Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

Health Impacts of PM<sub>2.5</sub> Emissions from Brake Pad Wear: A Comprehensive Study on Pulmonary, Metabolic, and Microbiota Alterations

Tue, 14/01/2025 - 12:00
Toxicology. 2025 Jan 12:154055. doi: 10.1016/j.tox.2025.154055. Online ahead of print.ABSTRACTThe environmental impact of harmful particles from tire and brake systems is a growing concern. This study investigated the health impacts of PM2.5 emissions from brake pad wear on adult C57BL/6 mice. The mice were exposed to brake pad particles via intratracheal infusion, and various health parameters were assessed. The results showed that brake pad particle exposure significantly reduced lung function parameters such as tidal volume, peak expiratory time ratio, and peak inspiratory flow rate, while increasing the apnea index and airway stenosis index. Histological analysis revealed particle deposition, inflammatory damage, and potential fibrosis in the lungs. Additionally, inflammatory markers and fibrosis indicators were elevated in the lung tissue. Metabolomic analysis indicated changes in metabolites related to purine metabolism, protein digestion, nucleic acid metabolism, and pathways involving Caffeine, Xanthine, Inosine, and others. Gut microbiota analysis showed increased abundance of Odoribacter and Tuzzerella, and decreased abundance of Desulfovibrio and Butyricimonas. Correlation analysis further suggested a significant link between the abundance of Odoribacter and plasma metabolic changes. Overall, this study underscores the health risks associated with brake dust pollution, particularly its adverse effects on lung function and induction of lung damage and fibrosis.PMID:39809340 | DOI:10.1016/j.tox.2025.154055

Gut microbial GABA imbalance emerges as a metabolic signature in mild autism spectrum disorder linked to overrepresented Escherichia

Tue, 14/01/2025 - 12:00
Cell Rep Med. 2025 Jan 7:101919. doi: 10.1016/j.xcrm.2024.101919. Online ahead of print.ABSTRACTGut microbiota (GM) alterations have been implicated in autism spectrum disorder (ASD), yet the specific functional architecture remains elusive. Here, employing multi-omics approaches, we investigate stool samples from two distinct cohorts comprising 203 children with mild ASD or typical development. In our screening cohort, regression-based analysis for metabolomic profiling identifies an elevated γ-aminobutyric acid (GABA) to glutamate (Glu) ratio as a metabolic signature of ASD, independent of age and gender. In the validating cohort, we affirm the GABA/Glu ratio as an ASD diagnostic indicator after adjusting for geography, age, gender, and specific food-consuming frequency. Integrated analysis of metabolomics, 16S rRNA sequencing, and metagenomics reveals a correlation between overrepresented Escherichia and disrupted GABA metabolism. Furthermore, we observe social behavioral impairments in weaning mice transplanted with E. coli, suggesting a potential link to ASD symptomatology. Collectively, these findings provide insights into potential diagnostic and therapeutic strategies aimed at evaluating and restoring gut microbial neurotransmitter homeostasis.PMID:39809266 | DOI:10.1016/j.xcrm.2024.101919

Epoxide hydrolases JHEH1 and JHEH2 deficiency impairs glucose metabolism in Drosophila

Tue, 14/01/2025 - 12:00
Biochem Biophys Res Commun. 2025 Jan 9;748:151313. doi: 10.1016/j.bbrc.2025.151313. Online ahead of print.ABSTRACTEpoxide hydrolases (EHs) play pivotal roles in detoxification, catabolism, and signaling by converting epoxides into diols and have been implicated in several diseases, such as cancers and diabetes. EH homologs in insects are designated as Juvenile hormone epoxide hydrolases (JHEHs) due to their catalytic activity toward Juvenile hormone (JH). However, the biological function of JHEHs has been controversial in the fruit fly Drosophila melanogaster. In this study, we generated and characterized flies deficient in Jheh1 and Jheh2 genes. We found that Jheh1/2 deficiency caused a developmental delay and enhanced the growth retardation effects of caffeine and paraquat. Additionally, we observed that the deficiency reduced tolerance to cold stress. These results indicate that JHEHs are required for growth promotion and stress tolerance. Metabolomic and transcriptomic analyses revealed that Jheh1/2 deficiency impaired glucose metabolism and downregulated genes involved in glycolysis and the TCA cycle. Furthermore, transgenic overexpression of Jheh1 increased glycolytic metabolites and restored the Jheh1/2 deficiency-associated phenotype. These results demonstrate that JHEHs play a crucial role in glucose metabolism in Drosophila, providing a valuable model to study the mechanisms underlying the function of EHs in energy metabolism.PMID:39809137 | DOI:10.1016/j.bbrc.2025.151313

Schisandrol B alleviates depression-like behavior in mice by regulating bile acid homeostasis in the brain-liver-gut axis via the pregnane X receptor

Tue, 14/01/2025 - 12:00
Phytomedicine. 2024 Dec 26;137:156340. doi: 10.1016/j.phymed.2024.156340. Online ahead of print.ABSTRACTBACKGROUND: Depression is a widely recognized neuropsychiatric disorder. Recent studies have shown a potential correlation between bile acid disorders and depression, highlighting the importance of maintaining bile acid balance for effective antidepressant treatment. Schisandrol B (SolB), a primary bioactive compound from Schisandra chinensis (Turcz.) Baill. or Schisandra sphenanthera Rehd.etWils, is pivotal in regulating bile acid homeostasis via pregnane X receptor (PXR) in cholestasis. However, the potential of SolB in alleviating depression-like symptoms, its pharmacological effects, and the underlying mechanisms remain to be fully elucidated.METHODS: We confirmed the effect of SolB against depression induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) in mice. The role of SolB in bile acid homeostasis in depression was analyzed using the metabolomic. Gene analyses and 16S rRNA sequencing were employed to investigate the involvement of PXR. Experiments with Pxr-/- mice were conducted to confirm the essential role of the PXR pathway in SolB's antidepressant effects.RESULTS: SolB treatment significantly increased sucrose consumption in the SPT and the locomotor activity in the OFT, while decreasing immobility time in the FST and TST in mice exposed to CRS and CUMS. Additionally, SolB treatment significantly preserved the integrity of the dendritic spine, elevated synaptic protein PSD95 levels, and augmented CREB/BDNF expression. Metabolomic and gene analyses indicated that SolB treatment significantly facilitated bile acid metabolism, promoted intestinal bile acid efflux, decreased hippocampal levels of the secondary bile acids DCA and TLCA, and upregulated expression of the PXR target proteins CYP3A11, SULT2A1, MRP2, and OATP1B1 in the liver, and MRP2 and MDR1 in hippocampus, which are integral to bile acid homeostasis. 16S rRNA sequencing revealed that SolB reduced the abundance of the bile salt hydrolase (BSH)-producing bacteria Lactobacillus johnsonii and Bacteroides fragilis and subsequently decreased the production of TLCA and DCA. Moreover, SolB failed to protect against depression induced by CRS in Pxr-null mice, suggesting that the antidepressant effect of SolB was PXR-dependent.CONCLUSIONS: These results provide direct evidence of the antidepressant effect of SolB via activation of PXR to regulate bile acid homeostasis in the brain-liver-gut axis, suggesting that SolB may serve as a novel potential target for preventing and treating depression.PMID:39809031 | DOI:10.1016/j.phymed.2024.156340

Developmental and molecular effects of pure-tone sine wave exposure on early zebrafish embryo development: Implications for reproductive health

Tue, 14/01/2025 - 12:00
Ecotoxicol Environ Saf. 2025 Jan 13;289:117718. doi: 10.1016/j.ecoenv.2025.117718. Online ahead of print.ABSTRACTNoise pollution has become a significant concern for human health, yet its effects on early embryonic development remain underexplored. Specifically, data on the impact of sine wave noise on newly fertilized embryos is limited. This study aimed to address this gap by using zebrafish embryos at the 1-cell stage as a model to assess the toxicity of sine waves, following OECD Test No. 236. We exposed embryos to sound levels of 90 decibels (dB) and above, observing increased deformity rates, delayed development, and reductions in body length, heart rate and brain size. To elucidate the molecular mechanisms underlying these effects, we employed transcriptomics, metabolomics, and epigenomics (m6A-MeRIP-seq). KEGG enrichment analysis revealed significant alterations in arachidonic acid metabolism, axon guidance, and ubiquitin-mediated proteolysis. In conclusion, our findings demonstrate that high levels of sine wave noise adversely affect early embryo development. These results provide crucial insights for developing strategies to mitigate noise pollution and protect early developmental stages.PMID:39808881 | DOI:10.1016/j.ecoenv.2025.117718

Serum metabolic fingerprinting on Ag@AuNWs for traumatic brain injury diagnosis

Tue, 14/01/2025 - 12:00
Nanotechnology. 2025 Jan 14. doi: 10.1088/1361-6528/ada9f2. Online ahead of print.ABSTRACTAccurate and rapid diagnosis of traumatic brain injury (TBI) is essential for high-quality medical services. Nonetheless, the current diagnostic platform still has challenges in rapidly and accurately analysing clinical samples. Here, we prepared a highly stable, repeatable and sensitive gold-plated silver core-shell nanowire (Ag@AuNWs) for surface-enhanced Raman spectroscopy (SERS) metabolic fingerprint diagnosis of TBI. The core-shell structure significantly enhanced SERS intensity and enables the direct detection of 10 μL serum within seconds. The principal component analysis-linear discriminant analysis (PCA-LDA) and partial least squaresdiscriminant analysis (PLS-DA) are used to evaluate the classification effect of this technology on TBI, respectively. The diagnosis accuracy rate of PCA-LDA and PLS-DA is 73.3% and 86.7% for diagnosing TBI, respectively. Consequently, the PLS-DA model is the optimal selection for distinguishing between the TBI and sham groups. This research will facilitate the application-oriented creation of novel materials with tailored structural designs and the formulation of innovative precision medical protocols in the imminent future.&#xD.PMID:39808836 | DOI:10.1088/1361-6528/ada9f2

Mycotoxin exposure through the consumption of processed cereal food for children (&lt; 5 years old) from rural households of Oshana, a region of Namibia

Tue, 14/01/2025 - 12:00
Mycotoxin Res. 2025 Jan 14. doi: 10.1007/s12550-024-00580-z. Online ahead of print.ABSTRACTMycotoxin exposure from contaminated food is a significant global health issue, particularly among vulnerable children. Given limited data on mycotoxin exposure among Namibian children, this study investigated mycotoxin types and levels in foods, evaluated dietary mycotoxin exposure from processed cereal foods in children under age five from rural households in Oshana region, Namibia. Mycotoxins in cereal-based food samples (n = 162) (mahangu flour (n = 35), sorghum flour (n = 13), mahangu thin/thick porridge (n = 54), oshikundu (n = 56), and omungome (n = 4)) were determined by liquid chromatography-tandem mass spectrometry. Aflatoxin B1 (AFB1, 35.8%), zearalenone (27.2%), fumonisin B1 (FB1, 24.1%), citrinin (CIT, 12.4%) and deoxynivalenol (10.5%) were the major mycotoxins quantified. Food samples (35.8% (n = 58) and 6.2% (n = 10)) exceeded the 0.1 µg/kg AFB1 and 200 µg/kg FB1 EU limit for children's food, respectively. Several emerging mycotoxins including the neurotoxic 3-nitropropionic acid, moniliformin (MON), and tenuazonic acid were quantified in over 50% of all samples. Co-occurrence of AFB1, CIT, and FB1 detected in 4.9% (n = 8) samples, which could heighten food safety concerns. Regarding exposure assessment and risk characterization, average probable dietary intake for AFB1 from all ready-to-eat-foods was 0.036 µg/kg bw/day, which resulted in margin of exposures (MOE) of 11 and 0.65 risk cancer cases/year/100,000 people, indicating a risk of chronic aflatoxicosis. High tolerable daily intake values for FB1, and MOE for beauvericin and MON exceeded reference values. Consumption of a diversified diet and interventions including timely planting and harvesting, best grain storage, and other standard postharvest food handling practices are needed to mitigate mycotoxin exposure through contaminated cereal foods and to safeguard the health of the rural children in Namibia.PMID:39808410 | DOI:10.1007/s12550-024-00580-z

Comprehensive Analysis of Fecal Microbiome and Metabolomics Uncovered dl-Norvaline-Ameliorated Obesity-Associated Disorders in High-Fat Diet-Fed Obese Mice by Targeting the Gut Microbiota

Tue, 14/01/2025 - 12:00
J Agric Food Chem. 2025 Jan 14. doi: 10.1021/acs.jafc.4c06638. Online ahead of print.ABSTRACTNorvaline is a nonproteinogenic amino acid and an important food ingredient supplement for healthy food. In this study, dl-norvaline administration reduced body weight by more than 40% and improved glucose metabolism and energy metabolism in obese mice induced by a high-fat diet (HFD). Combination analysis of microbiome and metabolomics showed that dl-norvaline supplementation regulated gut bacteria structure, such as increasing beneficial bacteria (Mollicutes_RF39, Ruminococcaceae, Bacteroidaceae, Rikenellaceae, Lactobacillaceae, Clostridiaceae_1, uncultured_bacterium_f_Muribaculaceae, and Rikenellaceae_RC9_gut_group) and decreasing harmful bacteria (Fusobacteriia, Desulfovibrionales, Enterobacteriaceae, Burkholderiaceae, Helicobacteraceae, and Veillonellaceae) and modulated the metabolites involved in arachidonic acid metabolism, thus further promoting short-chain fatty acid production and improving gut barrier, thereby inflammatory responses and oxidative stress were ameliorated. In addition, the pseudogerm-free mouse model verified that dl-norvaline ameliorated obesity-associated disorders in HFD-fed obese mice by targeting gut microbiota. These results clarified that dl-norvaline may be promising for developing and innovating potential functional food products.PMID:39808000 | DOI:10.1021/acs.jafc.4c06638

Detection and quantification of ergothioneine in human serum using surface enhanced Raman scattering (SERS)

Tue, 14/01/2025 - 12:00
Analyst. 2025 Jan 14. doi: 10.1039/d4an01323a. Online ahead of print.ABSTRACTErgothioneine (ERG) is a natural sulfur-containing amino acid found in many organisms, including humans. It accumulates at high concentrations in red blood cells and is distributed to various organs, including the brain. ERG has numerous health benefits and antioxidant capabilities, and it has been linked to various human physiological processes, such as anti-inflammatory, neuroprotective, and anti-aging effects. Accurate, rapid, and cost-effective quantification of ERG levels in human biofluids is crucial for understanding its role in oxidative stress-related diseases. Surface-enhanced Raman scattering (SERS) is an effective approach for measuring compounds at concentrations similar to those at which ERG is present in serum. However, while SERS has been used to characterize or detect ERG, quantification has not yet been achieved due to the variability in the signal enhancement that can arise during sample preparation and analysis. This study introduces a highly efficient and reliable technique for quickly (20 min is typical per sample) measuring ERG levels in human serum using SERS. This employs an internal standard highly specific for ERG which resulted in limit of quantification values of 0.71 μM. To validate this approach, we analysed real human serum with unknown ERG levels as a blind test set and primary reference levels of ERG were produced using a targeted UHPLC-MS/MS reference method.PMID:39807959 | DOI:10.1039/d4an01323a

Effects of hawthorn pectin and its oligomers on gut microbiota and metabolites in high-fat diet mice

Tue, 14/01/2025 - 12:00
Food Funct. 2025 Jan 14. doi: 10.1039/d4fo04686b. Online ahead of print.ABSTRACTPectin is an acidic heteropolysaccharide with natural, green, and inexpensive characteristics. Compared to polysaccharides, oligosaccharides are more easily utilized by the body, and the physiological function of hawthorn pectin oligosaccharides (POS) may vary depending on their degree of polymerization (DP). Therefore, we mainly studied the effects of hawthorn pectin (HP) and POS with different DP on gut microbiota disorders induced by high-fat diet (HFD). HP and POS both improved weight gain, dyslipidemia, and glucose homeostasis caused by HFD, and increased serum GLP-1 levels. Meanwhile, the increased expression of Gcg and Pcsk1 genes in the ileum of the treatment group further confirmed this result. In addition, HP and POS reduced certain opportunistic pathogens, while restoring the richness and diversity of the gut microbiota. Meanwhile, HP and POS can improve intestinal barrier dysfunction by increasing the claudin-1, occludin, ZO-1, and MUC2 genes. Furthermore, fecal metabolomics suggests that POS may enhance linoleic acid synthesis and improve lipid metabolism by upregulating 9,10-DHOME ((12Z)-9,10-dihydroxyoctadec-12-enoic acid), while HP cannot. Overall, the research results indicate that both HP and POS can improve the weight phenotype changes, gut microbiota disruption, and metabolites changes caused by HFD. Particularly, POS has a better effect than HP, and there are differences in the improvement effect of POS with different DP, among which POS with DP 5 has the most significant improvement effect. This discovery enhances a deeper comprehension of the biological activity of different POS, providing an important basis for further optimizing the application of POS as a functional food.PMID:39807952 | DOI:10.1039/d4fo04686b

Multi-omics investigation of <em>Porphyromonas gingivalis</em> exacerbating acute kidney injury through the gut-kidney axis

Tue, 14/01/2025 - 12:00
mSystems. 2025 Jan 14:e0113624. doi: 10.1128/msystems.01136-24. Online ahead of print.ABSTRACTPeriodontitis is closely related to renal health, but the specific influence of Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, on the development of acute kidney injury (AKI) in mice has not been fully elucidated. In our study, AKI was induced in mice through ischemia-reperfusion injury while administering oral infection with P. gingivalis. Comprehensive analyses were conducted, including 16S rRNA sequencing, liquid chromatography-mass spectrometry (LC-MS) metabolomics, and transcriptome sequencing. In vitro, the identified metabolite was used to stimulate mouse neutrophils. Subsequently, these modified neutrophils were co-cultured with mouse renal tubular epithelial cells. The results showed that oral infection with P. gingivalis significantly exacerbated AKI in mice. 16S rRNA sequencing revealed notable shifts in gut microbiota composition. LC-MS metabolomics analysis identified significant metabolic alterations, particularly the upregulation of 3-indoleacrylic acid in the serum. Transcriptome sequencing showed an increased expression of neutrophilic granule protein (Ngp), which was closely associated with 3-indoleacrylic acid, and the presence of Porphyromonas. Cellular experiments demonstrated that 3-indoleacrylic acid could activate neutrophils, leading to an elevation in NGP protein levels, a response that was associated with renal epithelial cell injury. Oral infection with P. gingivalis exacerbated AKI through the gut-kidney axis, involving gut microbiota dysbiosis, metabolic disturbances, and increased renal expression of Ngp.IMPORTANCE: This study provides novel insights into the relationship between periodontal health and renal function. Porphyromonas gingivalis oral infection disrupted the balance of gut microbiota and was an important modifier determining the severity of acute kidney injury. Under the "gut-kidney axis," P. gingivalis might cause an increase in the level of the gut microbial metabolite 3-indoleacrylic acid, interfering with kidney immunity and disrupting the maintenance of kidney epithelium.PMID:39807890 | DOI:10.1128/msystems.01136-24

Low Bone Mineral Density and Associated Factors Among People Living With HIV in Kerman, Iran: A Cross-Sectional Study in 2021-2022

Tue, 14/01/2025 - 12:00
J Assoc Nurses AIDS Care. 2025 Jan 14. doi: 10.1097/JNC.0000000000000521. Online ahead of print.ABSTRACTChronic diseases such as osteoporosis and low bone mineral density (BMD) are significant public health concerns for people living with HIV (PLWH), especially with the increased life expectancy because of antiretroviral therapy (ART). This study evaluated the prevalence and associated factors of low BMD among 94 PLWH in Kerman, Iran, from September 2021 to February 2022. Using dual-energy X-ray absorptiometry, BMD was measured, with low BMD defined by specific T-scores and Z-scores. Predictors were assessed through interviews, medical records, and blood tests. Bivariable and multivariable logistic regression models identified associations between low BMD and various factors. The study found a 51.1% prevalence of low BMD, with significant associations with hypogonadism (adjusted odds ratio [aOR]: 3.19), longer ART duration (aOR per month: 1.02), and lower body mass index (aOR per unit: 0.83). The findings highlight the need for regular screening and timely intervention for low BMD among PLWH, particularly with prolonged ART use.PMID:39807800 | DOI:10.1097/JNC.0000000000000521

Insights into the molecular underpinning of type 2 diabetes complications

Tue, 14/01/2025 - 12:00
Hum Mol Genet. 2025 Jan 14:ddae203. doi: 10.1093/hmg/ddae203. Online ahead of print.ABSTRACTType 2 diabetes (T2D) complications pose a significant global health challenge. Omics technologies have been employed to investigate these complications and identify the biological pathways involved. In this review, we focus on four major T2D complications: diabetic kidney disease, diabetic retinopathy, diabetic neuropathy, and cardiovascular complications. We discuss advancements in omics research, summarizing findings from genetic, epigenomic, transcriptomic, proteomic, and metabolomic studies across different ancestries and disease-relevant tissues. We stress the importance of integrating multi-omics techniques to elucidate the biological mechanisms underlying T2D complications and advocate for ancestrally diverse studies. Ultimately, these insights will improve risk prediction for T2D complications and inform translation strategies.PMID:39807636 | DOI:10.1093/hmg/ddae203

HIF1α Plays a Crucial Role in the Development of TFE3-Rearranged Renal Cell Carcinoma by Orchestrating a Metabolic Shift Toward Fatty Acid Synthesis

Tue, 14/01/2025 - 12:00
Genes Cells. 2025 Jan;30(1):e13195. doi: 10.1111/gtc.13195.ABSTRACTTumor development often requires cellular adaptation to a unique, high metabolic state; however, the molecular mechanisms that drive such metabolic changes in TFE3-rearranged renal cell carcinoma (TFE3-RCC) remain poorly understood. TFE3-RCC, a rare subtype of RCC, is defined by the formation of chimeric proteins involving the transcription factor TFE3. In this study, we analyzed cell lines and genetically engineered mice, demonstrating that the expression of the chimeric protein PRCC-TFE3 induced a hypoxia-related signature by transcriptionally upregulating HIF1α and HIF2α. The upregulation of HIF1α by PRCC-TFE3 led to increased cellular ATP production by enhancing glycolysis, which also supplied substrates for the TCA cycle while maintaining mitochondrial oxidative phosphorylation. We crossed TFE3-RCC mouse models with Hif1α and/or Hif2α knockout mice and found that Hif1α, rather than Hif2α, is essential for tumor development in vivo. RNA-seq and metabolomic analyses of the kidney tissues from these mice revealed that ketone body production is inversely correlated with tumor development, whereas de novo lipid synthesis is upregulated through the HIF1α/SREBP1-dependent mechanism in TFE3-RCC. Our data suggest that the coordinated metabolic shift via the PRCC-TFE3/HIF1α/SREBP1 axis is a key mechanism by which PRCC-TFE3 enhances cancer cell metabolism, promoting tumor development in TFE3-RCC.PMID:39807625 | DOI:10.1111/gtc.13195

Peptide pool instability of precancerous lesions in rats with chronic pancreatitis model and/or without type 1 diabetes mellitus

Tue, 14/01/2025 - 12:00
Adv Clin Exp Med. 2025 Jan 14. doi: 10.17219/acem/193243. Online ahead of print.ABSTRACTBACKGROUND: The search for early and minimally invasive diagnostic approaches to pancreatic cancer (PC) remains an important issue. One of the most promising directions is to find a sensitive key in the metabolic changes during widespread causes of PC, i.e., chronic pancreatitis (CP) and diabetes mellitus (DM).OBJECTIVES: The main objective of this study was to analyze the peptide pools in the blood plasma and pancreas of rats with modeling of CP and/or without type 1 DM in association with pancreas histopathological grading features.MATERIAL AND METHODS: The study was conducted on white non-linear male rats, divided into 3 groups: 1st group: control, 2nd group: rats with cerulein-stimulated CP, and 3rd group: rats with CP and streptozotocin-inducible type 1 DM. Total protein and peptide content were determined in the pancreas and blood plasma. The peptide pools were fractionated using size-exclusion chromatography.RESULTS: Rats with CP showed a high degree of fibrosis in the pancreas and grade 1 ductal pancreatic intraepithelial neoplasia (PanIN), associated with decreased total peptides in the pancreas. In rats with CP and DM, 2nd and 3rd grade PanIN with pronounced acinar metaplasia was observed in association with decreasing total pancreatic protein and peptide pools. While there was a decrease in total protein and an increase in total peptide in blood serum, the changes were more pronounced in rats with CP and DM. A study revealed both qualitative and quantitative differences in the distribution of peptide pools in 2 groups with pathologies. Qualitatively, plasma samples from pathological groups exhibited an increased number of peaks. Quantitatively, there was a higher proportion of peptides with molecular weights exceeding 700 Da observed in both plasma and pancreas.CONCLUSIONS: The analysis of peptide pools obtained from plasma and PanIN development demonstrated that the peptide pool can serve as an early and complementary indicator of PC emergence.PMID:39807606 | DOI:10.17219/acem/193243

Discovery of Peptidic Siderophore Degradation by Screening Natural Product Profiles in Marine-Derived Bacterial Mono- and Cocultures

Tue, 14/01/2025 - 12:00
Biochemistry. 2025 Jan 14. doi: 10.1021/acs.biochem.4c00706. Online ahead of print.ABSTRACTCoral reefs are hotspots of marine biodiversity, which results in the synthesis of a wide variety of compounds with unique molecular scaffolds, and bioactivities, rendering reefs an ecosystem of interest. The chemodiversity stems from the intricate relationships between inhabitants of the reef, as the chemistry produced partakes in intra- and interspecies communication, settlement, nutrient acquisition, and defense. However, the coral reefs are declining at an unprecedented rate due to climate change, pollution, and increased incidence of pathogenic diseases. Among pathogens, Vibrio spp. bacteria are key players resulting in high mortality. Thus, alternative strategies such as application of beneficial bacteria isolated from disease-resilient species are being explored to lower the burden of pathogenic species. Here, we apply coculturing of a coral-derived pathogenic species of Vibrio and beneficial bacteria and leverage recent advancements in untargeted metabolomics to discover engineerable beneficial traits. By chasing chemical change in coculture, we report Microbulbifer spp.-mediated degradation of amphibactins, produced by Vibrio spp. bacteria to sequester iron. Additional biochemical experiments revealed that the degradation occurs in the peptide backbone and requires the enzyme fraction of Microbulbifer. A reduction in iron affinity is expected due to the loss of one Fe(III) binding moiety. Therefore, we hypothesize that this degradation shapes community behaviors as it pertains to iron acquisition, a limiting nutrient in the marine environment, and survival. Furthermore, Vibrio sp. bacteria suppressed natural product synthesis by beneficial bacteria. Understanding biochemical mechanisms behind these interactions will enable engineering probiotic bacteria capable of lowering pathogenic burdens during heat waves and incidence of disease.PMID:39807563 | DOI:10.1021/acs.biochem.4c00706

Combined transcriptomic and metabolomic analyses reveal the pharmacognostic mechanism of the metabolism of flavonoids in different parts of Polygonum capitatum

Tue, 14/01/2025 - 12:00
Plant Genome. 2025 Mar;18(1):e20543. doi: 10.1002/tpg2.20543.ABSTRACTThe plant Polygonum capitatum (P. capitatum) contains a variety of flavonoids that are distributed differently among different parts. Nevertheless, differentially expressed genes (DEGs) associated with this heterogeneous distribution have not been identified. In this study, combined with transcriptomic and metabonomic analysis, we identified significant DEGs related to variations in flavonoid composition among different parts of P. capitatum. Subsequently, transcriptomic and nontargeted metabolomic analyses revealed that flavonoids and phenolic acids in different parts of P. capitatum were significantly enriched in the phenylpropanoid biosynthesis, shikimic acid biosynthesis, and flavonoid biosynthesis pathways. The expression levels of genes encoding enzymes, including shikimate O-hydroxycinnamoyltransferase (HCT), chalcone synthase (CHS), flavonoid 3',5'-hydroxylase (CYP75A), flavones 3-hydroxylase (F3H), flavonol synthase (FLS), leucoanthocyanidin reductase (LAR), trans-cinnamate 4-monooxygenase (CYP73A), and shikimate kinase (SK), were found to be the lowest in the leaves of P. capitatum via quantitative PCR. Interestingly, these genes are involved in the biosynthesis of quality markers such as gallic acid, quercetin, and quercitrin in P. capitatum. Finally, the targeted metabolomic results reconfirmed that the gallic acid, quercetin, and quercitrin contents were the highest in the leaves of P. capitatum. This research provides a theoretical basis for further understanding the differential regulatory mechanism of flavonoid metabolism in different parts of P. capitatum, providing novel insights into the pharmacognostic basis of P. capitatum.PMID:39807534 | DOI:10.1002/tpg2.20543

A microfluidic coculture model for mapping signaling perturbations and precise drug screening against macrophage-mediated dynamic myocardial injury

Tue, 14/01/2025 - 12:00
Acta Pharm Sin B. 2024 Dec;14(12):5393-5406. doi: 10.1016/j.apsb.2024.11.004. Epub 2024 Nov 13.ABSTRACTMacrophage-mediated inflammation plays a pivotal role in cardiovascular disease pathogenesis. However, current cell-based models lack a comprehensive understanding of crosstalk between macrophages and cardiomyocytes, hindering the discovery of effective therapeutic interventions. Here, a microfluidic model has been developed to facilitate the coculture of macrophages and cardiomyocytes, allowing for mapping key signaling pathways and screening potential therapeutic agents against inflammation-induced dynamic myocardial injury. Through metabolic profiling and bioinformatic enrichment analysis, the microchip model with dynamic cell-cell crosstalk reveals robust activation of inflammatory and oxidative stress-associated metabolic pathways, closely resembling metabolic profiles of myocardial infarction in both humans and rodents. Furthermore, an integrative screening strategy has been established to screen bioactive natural products precisely, identifying ginsenoside Rb1 and protocatechualdehyde as promising cardioprotective candidates in vitro and in vivo. Taken together, the microfluidic coculture model advances mechanistic insight into macrophage-mediated cardio-immunology and may accelerate the discovery of therapeutics for myocardial injury.PMID:39807320 | PMC:PMC11725091 | DOI:10.1016/j.apsb.2024.11.004

Corrigendum to "Integrated skin metabolomics and network pharmacology to explore the mechanisms of Goupi Plaster for treating knee osteoarthritis" [J Tradit, Complementary Altern Med 14 (6) (2024) 675-686]

Tue, 14/01/2025 - 12:00
J Tradit Complement Med. 2024 Nov 12;15(1):106. doi: 10.1016/j.jtcme.2024.11.003. eCollection 2025 Jan.ABSTRACT[This corrects the article DOI: 10.1016/j.jtcme.2024.04.004.].PMID:39807267 | PMC:PMC11725078 | DOI:10.1016/j.jtcme.2024.11.003

Polyphenol metabolomics reveals the applications and prospects of polyphenol-rich plants in natural dyes

Tue, 14/01/2025 - 12:00
For Res (Fayettev). 2024 Dec 19;4:e038. doi: 10.48130/forres-0024-0035. eCollection 2024.ABSTRACTPolyphenols, as one of the primary compounds produced by plant secondary metabolism, have garnered considerable attention because of their non-toxic, environmentally friendly, and biodegradable properties, as well as their notable medicinal value. This study presents a metabolomic analysis of polyphenols from 11 woody plants, including Camellia oleifera, Quercus acutissima, and Punica granatum, investigating a total of 40 polyphenolic metabolites. A differential metabolite dynamics map highlighted the five most differentiated substances among the 11 plants, including vitexin, dihydromyricetin, genistin, resveratrol, and isorhamnetin. To evaluate the application of polyphenol-rich plants as natural dyes, dye performance tests, and color fastness evaluations were conducted, focusing on the specific role of polyphenols in dyeing cotton fabrics. The composition of polyphenols had a minor effect on the color of dyed cotton fabrics, typically imparting only black or brown tones to the fabric. However, their effect on dyeing performance is notable, with the ratio of the dye absorption coefficient (k) to the dye scattering coefficient (s) (K/S) ranging from 1 to 20, and lightness varying from 26 to 78. The addition of mordants not only improved the dye's color fastness but also expanded the color range. Furthermore, this study identified four key substances that influence the dyeing performance of plant dyes, including naringenin, epicatechin, catechin, and dihydromyricetin, and discovered a novel natural dye compound, naringenin. Importantly, six of the 11 plant dyes selected in this study are derived from plant waste, thus providing a theoretical basis for advancing environmentally friendly and sustainable dyeing technologies.PMID:39807261 | PMC:PMC11727558 | DOI:10.48130/forres-0024-0035

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