PubMed

Lipids Health Dis. 2024 Oct 17;23(1):339. doi: 10.1186/s12944-024-02317-4.ABSTRACTBACKGROUND: Metabolic dysfunction associated steatotic liver disease (MASLD) is associated with increased cardiovascular disease (CVD) risk in persons with HIV (PWH). The lipidomic and metabolomic alterations contributing to this risk are poorly understood. We aimed to characterize the advanced lipoprotein and targeted metabolomic profiles in PWH and assess if the presence and severity of MASLD influence these profiles.METHODS: This is a cross-sectional analysis of a prospectively enrolled multicenter cohort. PWH without alcohol abuse or known liver disease underwent vibration-controlled transient elastography for controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Lipidomic and metabolomic profiling was undertaken with nuclear magnetic resonance (NMR) spectroscopy. Hepatic steatosis was defined as CAP ≥ 263 dB/m and clinically significant fibrosis (CSF) as LSM ≥ 8 kPa. Logistic regression models assessed associations between MASLD, CSF and lipidomic and metabolic parameters.RESULTS: Of 190 participants (71% cisgender male, 96% on antiretroviral therapy), 58% had MASLD and 12% CSF. Mean (SD) age was 48.9 (12.1) years and body mass index (BMI) 29.9 (6.4) kg/m2. Compared to PWH without MASLD (controls), PWH with MASLD had lower HDL-C but higher total triglyceride, VLDL-C, branched-chain amino acids, GlycA, trimethylamine N-oxide levels, Lipoprotein-Insulin Resistance and Diabetes Risk Indices. There were no significant differences in these parameters between participants with MASLD with or without CSF. In a multivariable regression analysis, MASLD was independently associated with changes in most of these parameters after adjustment for age, gender, race/ethnicity, type 2 diabetes mellitus, BMI, and lipid lowering medications use.CONCLUSIONS: MASLD in PWH is independently associated with altered advanced lipoprotein and targeted metabolic profiles, indicating a higher CVD risk in this population.PMID:39420356 | DOI:10.1186/s12944-024-02317-4

J Transl Med. 2024 Oct 17;22(1):945. doi: 10.1186/s12967-024-05757-9.ABSTRACTBACKGROUND: Although numerous studies have shown that bariatric surgery results in sustained weight loss and modifications in gut microbiota composition and cognitive function, the exact underlying mechanisms are unclear. This study aimed to investigate the effects of bariatric surgery on cognitive function through the microbiota-gut-brain axis (MGBA).METHODS: Demographic data, serum samples, fecal samples, cognitive assessment scales, and resting-state functional connectivity magnetic resonance imaging (rs-fMRI) scans were obtained from 39 obese patients before and after (6 months) laparoscopic sleeve gastrectomy (LSG). PCA analysis, OPLS-DA analysis, and permutation tests were used to conduct fecal 16 S microbiota profiling, serum metabolomics, and neuroimaging analyses, and a bariatric surgery-specific rs-fMRI brain functional connectivity network was constructed. Spearman correlation analysis and Co-inertia analysis were employed to correlate significant alterations in cognitive assessment scales and resting-state functional connectivity difference networks with differential serum metabolites and 16 S microbiota data to identify key gut microbiota and serum metabolic factors.RESULTS: LSG significantly reduced the weight of obese patients, with reductions of up to 28%. Furthermore, cognitive assessment scale measurements revealed that LSG enhanced cognitive functions, including memory (HVLT, p = 0.000) and executive function (SCWT, p = 0.008). Also, LSG significantly altered gut microbiota composition (p = 0.001), with increased microbial abundance and diversity (p < 0.05). Moreover, serum metabolite levels were significantly altered, revealing intergroup differences in 229 metabolites mapped to 72 metabolic pathways (p < 0.05, VIP > 1). Spearman correlation analysis among cognitive assessment scales, gut microbiota species, and serum metabolites revealed correlations with 68 gut microbiota species and 138 serum metabolites (p < 0.05). Furthermore, pairwise correlations were detected between gut microbiota and serum metabolites (p < 0.05). Functional neuroimaging analysis revealed that LSG increased functional connectivity in cognitive-related frontotemporal networks (FPN, p < 0.01). Additionally, normalization of the default mode network (DMN) and salience network (SN) connectivity was observed after LSG (p < 0.001). Further canonical correlation and correlation analysis suggested that the cognitive-related brain network changes induced by LSG were associated with key gut microbiota species (Akkermansia, Blautia, Collinsella, Phascolarctobacterium, and Ruminococcus, p < 0.05) and neuroactive metabolites (Glycine, L-Serine, DL-Dopa, SM (d18:1/24:1(15Z), p < 0.05).CONCLUSION: These findings indicate the pathophysiological role of the microbiota-gut-brain axis in enhancing cognitive function after bariatric surgery, and the study provides a basis for clinical dietary adjustments, probiotic supplementation, and guidance for bariatric surgery, but further research is still needed.TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100049403. Registered 02 August 2021, https://www.chictr.org.cn/ .PMID:39420319 | DOI:10.1186/s12967-024-05757-9

BMC Plant Biol. 2024 Oct 18;24(1):980. doi: 10.1186/s12870-024-05663-8.ABSTRACTBACKGROUND: Drought stress is a significant abiotic stressor that hinders growth, development, and crop yield in soybeans. Strigolactones (SLs) positively regulate plant resistance to drought stress. However, the impact of foliar application of SLs having different concentrations on soybean growth and metabolic pathways related to osmoregulation remains unknown. Therefore, to clarify the impact of SLs on soybean root growth and cellular osmoregulation under drought stress, we initially identified optimal concentrations and assessed key leaf and root indices. Furthermore, we conducted transcriptomic and metabolic analyses to identify differential metabolites and up-regulated genes.RESULTS: The results demonstrated that drought stress had a significant impact on soybean biomass, root length, root surface area, water content and photosynthetic parameters. However, when SLs were applied through foliar application at appropriate concentrations, the accumulation of ABA and soluble protein increased, which enhanced drought tolerance of soybean seedlings by regulating osmotic balance, protecting membrane integrity, photosynthesis and activating ROS scavenging system. This also led to an increase in soybean root length, lateral root number and root surface area. Furthermore, the effects of different concentrations of SLs on soybean leaves and roots were found to be time-sensitive. However, the application of 0.5 µM SLs had the greatest beneficial impact on soybean growth and root morphogenesis under drought stress. A total of 368 differential metabolites were screened in drought and drought plus SLs treatments. The up-regulated genes were mainly involved in nitrogen compound utilization, and the down-regulated metabolic pathways were mainly involved in maintaining cellular osmoregulation and antioxidant defenses.CONCLUSIONS: SLs enhance osmoregulation in soybean plants under drought stress by regulating key metabolic pathways including Arachidonic acid metabolism, Glycerophospholipid metabolism, Linoleic acid metabolism, and Flavone and flavonol biosynthesis. This study contributes to the theoretical understanding of improving soybean adaptability and survival in response to drought stress.PMID:39420293 | DOI:10.1186/s12870-024-05663-8

Nat Commun. 2024 Oct 17;15(1):8965. doi: 10.1038/s41467-024-53353-8.ABSTRACTInfection is a devastating post-surgical complication, often requiring additional procedures and prolonged antibiotic therapy. This is especially relevant for craniotomy and prosthetic joint infections (PJI), both of which are characterized by biofilm formation on the bone or implant surface, respectively, with S. aureus representing a primary cause. The local tissue microenvironment likely has profound effects on immune attributes that can influence treatment efficacy, which becomes critical to consider when developing therapeutics for biofilm infections. However, the extent to which distinct tissue niches influence immune function during biofilm development remains relatively unknown. To address this, we compare the metabolomic, transcriptomic, and functional attributes of leukocytes in mouse models of S. aureus craniotomy and PJI complemented with patient samples from both infection modalities, which reveals profound tissue niche-dependent differences in nucleic acid, amino acid, and lipid metabolism with links to immune modulation. These signatures are both spatially and temporally distinct, differing not only between infection sites but evolving over time within a single model. Collectively, this demonstrates that biofilms elicit unique immune and metabolic responses that are heavily influenced by the local tissue microenvironment, which will likely have important implications when designing therapeutic approaches targeting these infections.PMID:39420209 | DOI:10.1038/s41467-024-53353-8

EMBO J. 2024 Oct 17. doi: 10.1038/s44318-024-00271-6. Online ahead of print.ABSTRACTTriple-negative breast cancer (TNBC) metabolism and cell growth uniquely rely on glutamine uptake by the transporter ASCT2. Despite previous data reporting cell growth inhibition after ASCT2 knockdown, we here show that ASCT2 CRISPR knockout is tolerated by TNBC cell lines. Despite the loss of a glutamine transporter and low rate of glutamine uptake, intracellular glutamine steady-state levels were increased in ASCT2 knockout compared to control cells. Proteomics analysis revealed upregulation of macropinocytosis, reduction in glutamine efflux and increased glutamine synthesis in ASCT2 knockout cells. Deletion of ASCT2 in the TNBC cell line HCC1806 induced a strong increase in macropinocytosis across five ASCT2 knockout clones, compared to a modest increase in ASCT2 knockdown. In contrast, ASCT2 knockout impaired cell proliferation in the non-macropinocytic HCC1569 breast cancer cells. These data identify macropinocytosis as a critical secondary glutamine acquisition pathway in TNBC and a novel resistance mechanism to strategies targeting glutamine uptake alone. Despite this adaptation, TNBC cells continue to rely on glutamine metabolism for their growth, providing a rationale for targeting of more downstream glutamine metabolism components.PMID:39420093 | DOI:10.1038/s44318-024-00271-6

Nat Commun. 2024 Oct 17;15(1):8983. doi: 10.1038/s41467-024-52973-4.ABSTRACTH3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain.PMID:39419964 | DOI:10.1038/s41467-024-52973-4

Antonie Van Leeuwenhoek. 2024 Oct 17;118(1):21. doi: 10.1007/s10482-024-02028-x.ABSTRACTMicroalgae are significantly influenced by light quality and quantity, whether in their natural habitats or under laboratory and industrial culture conditions. The present study examines the adaptive responses of the marine microalga Tetraselmis chuii to different light regimes, using a cost-effective filtering method and a multi-omics approach. Microalgal growth rates were negatively affected by all filtered light regimes. After six days of cultivation, growth rate for cultures exposed to blue and green filtered light was 67%, while for red filter was 83%, compared to control cultures. Transcriptomic analysis revealed that the usage of green filters resulted in upregulation of transcripts involved in ribosome biogenesis or coding for elongation factors, exemplified by a 2.3-fold increase of TEF3. On the other hand, a 2.7-fold downregulation was observed in photosynthesis-related petJ. Exposure to blue filtered light led to the upregulation of transcripts associated with pyruvate metabolism, while photosynthesis was negatively impacted. In contrast, application of red filter induced minor transcriptomic alterations. Regarding metabolomic analysis, sugars, amino acids, and organic acids exhibited significant changes under different light regimes. For instance, under blue filtered light sucrose accumulated over 6-fold, while aspartic acid content decreased by 4.3-fold. Lipidomics analysis showed significant accumulation of heptadecanoic and linoleic acids under green and red light filters. Together, our findings indicate that filter light can be used for targeted metabolic manipulation.PMID:39419938 | DOI:10.1007/s10482-024-02028-x

Planta. 2024 Oct 17;260(5):118. doi: 10.1007/s00425-024-04544-6.ABSTRACTHeat stress reduces strawberry growth and fruit quality by impairing photosynthesis, disrupting hormone regulation, and altering mineral nutrition. Multi-omics studies show extensive transcriptional, post-transcriptional, proteomic and metabolomic under high temperatures. Garden strawberry is a globally cultivated, economically important fruit crop highly susceptible to episodic heat waves and chronically rising temperatures associated with climate change. Heat stress negatively affects the growth, development, and quality of strawberries. Elevated temperatures affect photosynthesis, respiration, water balance, hormone signaling, and carbohydrate metabolism in strawberries. Heat stress reduces the size and number of leaves, the number of crowns, the differentiation of flower buds, and the viability of pollen and fruit set, ultimately leading to a lower yield. On a physiological level, heat stress reduces membrane stability, increases the production of reactive oxygen species, and reduces the antioxidant capacity of strawberries. Heat-tolerant varieties have better physiological and biochemical adaptation mechanisms compared to heat-sensitive varieties. Breeding heat-tolerant strawberry cultivars involves selection for traits such as increased leaf temperature, membrane thermostability, and chlorophyll content. Multi-omics studies show extensive transcriptional, post-transcriptional, proteomic, metabolomic, and ionomic reprogramming at high temperatures. Integrative-omics approaches combine multiple omics datasets to obtain a systemic understanding of the responses to heat stress in strawberries. This article summarizes the deciphering of strawberry responses to heat stress using physiological, biochemical, and molecular approaches that will enable the development of resilient adaptation strategies that sustain strawberry production under global climate change.PMID:39419853 | DOI:10.1007/s00425-024-04544-6

J Appl Microbiol. 2024 Oct 17:lxae269. doi: 10.1093/jambio/lxae269. Online ahead of print.ABSTRACTAIMS: Vulvovaginal candidiasis (VVC) is a prevalent condition affecting a significant proportion of women worldwide, with recurrent episodes leading to detrimental effects on quality of life. While treatment with clotrimazole is common, the specific alterations it evokes in the vaginal bacteriome and metabolome were previously underexplored.METHODS AND RESULTS: In this prospective study, we enrolled reproductive-age women diagnosed with single VVC and conducted comprehensive analyses of vaginal fungi, bacteriome, and metabolome before and after local clotrimazole treatment. We observed a significant reduction in Candida albicans and notable improvements in vaginal cleanliness. Advanced sequencing revealed substantial shifts in the vaginal bacteriome, with an increase in Lactobacillus-dominant communities post-treatment. Our findings identified 17 differentially abundant bacterial species, including notable decreases in pathogenic anaerobes such as Gardnerella vaginalis, Dialister micraerophilus, and Aerococcus christensenii, suggesting a restoration of a healthier microbial balance. Furthermore, metabolomic analysis revealed significant changes in 230 metabolites, particularly within lipid metabolism pathways, with marked downregulation of lipid-related compounds linked to inflammation. Correlation studies indicated a strong interplay between lipid metabolites and specific bacterial species, emphasizing the influence of clotrimazole treatment on microbial and metabolic interactions. Importantly, predictive models using microbiota and metabolite signatures demonstrated high accuracy in distinguishing pre- and post-treatment states.CONCLUSIONS: This research highlights clotrimazole's dual role in effectively clearing Candida infection and promoting a healthier vaginal microenvironment, paving the way for novel microbial and metabolomic-based diagnostic approaches to enhance VVC management and understand its underlying mechanisms.PMID:39419780 | DOI:10.1093/jambio/lxae269

Autophagy. 2024 Oct 17:1-3. doi: 10.1080/15548627.2024.2411854. Online ahead of print.ABSTRACTThe plasma concentration of the macroautophagy/autophagy inhibitor DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) increases with aging and body mass index (BMI). Both advanced age and obesity are among the most important risk factors for the development of cancer. We observed that patients with cancer predisposition syndromes due to mutations in BRCA1, BRCA2 and TP53 exhibit abnormally high plasma DBI/ACBP levels. Additionally, patients without known cancer predisposition syndromes also manifest higher DBI/ACBP levels before imminent cancer diagnosis (within 0-3 years) as compared to age and BMI-matched controls who remain cancer-free. Thus, supranormal plasma DBI/ACBP constitutes a risk factor for later cancer development. Mouse experimentation revealed that genetic or antibody-mediated DBI/ACBP inhibition can delay the development or progression of cancers. In the context of chemoimmunotherapy, DBI/ACBP neutralization enhances tumor infiltration by non-exhausted effector T cells but reduces infiltration by regulatory T cells. This resulted in better cancer control in models of breast cancer, non-small cell lung cancer and sarcoma. We conclude that DBI/ACBP constitutes an actionable autophagy checkpoint for improving cancer immunosurveillance. Abbreviation: BMI, body mass index; CTL, cytotoxic T lymphocyte; DBI, diazepam binding inhibitor, acyl-CoA binding protein; mAb, monoclonal antibody; NSCLC, non-small cell lung cancer; PDCD1/PD-1, programmed cell death 1; scRNA-seq, single-cell RNA sequencing; Treg, regulatory T cell.PMID:39419485 | DOI:10.1080/15548627.2024.2411854

Bioresour Technol. 2024 Oct 15:131644. doi: 10.1016/j.biortech.2024.131644. Online ahead of print.ABSTRACTThe fixation of carbon dioxide (CO2) using microalgae is a promising CO2 capture and utilization technology. Microalgae have also been suggested as a potential treatment for biogas slurry (BS). This study screened microalgae capable of tolerating both high CO2 concentrations and BS, assessed their CO2 fixation and pollutant removal capabilities, and evaluated the potential use of the resulting algal biomass. Chlamydopodium sp. HS01, which showed the highest tolerance to 15% CO2 and BS, was selected due to its strong growth, CO2 fixation, and ammonia nitrogen removal abilities. The generated biomass also demonstrated significant potential for bioenergy production. Metabolomics analysis revealed that the lipid composition of HS01 underwent substantial changes under 15% CO2 alone and in combination with BS, likely as a stress adaptation strategy. Overall, HS01 presents high potential for resource utilization of CO2 coupled with actual BS.PMID:39419404 | DOI:10.1016/j.biortech.2024.131644

Chemosphere. 2024 Oct 15:143541. doi: 10.1016/j.chemosphere.2024.143541. Online ahead of print.ABSTRACTAlthough the hazards of environmental microplastics (MPs) are well known, it is unclear which of their characteristics have the greatest effects on organism. We investigated the toxic effects of oral administration according to physical properties, including the shape of fragmented polyethylene terephthalate (PET) (FrPET) and fibrous PET (FiPET) MPs. After 72 h of exposure, apoptosis and phagocytic activity varied significantly among juvenile rockfish (Sebastes schlegeli) exposed to both FrPET and FiPET. The levels of immune-related genes and hepatic metabolic activity also increased after exposure to both shapes of MPs, but the variation in responses was greater in fish exposed to FiPET compared with those exposed to FrPET. The transcriptomic and metabolomics analysis results indicated that the maintenance and homeostasis of immune system was affected by oral exposure to FrPET and FiPET. The amino acid metabolic processes were identified in rockfish exposed to FrPET, but the notch signaling pathway were evident in the FiPET exposure group. Metabolomics analysis revealed that oral ingestion of MP fibers led to a stronger inflammatory response and greater oxidative stress in juvenile rockfish. These results can be used to understand environmentally dominant MP toxic effects such as type, size, shapes, as well as to prioritize ecotoxicological management.PMID:39419335 | DOI:10.1016/j.chemosphere.2024.143541

Clin Chim Acta. 2024 Oct 15:120004. doi: 10.1016/j.cca.2024.120004. Online ahead of print.ABSTRACTAs a large and structurally diverse family of small molecules, bile acids play a crucial role in regulating lipid, glucose, and energy metabolism. In the human body, bile acids share a similar chemical structure with many isomers, exhibit little difference in polarity, and possess various physiological activities. The types and contents of bile acids present in different diseases vary significantly. Therefore, comprehensive and accurate detection of the content of various types of bile acids in different biological samples can not only provide new insights into the pathogenesis of diseases but also facilitate the exploration of novel strategies for disease diagnosis, treatment, and prognosis. The detection of disease-induced changes in bile acid profiles has emerged as a prominent research focus in recent years. Concurrently, targeted metabolomics methods utilizing high-performance liquid chromatography-mass spectrometry (HPLC-MS) have progressively established themselves as the predominant technology for the separation and detection of bile acids. Bile acid profiles will increasingly play an important role in diagnosis and guidance in the future as the relationship between disease and changes in bile acid profiles becomes clearer. This highlights the growing diagnostic value of bile acid profiles and their potential to guide clinical decision-making. This review aims to explore the significance of bile acid profiles in clinical diagnosis from four perspectives: the synthesis and metabolism of bile acids, techniques for detecting bile acid profiles, changes in bile acid profiles associated with diseases, and the challenges and future prospects of applying bile acid profiles in clinical settings.PMID:39419312 | DOI:10.1016/j.cca.2024.120004

J Ethnopharmacol. 2024 Oct 15:118950. doi: 10.1016/j.jep.2024.118950. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The Cissus gongylodes has traditionally been used in the diet of indigenous people in Brazil and in traditional medicine for kidney stone removal and inflammatory diseases. The active compounds responsible for these pharmacological activities are unknown.AIM OF THE STUDY: This study aims to isolate, for the first time, the compounds in the decoction of C. gongylodes leaves responsible for their anti-inflammatory and anti-urolithiatic ethnopharmacological properties.MATERIALS AND METHODS: The most active fractions of the C. gongylodes leaf decoction were fractionated using SPE-C18 and the compounds were purified through HPLC-UV-DAD. The decoction fractions and isolated compounds were evaluated for their anti-inflammatory and anti-urolithiatic activities. The anti-inflammatory activity was assessed using an ex vivo assay in human blood induced by LPS and calcium ionophore, measuring inflammatory mediators, PGE2 and LTB4. The anti-urolithiatic activity was evaluated using an in vitro experimental model with human urine to determine the dissolution of the most recurrent calcium oxalate (CaOx) crystals. Additionally, the decoction was chemically characterized through metabolomic analysis using UHPLC-ESI-HRMS.RESULTS: The isolated compounds from the decoction of C. gongylodes, including rutin, eriodictyol 3'-O-glycoside, and isoquercetin, have demonstrated significant multi-target actions. These components act as anti-inflammatory agents by inhibiting the release of main inflammatory mediators, PGE2 and LTB4. Additionally, they exhibit anti-urolithiatic properties, promoting the dissolution of calcium oxalate (CaOx) crystals. Furthermore, the characterization of the decoction by UHPLC-ESI-HRMS revealed a high content of flavonoids, mainly glycosylated flavonoids.CONCLUSIONS: The results support the traditional use of C. gongylodes decoction, identifying the compounds responsible for its anti-inflammatory and anti-urolithiatic effects. The decoction fractions and isolated compounds exhibited dual anti-inflammatory activity, effectively inhibiting key inflammatory pathways and potentially presenting fewer adverse effects while also promoting the dissolution of CaOx crystals associated with urolithiasis. The multi-target action displayed by C. gongylodes is particularly desirable in the treatment of urolithiasis, as inflammation and PGE2 production precede and contribute to the formation of CaOx crystals in the kidneys. Based on these actions, C. gongylodes emerges as a potent source of active compounds for the development of new treatments for urolithiasis.PMID:39419303 | DOI:10.1016/j.jep.2024.118950

J Ethnopharmacol. 2024 Oct 15:118946. doi: 10.1016/j.jep.2024.118946. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Currently, adverse reactions limit the development of traditional Chinese medicine injections (TCMI), and severe anaphylactoid shock is one of the serious adverse reactions, which presents a significant challenge. The presence of abnormal inflammatory mediators before the administration of TCMI will most likely result in severe anaphylactoid reactions. Not only that, the lack of clinically relevant safety evaluations impedes the widespread use of TCMI, and there is an urgent need for studies to reveal the mechanisms of anaphylactoid shock caused by TCMI.AIM OF THE STUDY: To investigate the effects and underlying mechanisms of lipopolysaccharide (LPS)-induced inflammation, which aggravates anaphylactoid reactions caused by TCMI, utilizing a guinea pig model.METHODS: The dose and duration of LPS administration and different doses of compound 48/80 (C48/80) were examined by using guinea pigs as a model. Shuanghuanglian (SHLI) and Qingkailing (QKLI) injections, these two representative TCMI, were used for validation. The plasma biochemical indices, including histamine, 5-hydroxytryptamine, tumor necrosis factor-α, interleukin 6, immunoglobulin E, C5a, tryptase, and platelet activating factor, as well as the pathological characteristics of the lung, were analyzed. Futhermore, plasma metabolomics was employed to reveal changes in metabolic pathways in vivo when inflammation co-exists with TCMI. In addition, Western blot analysis was conducted to assess the expression of critical signaling pathways.RESULTS: Stimulation with 2 mg/kg of LPS for 12 h induced inflammatory responses in the guinea pig model. C48/80 (3.0 mg/kg) in combination with LPS resulted in an increase in anaphylactoid-related indicators in the plasma. High doses of SHLI and QKLI aggravated plasma indices and lung histological injury caused by LPS-induced inflammation. A total of 36 and 63 differential metabolites were significantly altered after LPS stimulation in the SHLI-and QKLI-treated guinea pig groups, respectively. The associated metabolic pathways include central carbon metabolism in cancer, the tricarboxylic acid cycle, glyoxylate and dicarboxylate metabolism. The p38/ERK/NF-κB signal pathway may be significantly affected by TCMI in vivo after LPS stimulation.CONCLUSION: LPS-induced inflammation aggravated anaphylactoid reactions caused by SHLI and QKLI, with a correlation to dosage. After the presence of LPS, the administration of TCMI interferes with the immune response by over-activating the p38/ERK/NF-κB signaling pathway. This activation leads to an excessive release of inflammatory factors and anaphylactoid mediators. These results present a new direction for mitigating adverse clinical reactions associated with TCMI.PMID:39419299 | DOI:10.1016/j.jep.2024.118946

Sci Total Environ. 2024 Oct 15:176972. doi: 10.1016/j.scitotenv.2024.176972. Online ahead of print.ABSTRACTPhthalates, particularly butyl benzyl phthalate (BBP), are ubiquitous environmental contaminants with potential neurotoxic effects. However, their impact on soil organisms, especially earthworms (Eisenia fetida), remains poorly understood. The current study investigated the neurotoxic effects of BBP on Eisenia fetida in artificial and red soils using an integrated approach combining biochemical assays, metabolomics, and molecular docking. Earthworms were exposed to 0, 1, and 10 mg kg-1 BBP for 14 and 28 days. Biochemical assays revealed significant increases in oxidative stress markers and disruptions in neurotransmission-related enzyme activities. Metabolomic analysis of the cerebral ganglia identified alterations in energy metabolism, lipid metabolism, and neuroactive ligand-receptor interaction signaling pathways. Molecular docking studies corroborated these findings, showing strong interactions between BBP and essential neuronal proteins, particularly the sodium pump. The integration of these data suggests that BBP-induced neurotoxicity in Eisenia fetida is primarily mediated by calcium signaling pathway dysfunction and calcium homeostasis imbalance. Notably, neurotoxic effects were more pronounced in red soil than in artificial soil, highlighting the importance of considering soil type in ecotoxicological assessments. The current study provides novel insights into the mechanisms of BBP-induced neurotoxicity in soil invertebrates and underscores the potential ecological risks associated with phthalate contamination in agricultural environments.PMID:39419222 | DOI:10.1016/j.scitotenv.2024.176972

Immunity. 2024 Oct 9:S1074-7613(24)00458-8. doi: 10.1016/j.immuni.2024.09.014. Online ahead of print.ABSTRACTThe seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer's disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.PMID:39419029 | DOI:10.1016/j.immuni.2024.09.014

Poult Sci. 2024 Oct 13;103(12):104422. doi: 10.1016/j.psj.2024.104422. Online ahead of print.ABSTRACTThe pathogenesis of fatty liver is highly intricate. The role of the gut-liver axis in the development of fatty liver has gained increasing recognition in recent years. This study was conducted to explore the role of bile acid signaling and gut barrier in the pathogenesis of fatty liver. A total of 100 "Jing Tint 6" laying hens, 56-week-old, were used and fed basal diets until 60 weeks of age. At the end of the experiment, thirty individuals were selected based on the degree of hepatic steatosis. The hens with minimal hepatic steatosis (< 5 %) were chosen as healthy controls, while those with severe steatosis (> 33 %) in the liver were classified as the fatty liver group. Laying hens with fatty liver and healthy controls showed significant differences in body weight, liver index, abdominal fat ratio, feed conversion ratio (FCR), albumin height, Haugh unit, and biochemical indexes. The results of bile acid metabolomics revealed a clear separation in hepatic bile acid profiles between the fatty liver group and healthy controls, and multiple secondary bile acids were decreased in the fatty liver group, indicating disordered bile acid metabolism. Additionally, the mRNA levels of farnesoid X receptor (FXR) and genes related to bile acid transport were significantly decreased in both the liver and terminal ileum of hens with fatty liver. Moreover, the laying hens with fatty liver exhibited significant decreases in ileal crypt depth, the number of goblet cells, and the mRNA expression of tight junction-related proteins, alongside a significant increase in ileal permeability. Collectively, these findings suggest that disordered bile acids, suppressed FXR-mediated signaling, and impaired intestinal barrier function are potential factors promoting the development of fatty liver. These insights indicate that regulating bile acids and enhancing intestinal barrier function may become new preventive and therapeutic strategies for fatty liver in the near future.PMID:39418789 | DOI:10.1016/j.psj.2024.104422

Mult Scler Relat Disord. 2024 Oct 10;92:105936. doi: 10.1016/j.msard.2024.105936. Online ahead of print.ABSTRACTBACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a central nervous system inflammatory demyelinating immune-mediated ailment, which is influenced by genetic, epigenetic, and environmental elements. The escalating incidence of NMOSD in recent years implies alterations in environmental risk factors. Recent research has established a correlation between gut microbiomes and the development of NMOSD.METHODS: Metagenomic shotgun sequencing and gas chromatography-mass spectrometry (GC-MS) were employed to assess alterations of the structure and function in the fecal microbiome, as well as levels of short-chain fatty acids (SCFAs) in fecal and blood samples, among individuals with neuromyelitis optica spectrum disorder (NMOSD) during the acute phase (n = 25), the remission phase (n = 11), and a group of healthy controls (HCs) (n = 24). We further explored the correlation between gut microbiota and the pathogenesis of NMOSD through fecal microbiota transplantation (FMT). The gut microbiome from human donors diagnosed with NMOSD or HCs was transplanted into germ-free mice, followed by an analysis of the alterations in the structure and functionality of the transplanted mice's gut microbiome. Additionally, the impact of microbiome transfer on the immunity and spinal cord of germ-free mice was assessed through various techniques, including ELISA, flow cytometry, western blot, histopathology, and transcriptome sequencing.RESULTS: (1) At the taxonomic levels of genus and species, there were significant differences in the α-diversity of the microbiome between HCs and NMOSD patients in the acute phase, with NMOSD patients having higher species diversity. (2) In the acute phase, the gut microbiota of NMOSD patients was characterized by Ruminococcaceae_unclassified, Campylobacter, Parabacteroides, Lactobacillus, Akkermansia, Streptococcus oralis, Clostridium leptum, Clostridium asparagiforme, Firmicutes bacterium CAG 238, and Lactobacillus fermentum. (3) The relative abundances of Coprobacter, Turicimonas, Gemmiger, Enterobacter, Roseburia sp.CAG 471, Veillonella tobetsuensis, Proteobacteria bacterium CAG 139, Ruminococcus bicirculans, Lactococcus lactis, Flavonifractor plautii, and Streptococcus cristatus were notably lower in patients experiencing remission compared to NMOSD patients in the acute phase, On the other hand, the relative abundances of Flavonifractor (P = 0.049) and Clostridium aldenense (P = 0.049) were significantly higher. Following medication, the gut microbiome distribution in NMOSD patients during remission closely resembled that of healthy controls (HCs). (4) Compared with HCs, acetate levels in the feces of patients with NMOSD in the acute phase were significantly lower. (5) In addition, we transplanted feces from NMOSD patients into germ-free mice and revealed a significant increase in the levels of IL-6, IL-17A, and IL-23 in the blood of mice belonging to the NMOSD fecal transplantation (NFMT) group. Additionally, the IL-10 level exhibited a significant reduction. Moreover, the proportion of Th17 cells displayed a significant increase, while the proportion of Treg cells exhibited a significant decrease in the spleens of NFMT mice.CONCLUSION: Patients in the acute phase of neuromyelitis optica spectrum disorder (NMOSD) exhibited imbalances in their gut microbiota and a deficiency in short-chain fatty acids (SCFAs). Following drug treatment, the composition of intestinal microbes in NMOSD patients during the remission phase closely resembled that of the healthy control population. The FMT experiment provided evidence of the significant association between intestinal flora and the pathogenesis of NMOSD. Consequently, investigating gut microbiota and identifying novel microbial markers hold promise for the diagnosis and treatment of NMOSD patients.PMID:39418776 | DOI:10.1016/j.msard.2024.105936

Ecotoxicol Environ Saf. 2024 Oct 16;286:117177. doi: 10.1016/j.ecoenv.2024.117177. Online ahead of print.ABSTRACTEpidemiological studies have demonstrated exposure to cadmium ion (Cd2+) is significantly associated with the incidence and aggravation of nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Cd2+ exposure could alter lipid metabolism, and changed lipid metabolites are significantly associated with NASH. Arachidonic acid (ArA) is an omega-6 polyunsaturated fatty acid. Promotion of ArA synthesis and profile changes by Cd2+ exposure potentially to cause NAFLD. ArA metabolism pathway has been identified to enrich in Cd2+ exposure-facilitated NASH. ArA could be generation an impressive metabolic profile through mainly three pathways, including Cyclooxygenases (COX), Lipoxygenases (LOX) and Cytochrome P450 (CYP450) pathway. However, the functions of these metabolites and underlying mechanism in hepatic inflammation are still not clear. In present study, by integrative transcriptomics and metabolomics analysis, we identified that the fatty acid metabolic process and the pro-inflammatory NF-κB signaling pathway were enriched in Cd2+-regulated differentially expressed genes (DEGs) and Cd2+-altered differential metabolites, such as, fatty acid biosynthesis, degradation, and ArA metabolism. The metabolites levels of LOX pathway products 5-HETE and leukotriene C4 (LTC4), and COX catalytic product prostaglandin D2 (PGD2) were significantly elevated in Cd2+ exposed mouse livers. 5-HETE, LTC4, and PGD2 were significantly positive correlated with NF-κB signaling. In addition, the synthase of 20-Hydroxyeicosatetraenoic acid (20-HETE), CYP450 gene 4 family (CYP4A32), was also involved in NF-κB signaling network. Results from both in vitro and in vivo proved that Cd2+ exposure increased ArA metabolite to PGD2 and 20-HETE, and upregulated the mRNA level of their catalytic enzyme PGDS and CYP4A32. Cd2+-induced ArA metabolite to PGD2 and 20-HETE promoted activation of TLR4/IκBα/NF-κB signaling and pro-inflammatory of hepatocytes. Our study explores novel molecular mechanism of Cd2+ exposure-aggravated liver diseases and provides potential novel targets for in hepatic inflammatory treatments and prevention.PMID:39418721 | DOI:10.1016/j.ecoenv.2024.117177