11754. doi: 10.2147/JIR.S513935. eCollection 2024.ABSTRACT[This corrects the article DOI: 10.2147/JIR.S493892.].PMID:39749003 | PMC:PMC11693855 | DOI:10.2147/JIR.S513935

Front Vet Sci. 2024 Dec 19;11:1443856. doi: 10.3389/fvets.2024.1443856. eCollection 2024.ABSTRACTThe transition period is a crucial stage in the reproductive cycle for dams and is linked closely with postpartum recovery, reproduction performance, and health. The confronting problem in the yak industry is that transition yaks under a conventional grazing feeding regime endure nutritional deficiency since this period is in late winter and early spring of the Qinghai-Tibet Plateau with the lack of grass on natural pasture. Therefore, this study aimed to investigate the effects of perinatal nutritional supplementation and early weaning on serum biochemistry, reproductive performance, and metabolomics in transition yaks. Eighteen healthy yaks in late pregnancy (233.9 ± 18.3 kg, 2-4 parity) were randomly assigned to three groups: conventional grazing feeding (GF, n = 6), additional nutrition supplementation (SF, n = 6), and additional nutrition supplementation with early weaning (SW, n = 6). Yaks in the GF, SF, and SW groups were free grazing on the same pasture in the daytime from -30 to 90 d relative to parturition. Yaks in SF and SW groups received total mixed ration supplementation in the barn during the night throughout the trial. Calves in the SW group were early weaned and separated from the dam at 60 d postpartum. Maternal body weight was measured at -30 and 90 d, and serum samples were collected to analyze serum biochemistry, hormones, and metabolomics at -15, 30, and 90 d relative to calving. In the SF and SW groups, yaks showed significantly higher body weight gain, serum glucose, globulin, and total protein concentrations. Lipid transportation molecules apolipoprotein B100 and very low-density lipoprotein of SF and SW yaks were significantly increased along with the decreased lipid mobilization products non-esterified fatty acid and β-hydroxybutyric acid when compared to GF yaks at -15 and 30 d. At 90 d, serum non-esterified fatty acid and β-hydroxybutyric acid levels were significantly lower in SW yaks than in SF ones, while apolipoprotein B100 and very low-density lipoprotein levels were significantly higher in SW yaks than in GF yaks. The serum levels of metabolic regulatory hormones, including insulin, leptin, and insulin-like growth factor I were significantly increased, and glucagon was significantly reduced in the SF and SW groups than in the GF group at -15 and 30 d. Among serum reproductive hormones, SF and SW yaks had significantly higher estradiol and progesterone concentrations than GF ones at -15 and 30 d. Follicle-stimulating and luteinizing hormone levels were increased in SW group than in SF and GF ones at 90 d. The calving rates in the following year were 0% (GF), 16.7% (SF), and 83.3% (SW), respectively. The serum metabolomics analysis revealed 848 metabolites in positive mode and 350 in negative mode. With the perinatal nutritional supplementation, the lipid and energy metabolism of transition yaks were improved, meanwhile, lipid mobilization and estrogen production-related pathways were down-regulated. These data suggest that perinatal nutrition supplementation reduces body weight loss, improves glucose and lipid metabolic adaptation to the transition period, and improves yaks' reproductive performance. Additionally, the combination of early weaning and nutritional supplementation results in lower lipid mobilization and up-regulation of lipid transportation and reproductive hormone secretion, which may further contribute to postpartum recovery and acceleration of the reproductive cycle.PMID:39748870 | PMC:PMC11694451 | DOI:10.3389/fvets.2024.1443856

Alzheimers Dement (N Y). 2024 Oct 31;10(4):e70002. doi: 10.1002/trc2.70002. eCollection 2024 Oct-Dec.ABSTRACTNeurodegenerative disorders, including Alzheimer's disease and AD-related dementias (AD/ADRD), pose significant challenges to health care systems globally, particularly in Africa. With the advances in medical technology and research capabilities, especially in next-generation sequencing and imaging, vast amounts of data have been generated from AD/ADRD research. Given that the greatest increase in AD/ADRD prevalence is expected to occur in Africa, it is critical to establish comprehensive bioinformatics training programs to help African scientists leverage existing data and collect additional information to untangle AD/ADRD heterogeneity in African populations. The South Texas Alzheimer's Disease Research Center, with efforts from the National Institutes of Health and the Global Brain Health Institute, has partnered with the Brain Research Africa Initiative to develop the African Initiative on Bioinformatics Online Training in Neurodegenerative Disease (AI-BOND). AI-BOND is a comprehensive and accessible training program, the aim of which is to advance biostatistics and bioinformatics expertise in Africa in studying neurodegenerative diseases. This expertise is essential to enable African scientists to utilize the extensive AD/ADRD data and enhance the continent's ability to contribute to global research efforts in this field. The training addresses the gap in analyzing neurodegenerative disease data by providing skills and knowledge in genetic epidemiology, biostatistics, and bioinformatics to African students and researchers. This innovative online training program will last 6 months and provide training in skill sets R, SAS, and Python programing, genome-wide association studies, genomics, transcriptomics, proteomics, metabolomics, microbiome analysis, and advanced statistical methods. Additional training will include study design and manuscript and grant writing. The first cohort of the AI-BOND program will graduate in June 2024. The AI-BOND program is expected to build research computational capacities in Africa that will improve the ability of graduates to conduct and utilize large-scale studies, with the goal of curbing the growing incidence of neurodegenerative diseases in Africa.HIGHLIGHTS: Alzheimer's disease (AD) and AD-related dementias (ADRD) pose significant health challenges globally, particularly in Africa.The most significant AD/ADRD prevalence increase is predicted to occur in Africa.It is crucial to establish a bioinformatics training capacity in Africa to leverage the vast number of multi-omics and imaging biomarkers of AD/ADRD data being generated.The African Initiative on Bioinformatics Online Training in Neurodegenerative Disease (AI-BOND) training addresses the gaps in study design, biostatistics, genetic epidemiology, and bioinformatics related to neurodegenerative diseases in Africa.The success of AI-BOND is anticipated to help build computational research capacities in Africa.PMID:39748840 | PMC:PMC11694528 | DOI:10.1002/trc2.70002

Front Plant Sci. 2024 Dec 19;15:1484251. doi: 10.3389/fpls.2024.1484251. eCollection 2024.ABSTRACTThe impact of combined heat and drought stress was investigated in Arabidopsis thaliana and compared to individual stresses to reveal additive effects and interactions. A combination of plant metabolomics and root and rhizosphere bacterial metabarcoding were used to unravel effects at the plant holobiont level. Hierarchical cluster analysis of metabolomics signatures pointed out two main clusters, one including heat and combined heat and drought, and the second cluster that included the control and drought treatments. Overall, phenylpropanoids and nitrogen-containing compounds, hormones and amino acids showed the highest discriminant potential. A decrease in alpha-diversity of Bacteria was observed upon stress, with stress-dependent differences in bacterial microbiota composition. The shift in beta-diversity highlighted the pivotal enrichment of Proteobacteria, including Rhizobiales, Enterobacteriales and Azospirillales. The results corroborate the concept of stress interaction, where the combined heat and drought stress is not the mere combination of the single stresses. Intriguingly, multi-omics interpretations evidenced a good correlation between root metabolomics and root bacterial microbiota, indicating an orchestrated modulation of the whole holobiont.PMID:39748821 | PMC:PMC11693709 | DOI:10.3389/fpls.2024.1484251

Phytochem Anal. 2025 Jan 2. doi: 10.1002/pca.3492. Online ahead of print.ABSTRACTINTRODUCTION: Dangshen (DS) has been used for hundreds of years as a traditional Chinese medicine. It has a wide range of biological activities. Flavonoids are one of the important bioactive components with strong free radical scavenging and antioxidant capacity in DS. However, the biosynthesis process of flavonoids in DS remains unclear.OBJECTIVE: The aim of this study was to understand the biosynthesis molecular mechanism of flavonoids in DS.METHODS: In this study, metabolomics research and transcriptome sequencing for DS were carried out. Transcript and metabolite profiles were generated by high-throughput RNA sequencing (RNA-seq) data analysis and liquid chromatography-tandem mass spectrometry, respectively.RESULTS: In total, 256 metabolites were identified in the root, stem, leaf, and flower of DS using untargeted metabolomics. Among them, 55 flavonoids, including pinobanksin, butein, fustin, pelargonidin, apigenin, luteolin, and eriodictyol, were closely related to flavonoid metabolism, and most of them were upregulated in different tissues of DS. Furthermore, the differentially expressed genes identified by transcriptomics were mainly enriched in the biosynthesis of flavonoid, isoflavonoid, flavone, and flavonol. A number of genes, including ANS, CCOAOMT, CHI, CHS, CYP75B1, CYP75A, CYP93B2_16, CYP98A/C3'H, DFR, F3H, FLS, and HCT, may regulate the production of flavonoids in different tissues of DS. An integrated analysis of transcriptome and metabolome revealed the flavonoid biosynthetic network in DS and elucidated the diversity of flavonoid biosynthetic pathway in roots, stems, leaves, and flowers of DS.CONCLUSION: Our findings provide a molecular basis and new insights into flavonoid biosynthesis in DS and lay the foundation for breeding new valuable DS cultivars.PMID:39748559 | DOI:10.1002/pca.3492

Vet Res. 2025 Jan 2;56(1):1. doi: 10.1186/s13567-024-01388-6.ABSTRACTGlutathione reductase (GR) plays a pivotal role in managing oxidative stress, a process crucial for microbial virulence and adaptation, yet it has not been extensively explored in bacteria such as Avibacterium paragallinarum (Av. paragallinarum). This study examined the specific roles of GR in Av. paragallinarum, focusing on how GR modulates the bacterium's response to oxidative stress and impacts its pathogenic behavior. Using gene knockouts together with transcriptomic and metabolomic profiling, we identified an important shift in redox balance due to GR deficiency, which disrupted energy metabolism and weakened the oxidative stress defense, culminating in a notable decline in virulence. In addition, decreased growth rates, reduced biofilm production, and weakened macrophage interactions were observed in GR-deficient strains. Notably, our findings reveal a sophisticated adaptation mechanism wherein the bacterium recalibrated its metabolic pathways in response to GR deficiency without fully restoring virulence. Our in vivo studies further highlight the pivotal role of GR in pathogen fitness. Together, our findings connect GR-mediated redox control to bacterial virulence, thereby furthering the understanding of microbial adaptation and positioning GR as a potential antimicrobial target. Our insights into the GR-centric regulatory network pave the way for leveraging bacterial redox mechanisms in the development of novel antimicrobial therapies, highlighting the importance of oxidative stress management in bacterial pathogenicity.PMID:39748435 | DOI:10.1186/s13567-024-01388-6

BMC Infect Dis. 2025 Jan 2;25(1):10. doi: 10.1186/s12879-024-10402-3.ABSTRACTBACKGROUND: The rapid evolution of the COVID-19 pandemic and subsequent global immunization efforts have rendered early metabolomics studies potentially outdated, as they primarily involved non-exposed, non-vaccinated populations. This paper presents a predictive model developed from up-to-date metabolomics data integrated with clinical data to estimate early mortality risk in critically ill COVID-19 patients. Our study addresses the critical gap in current research by utilizing current patient samples, providing fresh insights into the pathophysiology of the disease in a partially immunized global population.METHODS: One hundred elderly patients with severe COVID-19 infection, including 46 survivors and 54 non-survivors, were recruited in January-February 2023 at the Second Hospital affiliated with Harbin Medical University. A predictive model within 24 h of admission was developed using blood metabolomics and clinical data. Differential metabolite analysis and other techniques were used to identify relevant characteristics. Model performance was assessed by comparing the area under the receiver operating characteristic curve (AUROC). The final prediction model was externally validated in a cohort of 50 COVID-19 elderly critically ill patients at the First Hospital affiliated with Harbin Medical University during the same period.RESULTS: Significant disparities in blood metabolomics and laboratory parameters were noted between individuals who survived and those who did not. One metabolite indicator, Itaconic acid, and four laboratory tests (LYM, IL-6, PCT, and CRP), were identified as the five variables in all four models. The external validation set demonstrated that the KNN model exhibited the highest AUC of 0.952 among the four models. When considering a 50% risk of mortality threshold, the validation set displayed a sensitivity of 0.963 and a specificity of 0.957.CONCLUSIONS: The prognostic outcome of COVID-19 elderly patients is significantly influenced by the levels of Itaconic acid, LYM, IL-6, PCT, and CRP upon admission. These five indicators can be utilized to assess the mortality risk in affected individuals.PMID:39748307 | DOI:10.1186/s12879-024-10402-3

BMC Plant Biol. 2025 Jan 2;25(1):6. doi: 10.1186/s12870-024-05876-x.ABSTRACTHigh temperature stress seriously affects the quality and yield of vegetable crops, especially cucumber (Cucumis sativus L.). However, the metabolic dynamics and gene regulatory network of cucumber in response to high temperature stress remain poorly studied. In this study, we identified a heat-tolerant cucumber Gy14 and a heat-sensitive cucumber 32X. RNA-seq analysis of Gy14 and 32X under high temperature stress showed that some differentially expressed genes (DEGs) were related to the biosynthesis of secondary metabolites. Metabolomic analysis revealed that there were more phenylpropanoids and their downstream derivatives in Gy14 compared to that in 32X under Re_2d condition (2 normal days recovery after heat). Integrated analysis of transcriptome and metabolome revealed that these upregulated genes played a pivotal role in flavonoid biosynthesis. Moreover, high temperature stress significantly induced the expression of the gibberellin (GA) biosynthesis genes and exogenous application of GA3 alleviated the damage of high temperature to cucumber seedlings. Together, these findings provided new insights into the transcriptome response and metabolomic reprogramming of cucumber against high temperature stress.PMID:39748295 | DOI:10.1186/s12870-024-05876-x

Biomed Chromatogr. 2025 Feb;39(2):e6066. doi: 10.1002/bmc.6066.ABSTRACTThe objective of this study is to comprehensively to identify the core pharmacological components and their respective targets of three medicinal fungi Sanghuangs including Sanghuangporus vaninii (SV), Sanghuangporus lonicericola (SL), and Inonotus hispidus (IH). Metabolomics analysis indicated that a total of 495 and 660 differential metabolites were obtained in mycelium and fermentation broth samples among three Sanghuangs, respectively. The network pharmacology analysis showed that 6-[1]-ladderane hexanol, R-nostrenol, candidone, ellagic acid, and quercetin were the overlapping active ingredients of three Sanghuang species for diabetes mellitus, immune system disease, and neoplasm. Certonardosterol A, dalamid, and ethylene brassylate are unique active ingredients in SV, and certonardosterol K, kaempferide, and esculetin are unique active ingredients in SL. Asbestinine, neoandrographolide, isosakuranetin, and daucosterin are unique active ingredients in IH. Accordingly, the common core targets of active ingredients of the three Sanghuangs were ESR1, PIK3CA, and LYN. PRKCA, EGFR, and STAT3 were the unique targets of SV, SL, and IH, respectively. The primary active components and their respective targets, in addition to the component-target interaction of Sanghuangs that have been identified in the present study, provide a foundation for future research on the prevention and treatment of disease using Sanghuangs.PMID:39748251 | DOI:10.1002/bmc.6066

Biomed Chromatogr. 2025 Feb;39(2):e6065. doi: 10.1002/bmc.6065.ABSTRACTThe high mortality rate of chronic heart failure (CHF) makes it a primary battlefield in the field of cardiovascular diseases. Qiangxin Lishui Prescription (QLP) is a traditional Chinese medicine (TCM) prescription used clinically for treating CHF, but its underlying mechanism remains unclear. This study integrated plasma metabolomics, network pharmacology, and experimental validation to reveal the pharmacological effects of QLP and its potential mechanism of anti-CHF. Using ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS/MS), 119 absorbed prototype compounds of QLP were identified from rat plasma. By applying network pharmacology and molecular docking techniques, a QLP absorption components-target-CHF network was constructed. The IL6/JAK/STAT3 signaling pathway is likely critical to QLP's therapeutic effect on CHF. A CHF mouse model was established using aortic ligation surgery to investigate the regulation of the IL6/JAK/STAT3 pathway by QLP in CHF mice. Network pharmacology analysis and in vivo experimental data indicate that QLP alleviates myocardial injury and inflammatory response in CHF mice by modulating the IL6/JAK/STAT3 pathway, significantly improving cardiac function. This presents a promising therapeutic strategy for CHF treatment.PMID:39748248 | DOI:10.1002/bmc.6065

Sci Rep. 2025 Jan 2;15(1):483. doi: 10.1038/s41598-024-84207-4.ABSTRACTThe gut microbiome and its metabolites may be important role in regulating the pathogenesis of obesity. This study aimed to characterize the gut microbiome and short-chain fatty acid (SCFA) metabolome in obese children. This case-control study recruited children aged 7‒14 years and divided them into a normal group (NG) and an obese group (OG) based on their body mass index. Whole-genome shotgun metagenomic analysis was performed on fecal samples from the OG and NG groups to characterize the signatures and functional potential of the gut microbiota. Serum metabolite profiles were analyzed using high-performance liquid chromatography/mass spectrometry (LC/MS). The Statistical Package for the Social Sciences (SPSS, version 26) and R software were used for data analysis. A total of 99 children were recruited, with 49 in the OG and 50 in the NG. At the phylum level, Proteobacteria were significantly more abundant in children in the OG than those in the NG. At the genus level, Oscillibacter and Alistipes were significantly lower in children in the OG than those in the NG. Caproate levels significantly increased, whereas butyrate and isobutyrate levels decreased in children in the OG than those in the NG. Kyoto encyclopedia of genes and genomes (KEGG) functional analysis revealed 28 enriched KEGG pathways, of which/with the phosphotransferase system (PTS) and enhanced biofilm formation by Escherichia coli were particularly significant in the OG. Spearman's correlation analysis indicated that the genus Oscillibacter and species Clostridium_sp._CAG:302 connect serum metabolites and the gut microbiota in childhood obesity. Childhood obesity is correlated with the symbiotic status of the gut microbiota. The microbiota influences human metabolism via specific pathways, particularly butyrate, caproate, and the genus Oscillibacter, all closely associated with obesity.PMID:39748068 | DOI:10.1038/s41598-024-84207-4

Nat Genet. 2025 Jan 2. doi: 10.1038/s41588-024-01965-7. Online ahead of print.ABSTRACTGenetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene-metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models of human metabolism) and one experimental proof of principle) provided orthogonal evidence that studies of rare, damaging variants in the heterozygous state permit inferences concordant with those from inborn errors of metabolism. Allelic series of functional variants in transporters responsible for transcellular sulfate reabsorption (SLC13A1, SLC26A1) exhibited graded effects on plasma sulfate and human height and pinpointed alleles associated with increased odds of diverse musculoskeletal traits and diseases in the population. This integrative approach can identify new players in incompletely characterized human metabolic reactions and reveal metabolic readouts informative of human traits and diseases.PMID:39747595 | DOI:10.1038/s41588-024-01965-7

Sci Rep. 2025 Jan 2;15(1):422. doi: 10.1038/s41598-024-84515-9.ABSTRACTHeart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We developed a novel "two-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57Bl6/NJ mice fed a high-fat diet (HFD) for > 10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d. HFD-Renin (aka "HFpEF") mice demonstrated obesity and insulin resistance, moderate left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by echocardiographic measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to human HFpEF. Treatment with empagliflozin, an effective but incompletely understood HFpEF therapy, improved multiple endpoints. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Additional preclinical HFpEF models allow for orthogonal studies to increase validity in assessment of interventions.PMID:39747575 | DOI:10.1038/s41598-024-84515-9

Sci Rep. 2025 Jan 2;15(1):479. doi: 10.1038/s41598-024-84191-9.ABSTRACTThe development of targeted therapies that correct the effect of mutations in patients with cystic fibrosis (CF) and the relevant heterogeneity of the clinical expression of the disease require biomarkers correlated to the severity of the disease useful for monitoring the therapeutic effects. We applied a targeted metabolomic approach by LC-MS/MS on saliva samples from 70 adult CF patients and 63 age/sex-matched controls to investigate alterations in metabolic pathways related to pancreatic insufficiency (PI), Pseudomonas aeruginosa (PA) colonization, CF liver disease (CFLD), and CF related diabetes (CFRD). Sixty salivary metabolites were differentially expressed, with 11 being less abundant and 49 more abundant in CF patients. Among these, the most relevant alterations involved salivary ADMA, N-acetylornithine, methionine and methionine sulfoxide levels. Furthermore, methionine was significantly lower in CF patients with PI and salivary histamine levels were significantly lower in patients colonized by PA. Moreover, ADMA as well as N-acetylornithine and methionine were significantly lower in CF patients with CFRD than in patients without CFRD. Finally, the levels of DOPA resulted significantly lower in saliva from patients with liver disease. Our study revealed an imbalance in arginine methylation and tryptophan pathway related to CFRD and PI as well as alterations in dopaminergic pathway and Krebs cycle related to CFLD. This study also highlights different salivary metabolites as new potential biomarkers in a non-invasive sample that could represent a useful tool for the stratification and management of CF patients.PMID:39747338 | DOI:10.1038/s41598-024-84191-9

Sci Rep. 2025 Jan 2;15(1):46. doi: 10.1038/s41598-024-83544-8.ABSTRACTTibetan donkeys inhabit the harsh environment of the Qinghai-Tibet Plateau. Research on serum metabolites related to their high-altitude adaptation is limited compared to other livestock. We used liquid chromatography-mass spectrometry (LC-MS) to analyze serum samples from healthy adult donkeys in Shigatse, Changdu, and Dezhou to evaluate the effects of high altitudes on serum metabolites. Metabolomics analysis identified 443 differential metabolites (DMs) across the three groups, meeting criteria of VIP ≥ 1, p-value < 0.05, and Fold-Change ≥ 1.2 or ≤ 0.5. Significant upregulation was observed in deoxycholic acid, vitamin A, vitamin C, flavin mononucleotide, n-acetylserotonin, N'-formyl-kynurenine, calcidiol, and adenosine monophosphate in the high-altitude group compared to the low-altitude control group. The DMs were involved in processes such as bile secretion, vitamin digestion and absorption, tryptophan metabolism, and parathyroid hormone synthesis, secretion, and action. All these are crucial for nutrient metabolism, immune function, and antioxidant stress response. This study constructed a metabolomics dataset of Tibetan donkey serum and revealed differential metabolites among donkeys from different geographic regions and environments. The results offer crucial insights into the adaptive regulatory mechanisms.PMID:39747337 | DOI:10.1038/s41598-024-83544-8

Nat Commun. 2025 Jan 2;16(1):173. doi: 10.1038/s41467-024-55596-x.ABSTRACTLung fibrosis development utilizes alveolar macrophages, with mechanisms that are incompletely understood. Here, we fate map connective tissue during mouse lung fibrosis and observe disassembly and transfer of connective tissue macromolecules from pleuro-alveolar junctions (PAJs) into deep lung tissue, to activate fibroblasts and fibrosis. Disassembly and transfer of PAJ macromolecules into deep lung tissue occurs by alveolar macrophages, activating cysteine-type proteolysis on pleural mesothelium. The PAJ niche and the disassembly cascade is active in patient lung biopsies, persists in chronic fibrosis models, and wanes down in acute fibrosis models. Pleural-specific viral therapeutic carrying the cysteine protease inhibitor Cystatin A shuts down PAJ disassembly, reverses fibrosis and regenerates chronic fibrotic lungs. Targeting PAJ disassembly by targeting the pleura may provide a unique therapeutic avenue to treat lung fibrotic diseases.PMID:39747171 | DOI:10.1038/s41467-024-55596-x

Nat Commun. 2025 Jan 2;16(1):237. doi: 10.1038/s41467-024-55543-w.ABSTRACTProtective immunity to malaria depends on acquisition of parasite-specific antibodies, with Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) being one of the most important target antigens. The effector functions of PfEMP1-specific IgG include inhibition of infected erythrocyte (IE) sequestration and opsonization of IEs for cell-mediated destruction. IgG glycosylation modulates antibody functionality, with increased affinity to FcγRIIIa for IgG lacking fucose in the Fc region (Fc-afucosylation). We report here that selective Fc-afucosylation of PfEMP1-specific IgG1 increases with age in P. falciparum-exposed children and is associated with reduced risk of anemia, independent of the IgG levels. A similar association was found for children having PfEMP1-specific IgG1 inducing multiple effector functions against IEs, particularly those associated with antibody-dependent cellular cytotoxicity (ADCC) by NK cells. Our findings provide new insights regarding protective immunity to P. falciparum malaria and highlight the importance of cell-mediated destruction of IgG-opsonized IEs.PMID:39747065 | DOI:10.1038/s41467-024-55543-w