PubMed

Res Sq [Preprint]. 2024 Dec 9:rs.3.rs-5530702. doi: 10.21203/rs.3.rs-5530702/v1.ABSTRACTNon-steroidal anti-inflammatory drugs (NSAIDs) are popular choices for the mitigation of pain and inflammation; however, they are accompanied by side effects in the gastrointestinal and cardiovascular systems. We compared the effects of naproxen, a traditional NSAID, and celecoxib, a cyclooxygenase - 2 (Cox-2) inhibitor, in humans. Our findings showed a decrease in tryptophan and kynurenine levels in plasma of volunteers treated with naproxen. We further validated this result in mice. Additionally, we find that the depression of tryptophan was independent of both Cox-1 and Cox-2 inhibition, but rather was due to the displacement of bound tryptophan by naproxen. Supplementation of tryptophan in naproxen-treated mice rescued fecal blood loss and inflammatory gene expression driven by IL-1β in the heart.PMID:39711561 | PMC:PMC11661377 | DOI:10.21203/rs.3.rs-5530702/v1

Food Funct. 2024 Dec 23. doi: 10.1039/d4fo04019h. Online ahead of print.ABSTRACTFood allergies are pathological adverse reactions against harmless dietary proteins. While studies have shown the involvement of host metabolic changes (e.g., lipid metabolism and amino acid metabolism) in the development of food allergy (FA), the adaptive changes in glucose metabolism induced by food allergen exposure remain largely unclear. In this study, BALB/c mice were sensitized intraperitoneally with an ovalbumin (OVA)/aluminum adjuvant, followed by oral OVA challenges to induce anaphylaxis. Increased levels of serum OVA-specific IgE and MCPT-1, and Th2 response bias were also presented in FA mice. Subsequently, the intestinal untargeted metabolomic analysis revealed the signature enrichment of glycolysis, manifested by increases in glycolytic metabolites including glucose-6-phosphate, fructose-6-phosphate, 2-phosphoglycerate, and lactate in FA mice. Consistently, the serum lactate level was found to be significantly elevated in allergic mice. Oral administration of OVA also upregulated the expression of critical metabolic enzymes in glycolysis, namely hexokinase 2, phosphoglycerate mutase 1, and lactate dehydrogenase. Moreover, the hypoxia inducible factor-1 (HIF-1) signaling pathway was activated in FA mice, and the expression of HIF-1α, known as the upstream regulator of glycolysis, was increased after oral OVA challenges. In vitro inhibition of HIF-1α was found to impede mast cell inflammatory responses to allergens. In summary, this study demonstrated that OVA-induced FA exhibited a glucose metabolic feature of HIF-1α-mediated glycolysis upregulation, suggesting the potential of HIF-1α/glycolysis targeted strategies in the alleviation of FA.PMID:39711353 | DOI:10.1039/d4fo04019h

Nat Prod Res. 2024 Dec 23:1-6. doi: 10.1080/14786419.2024.2441494. Online ahead of print.ABSTRACTThe fall armyworm Spodoptera frugiperda is the most prevalent plague in crops associated with a reduction in corn production by up to 34%. Pesticides have been used to reduce this plague, but they cause several environmental problems including resistance, ecological imbalance, and toxicity to the final consumer. The use of plant extracts has been an effective manner of eradicating this plague from crop plantations. In this sense, the hexane, EtOAc, and EtOH/H2O fractions from EtOH extract from different parts of Cenostigma pluviosum were investigated against this fall armyworm leading to a percentage of mortality around 96% in the larval phase for the fraction EtOAc of fruits (FrEA). The fractions were analysed in HPLC-ESI-HRMS for dereplication. Additionally, using multivariate statistical analysis permitted the development of an O2PLS-DA method based on the chemical constitution of fractions shedding light on promising constituents to the insecticidal activity of C. pluviosum against the Spodoptera frugiperda.PMID:39711208 | DOI:10.1080/14786419.2024.2441494

NMR Biomed. 2025 Feb;38(2):e5304. doi: 10.1002/nbm.5304.ABSTRACTMagnetic resonance spectroscopic imaging (MRSI) enables the simultaneous noninvasive acquisition of MR spectra from multiple spatial locations inside the brain. Although 1H-MRSI is increasingly used in the human brain, it is not yet widely applied in the preclinical setting, mostly because of difficulties specifically related to very small nominal voxel size in the rat brain and low concentration of brain metabolites, resulting in low signal-to-noise ratio (SNR). In this context, we implemented a free induction decay 1H-MRSI sequence (1H-FID-MRSI) in the rat brain at 14.1 T. We combined the advantages of 1H-FID-MRSI with the ultra-high magnetic field to achieve higher SNR, coverage, and spatial resolution in the rat brain and developed a custom dedicated processing pipeline with a graphical user interface for Bruker 1H-FID-MRSI: MRS4Brain toolbox. LCModel fit, using the simulated metabolite basis set and in vivo measured MM, provided reliable fits for the data at acquisition delays of 1.30 ms. The resulting Cramér-Rao lower bounds were sufficiently low (< 30%) for eight metabolites of interest (total creatine, N-acetylaspartate, N-acetylaspartate + N-acetylaspartylglutamate, total choline, glutamine, glutamate, myo-inositol, and taurine), leading to highly reproducible metabolic maps. Similar spectral quality and metabolic maps were obtained with one and two averages, with slightly better contrast and brain coverage due to increased SNR in the latter case. Furthermore, the obtained metabolic maps were accurate enough to confirm the previously known brain regional distribution of some metabolites. The acquisitions proved high reproducibility over time. We demonstrated that the increased SNR and spectral resolution at 14.1 T can be translated into high spatial resolution in 1H-FID-MRSI of the rat brain in 13 min using the sequence and processing pipeline described herein. High-resolution 1H-FID-MRSI at 14.1 T provided robust, reproducible, and high-quality metabolic mapping of brain metabolites with minimal technical limitations.PMID:39711201 | DOI:10.1002/nbm.5304

Future Microbiol. 2024 Dec 22:1-10. doi: 10.1080/17460913.2024.2444761. Online ahead of print.ABSTRACTAIMS: A notable scarcity of research has focused on examining alterations in gut microbiota and its metabolites within tacrolimus (TAC)-induced diabetes models.METHODS: Tacrolimus-induced changes in glucose and lipid metabolism indices were analyzed through different routes of administration. The potential role of gut microbiota and its metabolites in TAC-induced diabetes was investigated using 16S rRNA sequencing and non-targeted metabolomics.RESULTS: After intraperitoneal(ip) and oral(po) administration of TAC, the α-diversity index of gut microbiota was significantly increased. The gut microbiota of the three groups of mice was significantly separated, and there were significant changes in composition and functional genes. Fecal metabolites changed significantly after TAC administration by different routes, and 53 metabolites (38 down-regulated and 15 up-regulated) were identified (CON vs. TACip). Similarly, 29 metabolites (8 down-regulated and 21 up-regulated) were identified (CON vs. TACpo). KEGG pathway analysis identified 4 and 13 significantly altered metabolic pathways, respectively. Correlation analysis suggested that microbiota and metabolites were involved in the pathogenesis of TAC-induced diabetes.CONCLUSION: This study investigated the alterations in gut microbiota and fecal metabolites in TAC-induced diabetic mice and evaluated the correlation between these changes. These findings provide valuable insights into potential biomarkers in the development of TAC-induced diabetes.PMID:39711145 | DOI:10.1080/17460913.2024.2444761

Expert Rev Proteomics. 2024 Dec 22. doi: 10.1080/14789450.2024.2445809. Online ahead of print.ABSTRACTINTRODUCTION: Spatial biology is an emerging interdisciplinary field facilitating biological discoveries through the use of spatial omics technologies. Recent advancements in spatial transcriptomics, spatial genomics (e.g. genetic mutations and epigenetic marks), multiplexed immunofluorescence, and spatial metabolomics/lipidomics has enabled high-resolution spatial profiling of gene expression, genetic variation, protein expression, and metabolites/lipids profiles in tissue. These developments contribute to a deeper understanding of the spatial organization within tissue microenvironments at the molecular level.AREAS COVERED: This report provides an overview of the untargeted, bottom-up mass spectrometry (MS)-based spatial proteomics workflow. It highlights recent progress in tissue dissection, sample processing, bioinformatics, and liquid chromatography (LC)-MS technologies that are advancing spatial proteomics toward cellular resolution.EXPERT OPINION: The field of untargeted MS-based spatial proteomics is rapidly evolving and holds great promise. To fully realize the potential of spatial proteomics, it is critical to advance data analysis and develop automated and intelligent tissue dissection at the cellular or subcellular level, along with high-throughput LC-MS analyses of thousands of samples. Achieving these goals will necessitate significant advancements in tissue dissection technologies, LC-MS instrumentation, and computational tools.PMID:39710940 | DOI:10.1080/14789450.2024.2445809

J Mass Spectrom. 2025 Jan;60(1):e5102. doi: 10.1002/jms.5102.ABSTRACTLC-ESI-MS/MS is a preferred method for detecting and identifying metabolites, including those that are unpredictable from the genome, especially in basal metazoans like Cnidaria, which diverged earlier than bilaterians and whose metabolism is poorly understood. However, the unexpected appearance of a "ghost peak" for dopamine, which exhibited the same m/z value and MS/MS product ion spectrum during an analysis of Nematostella vectensis, a model cnidarian, complicated its accurate identification. Understanding the mechanism by which "ghost peaks" appear is crucial to accurately identify the monoamine repertoire in early animals so as to avoid misassignments. Verification experiments showed that in-source oxidation of tyramine, which produced an intense signal, was responsible for this "ghost peak." This artifact commonly occurs among aromatic compounds with high signal intensities and appears at the same m/z as their respective in vivo oxidized metabolites. In metabolomics, spectra contain diverse signals from complex biological mixtures, making it difficult to recognize artifact peaks. To prevent misassignments, despite +16 Da differences, adequate chromatographic separation of metabolites from their respective in vivo oxidation precursors is necessary. Whereas both electrolysis and gas-phase corona discharge can cause in-source oxidation in ESI, corona discharge proved to be the dominant factor. Additionally, the presence of multiple oxygen atom sources was suggested by the voltage-dependent mass shift of +16 Da to +18 Da of the "ghost peak" when using 18O-labeled water as a solvent. Accurate metabolite identification using LC-ESI-MS/MS requires accounting for in-source products that can mimic in vivo products.PMID:39710888 | DOI:10.1002/jms.5102

J Dairy Sci. 2024 Dec 20:S0022-0302(24)01424-3. doi: 10.3168/jds.2024-25788. Online ahead of print.ABSTRACTDemands for animal products are projected to increase in the future, and animal production is key to agricultural sustainability and food security; consequently, enhancing ruminant livestock production efficiencies in sustainable ways is a major goal for the livestock industry. Developmental programming is the concept that various stressors, including compromised maternal nutrition during critical developmental windows will result in both short- and long-term changes in the offspring. Ruminant models of developmental programming indicate that compromised maternal nutrition, including global under and over-nutrition, macronutrients, and specific micronutrients, including amino acids (Met and Arg), vitamins (folate, B12, and choline), and minerals (sulfur, cobalt, and selenium) can alter offspring outcomes. Data also suggest that maternal histotrophic composition, placental function, and likely fetal nutrient supply are altered by compromised maternal nutrition. Likewise, in offspring, visceral organ mass and function, metabolism, growth, and reproduction are affected. Findings from multi-omics approaches demonstrate that compromised maternal nutrition alters transcript abundance, metabolomic profiles, and multiple metabolic pathways. The underlying mechanisms of developmental programming are driven by epigenetic events, which depend on one-carbon metabolism and micronutrient supply. Current findings indicate that developmental programming in ruminants is real, that maternal nutrition can be a major driver of developmental programming, and that genomic and metabolomic changes in offspring are modulated by altered maternal nutrition during critical windows of development. Research needs in the area of developmental programming in ruminants include: enhanced understanding of the underlying mechanisms, practical relevance to production systems, impacts on short- and long-term animal health including longevity, interrelationships between maternal and paternal influences, intergenerational impacts, and interrelationships with the host microbiome. Additionally, strategic supplementation and precision nutrition approaches should be developed to foster the positive and mitigate the negative aspects of developmental programming to improve the efficiency and sustainability of ruminant livestock production systems.PMID:39710263 | DOI:10.3168/jds.2024-25788

Biosystems. 2024 Dec 20:105378. doi: 10.1016/j.biosystems.2024.105378. Online ahead of print.ABSTRACTAny homeostatic protometabolism would have required orchestration of disparate biochemical pathways into integrated circuits. Extraordinarily specific molecular assemblies were also required at the right time and place. Assembly Theory conflated with its cousins-Complexity Theory, Chaos theory, Quantum Mechanics, Irreversible Nonequilibrium Thermodynamics and Molecular Evolution theory- collectively have great naturalistic appeal in hopes of their providing the needed exquisite steering and controls. They collectively offer the best hope of circumventing the need for active selection required to formally orchestrate bona fide formal organization (as opposed to the mere self-ordering of chaos theory) (Abel and Trevors, 2006b). This paper focuses specifically on AT's contribution to naturalistic life-origin models.PMID:39710183 | DOI:10.1016/j.biosystems.2024.105378

BMC Plant Biol. 2024 Dec 23;24(1):1231. doi: 10.1186/s12870-024-05957-x.ABSTRACTThis study delves into the combined effects of seasonal climate variations and MIPS1 gene mutations on the germination rates of soybean cultivars TW-1 and TW75. Through comprehensive metabolomic and transcriptomic analyses, we identified key KEGG pathways significantly affected by these factors, including starch and sucrose metabolism, lipid metabolism, and amino acid biosynthesis. These pathways were notably disrupted during the spring, leading to an imbalance in metabolic reserves critical for seedling development. Additionally, MIPS1 gene mutations further altered these pathways, exacerbating the metabolic disturbances. Our results underscore the intricate network of environmental and genetic interactions influencing soybean seed vigor and underscore the importance of understanding these pathways to enhance agricultural resilience and seed quality in fluctuating climates.PMID:39710639 | DOI:10.1186/s12870-024-05957-x

Gut Microbes. 2025 Dec;17(1):2442526. doi: 10.1080/19490976.2024.2442526. Epub 2024 Dec 22.ABSTRACTMaternal gut microbiota composition contributes to the status of the neonatal immune system and could influence the early life higher susceptibility to viral respiratory infections. Using a novel protocol of murine maternal probiotic supplementation, we report that perinatal exposure to Lacticaseibacillus rhamnosus (L.rh) or Bifidobacterium animalis subsp. lactis (B.lac) increases the influenza A/PR8 virus (IAV) clearance in neonates. Following either supplementation, type 1 conventional dendritic cells (cDC1) were amplified in the lymph nodes leading to an enhanced IAV antigen-experienced IFN-γ producing effector CD8 T cells in neonates and IAV-specific resident memory CD8 T cells in adulthood. This was compatible with a higher protection of the offspring upon a secondary infection. Interestingly, only mice born to L.rh supplemented mothers further displayed an increased activation of IFN-γ producing virtual memory CD8 T cells and a production of IL-10 by CD4 and CD8 T cells that could explain a better control of the lung damages upon infection. In the offspring and the mothers, no disturbance of the gut microbiota was observed but, as analyzed through an untargeted metabolomic approach, both exposures modified neonatal plasma metabolites. Among them, we further demonstrated that genistein and 3-(3-hydroxyphenyl)propionic acid recapitulate viral clearance or cDC1 activation in neonates exposed to IAV. We conclude that maternal L.rh or B.lac supplementation confers the neonates specific metabolomic modulations with a better CD8 T cell-mediated immune protection against IAV infection.PMID:39710590 | DOI:10.1080/19490976.2024.2442526

Gut Microbes. 2025 Dec;17(1):2438823. doi: 10.1080/19490976.2024.2438823. Epub 2024 Dec 22.ABSTRACTThe development of cardiometabolic (CM) diseases is associated with chronic low-grade inflammation, partly linked to alterations of the gut microbiota (GM) and reduced intestinal integrity. The SINFONI project investigates a multifunctional (MF) nutritional strategy's impact combining different bioactive compounds on inflammation, GM modulation and CM profile. In this randomized crossover-controlled study, 30 subjects at CM-risk consumed MF cereal-products, enriched with polyphenols, fibers, slowly-digestible starch, omega-3 fatty acids or Control cereal-products (without bioactive compounds) for 2 months. Metabolic endotoxemia (lipopolysaccharide (LPS), lipopolysaccharide-binding protein over soluble cluster of differentiation-14 (LBP/sCD14), systemic inflammation and cardiovascular risk markers, intestinal inflammation, CM profile and response to a one-week fructose supplementation, were assessed at fasting and post mixed-meal. GM composition and metabolomic analysis were conducted. Mixed linear models were employed, integrating time (pre/post), treatment (MF/control), and sequence/period. Compared to control, MF intervention reduced intestinal inflammation (fecal calprotectin, p = 0.007) and endotoxemia (fasting LPS, p < 0.05), without alteration of systemic inflammation. MF decreased serum branched-chain amino acids compared to control (p < 0.05) and increased B.ovatus, B.uniformis, A.butyriciproducens and unclassified Christensenellaceae.CAG-74 (p < 0.05). CM markers were unchanged. A 2-month dietary intervention combining multiple bioactive compounds improved intestinal inflammation and induced GM modulation. Such strategy appears as an effective strategy to target low-grade inflammation through multi-target approach.PMID:39710576 | DOI:10.1080/19490976.2024.2438823

Physiol Plant. 2025 Jan-Feb;177(1):e70022. doi: 10.1111/ppl.70022.ABSTRACTSteryl esters (SE) are a storage pool of sterols that accumulates in cytoplasmic lipid droplets and helps to maintain plasma membrane sterol homeostasis throughout plant growth and development. Ester formation in plant SE is catalyzed by phospholipid:sterol acyltransferase (PSAT) and acyl-CoA:sterol acyltransferase (ASAT), which transfer long-chain fatty acid groups to free sterols from phospholipids and acyl-CoA, respectively. Comparative mass spectrometry-based metabolomic analysis between ripe fruits and seeds of a tomato (Solanum lycopersicum cv Micro-Tom) mutant lacking functional PSAT and ASAT enzymes (slasat1xslpsat1) shows that disruption of SE biosynthesis has a differential impact on the metabolome of these organs, including changes in the composition of free and glycosylated sterols. Significant perturbations were observed in the fruit lipidome in contrast to the mild effect detected in the lipidome of seeds. A contrasting response was also observed in phenylpropanoid metabolism, which is down-regulated in fruits and appears to be stimulated in seeds. Comparison of global metabolic changes using volcano plot analysis suggests that disruption of SE biosynthesis favours a general state of metabolic activation that is more evident in seeds than fruits. Interestingly, there is an induction of autophagy in both tissues, which may contribute along with other metabolic changes to the phenotypes of early seed germination and enhanced fruit tolerance to Botrytis cinerea displayed by the slasat1xslpsat1 mutant. The results of this study reveal unreported connections between SE metabolism and the metabolic status of plant cells and lay the basis for further studies aimed at elucidating the mechanisms underlying the observed effects.PMID:39710490 | DOI:10.1111/ppl.70022

Environ Pollut. 2024 Dec 20:125559. doi: 10.1016/j.envpol.2024.125559. Online ahead of print.ABSTRACTThe potential health risks of microplastics (MPs) and their combined exposure with heavy metals such as mercury (Hg) in aquatic environment are increasingly concerned recently. In this work, zebrafish embryos were exposed to different levels of polystyrene microplastics (PS-MPs, ∼0.1 μm) coupled with Hg(II) or/and MeHg at 20 μg/L, to investigate the tissue biodistribution and accumulation of PS-MPs and Hg species, and their interaction, as well as embryo toxicity, oxidative stress and metabolic profiles. With zebrafish embryo development, PS-MPs were ingested and then primarily translocated to yolk sac, liver, and intestinal tissues, further acted as a significant vector for improving the bioaccumulation of MeHg vs. Hg(II). Whatever single or combined exposure of PS-MPs and Hg species, embryo disorders, such as delayed hatching, developmental abnormalities, and motor behavioral, and increased oxidative stress indications were obviously found. Herein, PS-MPs + MeHg aggravated oxidative stress compared with MeHg alone, which might been relevant to the highly accumulation of Hg level in zebrafish larvae induced by PS-MPs. Non-targeted metabolomics results proved PS-MPs involvement disturbed lipid metabolism, amino acid metabolism, and energy metabolism compared with alone Hg(II) or MeHg exposure, of which excessive energy metabolism by activating the glycolysis process was found in PS-MPs + MeHg treatment. This work reveals the enhancement efficacy of PS-MPs on MeHg induced toxicity and adverse stress, further proving the differentiated effect of elemental chemical forms with microplastics. In the future, elemental species must be considered for the combined toxicity evaluation and ecological risk assessments of microplastics and heavy metals.PMID:39710179 | DOI:10.1016/j.envpol.2024.125559

Ann Epidemiol. 2024 Dec 20:S1047-2797(24)00280-1. doi: 10.1016/j.annepidem.2024.12.009. Online ahead of print.ABSTRACTPURPOSE: Although the gut microbiome is important in human health, its relation to adolescent obesity remains unclear. Here we assessed the associations of the gut microbiome with adolescent obesity in a case-control study.METHODS: In the "Children of 1997" birth cohort, participants with and without obesity at ~17.4 years were 1:1 matched on sex, physical activity, parental education and occupation (n=312). Fecal gut microbiome composition and pathways were assessed via shotgun metagenomic sequencing. The association of microbiota species with obesity was evaluated using conditional logistic regression. We explored the association of the obesity-relevant species with adolescent metabolomics using multivariable linear regression, and causal relationships with type 2 diabetes using Mendelian randomization analysis.RESULTS: Gut microbiota in the adolescents with obesity exhibited lower richness (p=0.031) and evenness (p=0.014) compared to controls. Beta diversity revealed differences in the microbiome composition in two groups (p=0.034). Lower relative abundance of Clostridium spiroforme, Clostridium phoceensis and Bacteroides uniformis were associated with higher obesity risk (q<0.15). Lower Bacteroides uniformis was associated with higher branched-chain amino acid, potentially contributing to higher type 2 diabetes risk.CONCLUSION: Adolescents with obesity had a distinct gut microbiota profile compared to the controls, possibly linked to metabolic pertubation and related diseases.PMID:39710013 | DOI:10.1016/j.annepidem.2024.12.009

Biomed Chromatogr. 2025 Jan;39(1):e6054. doi: 10.1002/bmc.6054.ABSTRACTAstragali Radix (AR) is one of the monarch drugs of Fangji Huangqi decoction and has the effects of inducing diuresis to alleviate edema, tonifying and strengthening the body. However, there is a paucity of research regarding the effective fraction and the underlying metabolic mechanism of AR on nephrotic syndrome (NS). This work aims to elucidate the potential mechanisms of AR treating NS, as well as to identify effective part and components. Firstly, body weight, kidney index, 24-h urea protein, and biochemical parameters were used to confirm the kidney injury. The most effective part of AR was determined based on the indicators above. Then, 1H NMR, UHPLC-QTOF/MS, and GC-MS-based metabolomic approaches were used to investigate differential metabolites closely associated with the effective part against NS. A "C-T-P-D" network (a network diagram of "TCM prescription-herbs-components-targets-metabolites-pathways-disease") was constructed by intersecting the targets of differential metabolites with those of AR treating NS. The efficacy indicators determined the n-butanol part of AR as the best effective part. Multiplatform metabolomics and network pharmacology study indicated that the potential mechanism for treating NS may be related to targets (MIF, SRC, and GBA) and metabolic pathways (citrate cycle, glyoxylate and dicarboxylate metabolism, alanine, aspartate and glutamate metabolism, and glycolysis/gluconeogenesis).PMID:39709944 | DOI:10.1002/bmc.6054

Biomed Pharmacother. 2024 Dec 21;182:117771. doi: 10.1016/j.biopha.2024.117771. Online ahead of print.ABSTRACTMild cognitive impairment is increasingly recognized as a complication of type 2 diabetes (T2D). Although currently no disease-modifying treatments for cognitive disorders exist, interest surged in potential neuroprotective effects of newer anti-diabetic drugs. This study investigates the impact of newer anti-diabetic drug classes, dipeptidyl peptidase-4 (DPP-4i) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) - on cognitive decline in T2D patients on metformin therapy. A prospective observational cohort study was conducted, with a follow-up duration of 6 months. The study compared the cognitive performance of T2D patients on metformin monotherapy to those on a combination of metformin with DPP-4i or SGLT2i, using the Montreal Cognitive Assessment Battery. A group of healthy volunteers served as a reference. At baseline, patients receiving combination therapy had a cognitive performance comparable to that of healthy volunteers, while those on metformin monotherapy scored lower. These differences persisted for patients who completed the follow-up, though there was no change within group. Baseline differences were independent of glycemic control, blood lipids, renal function, and serum inflammatory markers. Comprehensive metabolomics and lipidomics revealed that T2D patients on metformin monotherapy exhibited enriched purine, glutathione and sphingolipid metabolism, with alterations in xanthine, L-pyroglutamic acid, and several sphingomyelins. These changes suggest increased oxidative stress in T2D, mitigated in the combination therapy group, as evidenced by total serum antioxidant capacity. As such, we conclude that the combination of DPP-4i or SGLT2i with metformin positively impacts cognitive function in T2D patients by modulating metabolic pathways rather than improving glycemic control, peripheral diabetic complications, or systemic inflammation.PMID:39709941 | DOI:10.1016/j.biopha.2024.117771

Int Immunopharmacol. 2024 Dec 21;146:113866. doi: 10.1016/j.intimp.2024.113866. Online ahead of print.ABSTRACTImmune injury is the main side effect caused by cyclophosphamide and the disruption of the intestinal barrier may be an important cause. Yupingfeng granules have been reported to have immunomodulatory effects and polysaccharides are important components of them. This study aimed to investigate the ameliorative effect of polysaccharides from Yupingfeng granules (YPFP) on cyclophosphamide induced immune injury and reveal their potential mechanisms based on its protective effect on the intestine. YPFP were isolated and preliminarily characterized. Pharmacodynamic evaluation revealed that YPFP treatment could effectively mitigate lesions of immune organs, ameliorate white blood cells and downregulate IL-10 level. Further, the protective effect of intestinal barrier on the basis of intestinal tight junctions, MUC-2, microflora, endogenous metabolites, pathways and immune cells was discussed to outline mechanisms. The results showed that YPFP repaired the integrity of intestinal epithelium, enhanced the abundance of Muribaculaceae_unclassified, Bacteroide and Muribaculum, downgraded the abundance of Lachnospiraceae_NK4A136_group, improved the excretion of lipids and bile acids especially 3-oxo-LCA, increased the content of SCFAs in feces and inhibited the expression of key proteins of PI3K-AKT and MAPK-JUN pathways. More importantly, Th17 and Treg balance was remodeled after YPFP administration, which might be related to certain differential metabolites and pathways enriched by metabolomics. This study provides a rich understanding of YPFP and lays a foundation for further development of Yupingfeng granules. It was shown for the first time that the immunomodulatory effect of YPFP might be involved in multiple mechanisms of intestinal homeostasis. YPFP could be regarded as an immunomodulator to alleviate immune damage caused by cyclophosphamide.PMID:39709910 | DOI:10.1016/j.intimp.2024.113866

Phytomedicine. 2024 Dec 17;136:156335. doi: 10.1016/j.phymed.2024.156335. Online ahead of print.ABSTRACTBACKGROUND: Renal fibrosis (RF) is an inevitable consequence of multiple manifestations of progressive chronic kidney diseases (CKDs). Mechanism of Amygdalus mongolica (Maxim.) in the treatment of RF needs further investigation.PURPOSE: The study further investigated the potential mechanism of A. mongolica in the treatment of RF.METHODS: A rat model of RF was induced by unilateral ureteral obstruction (UUO), followed by treatment with varying dosages of A. mongolica oil for 4 weeks. Body weight was measured weekly. We detected serum levels of interleukin (IL)-6, IL-1β, type Ⅲ procollagen (Col-Ⅲ), type IV collagen (Col-Ⅳ), laminin (LN), hyaluronidase (HA), and tissue levels of albumin (ALB), blood urea nitrogen (BUN), creatinine (Cre), superoxide dismutase (SOD), malondialdehyde (MDA), and hydroxyproline (HYP). Shotgun metagenomics analyzed the composition of the intestinal microbiota. High-performance liquid chromatography coupled with a quadrupole-exactive mass spectrometer (HPLC-Q-Exactive-MS) monitored changes in metabolite levels in serum and gut. Multiple reaction monitoring-mass spectrometry (MRM-MS) determined the levels of amino acids in serum.RESULTS: A. mongolica oil significantly alleviated indicators related to RF (p < 0.05). A. mongolica oil reduced the ratio of Firmicutes to Bacteroidetes and restored the balance of intestinal microbiota in rats with RF. A. mongolica oil modulated levels of metabolites in gut content and serum. It regulated 11 metabolic pathways including arachidonic acid metabolism. Targeted metabolomics of amino acids showed that 17 amino acids were significantly changed by A. mongolica oil, including L-glycine, L-serine and L-glutamine.CONCLUSION: A. mongolica oil regulates intestinal microbiota and metabolites, restoring amino acid metabolism to treat RF.PMID:39709798 | DOI:10.1016/j.phymed.2024.156335

Redox Biol. 2024 Dec 16;79:103464. doi: 10.1016/j.redox.2024.103464. Online ahead of print.ABSTRACTNon-communicable chronic diseases (NCDs) are most commonly characterized by age-related loss of homeostasis and/or by cumulative exposures to environmental factors, which lead to low-grade sustained generation of reactive oxygen species (ROS), chronic inflammation and metabolic imbalance. Nuclear factor erythroid 2-like 2 (NRF2) is a basic leucine-zipper transcription factor that regulates the cellular redox homeostasis. NRF2 controls the expression of more than 250 human genes that share in their regulatory regions a cis-acting enhancer termed the antioxidant response element (ARE). The products of these genes participate in numerous functions including biotransformation and redox homeostasis, lipid and iron metabolism, inflammation, proteostasis, as well as mitochondrial dynamics and energetics. Thus, it is possible that a single pharmacological NRF2 modulator might mitigate the effect of the main hallmarks of NCDs, including oxidative, proteostatic, inflammatory and/or metabolic stress. Research on model organisms has provided tremendous knowledge of the molecular mechanisms by which NRF2 affects NCDs pathogenesis. This review is a comprehensive summary of the most commonly used model organisms of NCDs in which NRF2 has been genetically or pharmacologically modulated, paving the way for drug development to combat NCDs. We discuss the validity and use of these models and identify future challenges.PMID:39709790 | DOI:10.1016/j.redox.2024.103464