PubMed

Phytomedicine. 2023 Sep 2;121:155054. doi: 10.1016/j.phymed.2023.155054. Online ahead of print.ABSTRACTBACKGROUND: Tripterygium wilfordii has been widely used for the treatment of rheumatoid arthritis, which is frequently accompanied by severe gastrointestinal damage. The molecular mechanism underlying the gastrointestinal injury of Tripterygium wilfordii are yet to be elucidated.METHODS: Transmission electron microscopy, and pathological and biochemical analyses were applied to assess intestinal bleeding. Metabolic changes in the serum and intestine were determined by metabolomics. In vivo (time-dependent effect and dose-response) and in vitro (double luciferase reporter gene system, DRATs, molecular docking, HepG2 cells and small intestinal organoids) studies were used to identify the inhibitory role of celastrol on intestinal farnesoid X receptor (FXR) signaling. Fxr-knockout mice and FXR inhibitors and agonists were used to evaluate the role of FXR in the intestinal bleeding induced by Tripterygium wilfordii.RESULTS: Co-treatment with triptolide + celastrol (from Tripterygium wilfordii) induced intestinal bleeding in mice. Metabolomic analysis indicated that celastrol suppressed intestinal FXR signaling, and further molecular studies revealed that celastrol was a novel intestinal FXR antagonist. In Fxr-knockout mice or the wild-type mice pre-treated with pharmacological inhibitors of FXR, triptolide alone could activate the duodenal JNK pathway and induce intestinal bleeding, which recapitulated the pathogenic features obtained by co-treatment with triptolide and celastrol. Lastly, intestinal bleeding induced by co-treatment with triptolide and celastrol could be effectively attenuated by the FXR or gut-restricted FXR agonist through downregulation of the duodenal JNK pathway.CONCLUSIONS: The synergistic effect between triptolide and celastrol contributed to the gastrointestinal injury induced by Tripterygium wilfordii via dysregulation of the FXR-JNK axis, suggesting that celastrol should be included in the quality standards system for evaluation of Tripterygium wilfordii preparations. Determining the mechanism of the FXR-JNK axis in intestinal bleeding could aid in the identification of additional therapeutic targets for the treatment of gastrointestinal hemorrhage diseases. This study also provides a new standard for the quality assessment of Tripterygium wilfordii used in the treatment of gastrointestinal disorders.PMID:37738906 | DOI:10.1016/j.phymed.2023.155054

J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Sep 16;1229:123889. doi: 10.1016/j.jchromb.2023.123889. Online ahead of print.ABSTRACTQingxue Bawei (QXBW) tablets, a Mongolian medicine prescription, have proved to possess good lipid-lowering and antihypertensive effects in previous studies. However, the therapeutic effects and potential mechanisms of QXBW tablets on atherosclerosis (AS) have not been well studied yet. This study aimed to investigate the potential liver-protective mechanism of QXBW tablets on AS mice by hepatic lipidomics analysis. After 10 weeks of administration, serum and liver were collected for biochemical, histopathological, and lipid metabolomics analysis to evaluate the efficacy of the QXBW tablets on high-fat diet (HFD) induced mice. The experimental results indicated that QXBW tablets could ameliorate liver injury and inflammatory response in AS mice. Liver lipid data from different groups of mice were collected by UPLC-Q-Orbitrap-MS, and a total of 22 potential biomarkers with significant differences between the model and control groups were identified finally, of which 16 potential biomarkers were back-regulated after the QXBW tablets intervention. These 22 potential differential metabolic markers were mainly involved in glycerolipid metabolism, glycerophospholipid metabolism, and cholesterol ester metabolism pathways. The results of this study showed that serum inflammatory factors, liver function indices, and lipid metabolism disorders were positively alleviated in AS mice after QXBW tablets treatment.PMID:37738809 | DOI:10.1016/j.jchromb.2023.123889

Biomed Pharmacother. 2023 Sep 20;167:115438. doi: 10.1016/j.biopha.2023.115438. Online ahead of print.ABSTRACTLung cancer is a major health concern and significant barrier to human well-being and social development. Although targeted therapy has shown remarkable progress in the treatment of lung cancer, the emergence of drug resistance has limited its clinical efficacy. Sijunzi Tang (SJZ) is a classical Chinese herbal formula known for tonifying qi and nourishing the lungs, has been recognized for its potential in lung cancer management. However, the underlying mechanism of its combined use with anti-cancer drugs remains unclear. Here, we investigated the anti-lung cancer efficacy and underlying mechanisms of the combination of gefitinib and SJZ in gefitinib-resistant human lung adenocarcinoma cells (PC-9/GR). We conducted in vitro and in vivo experiments using histopathology and targeted metabolomics approaches. Our results demonstrated that the combination of SJZ and gefitinib exhibited synergistic effects on tumor growth inhibition in PC-9/GR-bearing nude mice. Notably, the co-administration of SJZ and gefitinib synergistically promoted tumor cell apoptosis, potentially through the regulation of BAX and BCL-2 expression. Immunohistochemistry and western blot analysis found down-regulation of GLS, GS, and SLC1A5 expression in the co-administration group compared to the control and the individual treatment groups. Targeted metabolomics revealed significant alterations in the plasma glutamine metabolic markers glutamine, alanine, succinate, glutamate, and pyruvate. Of the glutamine metabolism markers measured in tumor tissues, glutamine and pyruvate demonstrated significant differences across the treatment groups. These findings suggest that administration of SJZ improves gefitinib resistance in the treatment of lung cancer without toxic effects. Moreover, SJZ may affect glutamine metabolism by regulating key targets involved in glutamine metabolism (SLC1A5, GLS, and GS) and modulating the levels of related metabolic markers, ultimately reducing gefitinib resistance.PMID:37738796 | DOI:10.1016/j.biopha.2023.115438

Sci Rep. 2023 Sep 22;13(1):15834. doi: 10.1038/s41598-023-43056-3.ABSTRACTNot only in metabolomics studies, but also in natural product chemistry, reliable identification of metabolites usually requires laborious steps of isolation and purification and remains a bottleneck in many studies. Direct metabolite identification from a complex mixture without individual isolation is therefore a preferred approach, but due to the large number of metabolites present in natural products, this approach is often hampered by signal overlap in the respective 1H NMR spectra. This paper presents a method for the three-dimensional mathematical correlation of NMR with MS data over the third dimension of the time course of a chromatographic fractionation. The MATLAB application SCORE-metabolite-ID (Semi-automatic COrrelation analysis for REliable metabolite IDentification) provides semi-automatic detection of correlated NMR and MS data, allowing NMR signals to be related to associated mass-to-charge ratios from ESI mass spectra. This approach enables fast and reliable dereplication of known metabolites and facilitates the dynamic analysis for the identification of unknown compounds in any complex mixture. The strategy was validated using an artificial mixture and further tested on a polar extract of a pine nut sample. Straightforward identification of 40 metabolites could be shown, including the identification of β-D-glucopyranosyl-1-N-indole-3-acetyl-N-L-aspartic acid (1) and Nα-(2-hydroxy-2-carboxymethylsuccinyl)-L-arginine (2), the latter being identified in a food sample for the first time.PMID:37740032 | DOI:10.1038/s41598-023-43056-3

Trends Endocrinol Metab. 2023 Sep 20:S1043-2760(23)00185-6. doi: 10.1016/j.tem.2023.08.018. Online ahead of print.ABSTRACTMetabolic abnormalities are a hallmark of cancer cells and are essential to tumor progression. Oncometabolites have pleiotropic effects on cancer biology and affect a plethora of processes, from oncogenesis and metabolism to therapeutic resistance. Targeting oncometabolites, therefore, could offer promising therapeutic avenues against tumor growth and resistance to treatments. Recent advances in characterizing the metabolic profiles of cancer cells are shedding light on the underlying mechanisms and associated metabolic networks. This review summarizes the diverse detection methods, molecular mechanisms, and therapeutic targets of oncometabolites, which may lead to targeting oncometabolism for cancer therapy.PMID:37739878 | DOI:10.1016/j.tem.2023.08.018

Gene. 2023 Sep 20:147799. doi: 10.1016/j.gene.2023.147799. Online ahead of print.ABSTRACTThe insecticide dimethoate, an organophosphate, has been used on crops, soybeans, fruits, and vegetables since the 1960s and is considered one of the most widely used pesticides. However, the understanding of the molecular mechanisms of dimethoate in crops, especially crop seedlings, is still limited. The green vegetable soya bean (Glycine max merr) is usually used as a vegetable-like fruit of soybean in many Asian countries. This study aimed to analyze the effect of dimethoate on the growth of green vegetable soya bean seedlings at the metabolic and transcriptional levels. An integrated analysis of the transcriptome and metabolome was performed to determine the responses of green vegetable soya bean seedlings to different concentrations (D1 for low dose, D2 for high dose and C for control) of dimethoate. In omics analyses, 4156 differentially expressed genes (DEGs) and 1935 differentially abundant metabolites (DAMs) were identified in the D1/C comparison, and 11162 DEGs and 819 DAMs were identified in D2/C. Correlation analyses revealed dimethoate affected the metabolic pathways of green vegetable soya beans such as the biosynthesis of secondary metabolites and microbial metabolism in diverse environmental pathways, demonstrating that even small doses of dimethoate can affect green vegetable soya bean seedlings in a short period of time. Our study further enriches our understanding of the molecular mechanisms by which green vegetable soya beans are treated with dimethoate and provides a deeper understanding of the effects of dimethoate on crops.PMID:37739194 | DOI:10.1016/j.gene.2023.147799

Comp Biochem Physiol C Toxicol Pharmacol. 2023 Sep 20:109747. doi: 10.1016/j.cbpc.2023.109747. Online ahead of print.ABSTRACTSpiders are dominant predators in the paddy ecosystem, but the immunotoxicity induced by environmental contaminants like heavy metals is still largely unknown. The gut microbiota-host interaction was the basic immune mechanism discovered in the arthropods. Here, we investigated the gut microflora and immune responses of wolf spider Pardosa pseudoannulata under Cd burden. Cd exposure was identified to shape the gut microbial community structure of spiders, with increased levels of Firmicutes and pathogens, and decreased levels of Proteobacteria and Bacteroidota. The alteration of microbiota-derived immune messengers like peptidoglycan (PGN) was also observed. ELISA and hemolymph metabolomic analysis showed that the activities of immune effectors phenoloxidase (PO) and lysozyme (LZM) and the abundance of tyrosine derivates were decreased, which indicated the suppression of Cd on the melanization immune response of spiders. Correlation analysis revealed a close relationship between the impaired immune system and the disordered microbiota. This study provides insight into the underlying mechanisms of the gut microflora-immune system interaction of P. pseudoannulata in response to Cd burden.PMID:37739022 | DOI:10.1016/j.cbpc.2023.109747

Plant Sci. 2023 Sep 20:111873. doi: 10.1016/j.plantsci.2023.111873. Online ahead of print.ABSTRACTThis study aimed to assess the effectiveness of plant growth-promoting rhizobacteria (PGPR; Pseudomonas strain So_08) and arbuscular mycorrhizal fungi (AMF; Rhizoglomus irregulare BEG72 and Funneliformis mosseae BEG234) in mitigating the detrimental effects of cadmium (Cd) and zinc (Zn) stress in tomato plants. Plant biomass, root morphology, leaf relative water content, membrane stability, photosynthetic performance, chlorophyll content, and heavy metals (HMs) accumulation were determined. Furthermore, an ionomic profile was conducted to investigate whether microbial inoculants affected the uptake and allocation of macro- and micronutrients. Metabolomics with pathway analysis of both roots and leaves was performed to unravel the mechanisms underlying the differential responses to HMs stress. The findings revealed that the levels of HMs did not significantly affect plant growth parameters; however, they affected membrane stability, photosynthetic performance, nutrient allocation, and chlorophyll content. Cadmium was mainly accumulated in roots, whilst Zn exhibited accumulation in various plant organs. Our findings demonstrate the beneficial effects of PGPR and AMF in mitigating Cd and Zn stress in tomato plants. The microbial inoculations improved physiological parameters and induced differential accumulation of macro- and micronutrients, modulating nutrient uptake balance. These results provide insights into the mechanisms underlying the plant-microbe interactions and highlight the differential modulation of the biosynthetic pathways of secondary metabolites related to oxidative stress response, membrane lipids stability, and phytohormone crosstalk.PMID:37739018 | DOI:10.1016/j.plantsci.2023.111873

Sci Adv. 2023 Sep 22;9(38):eadg3919. doi: 10.1126/sciadv.adg3919. Epub 2023 Sep 22.ABSTRACTProlonged cytopenias after chimeric antigen receptor (CAR) T cell therapy are a significant clinical problem and the underlying pathophysiology remains poorly understood. Here, we investigated how (CAR) T cell expansion dynamics and serum proteomics affect neutrophil recovery phenotypes after CD19-directed CAR T cell therapy. Survival favored patients with "intermittent" neutrophil recovery (e.g., recurrent neutrophil dips) compared to either "quick" or "aplastic" recovery. While intermittent patients displayed increased CAR T cell expansion, aplastic patients exhibited an unfavorable relationship between expansion and tumor burden. Proteomics of patient serum collected at baseline and in the first month after CAR-T therapy revealed higher markers of endothelial dysfunction, inflammatory cytokines, macrophage activation, and T cell suppression in the aplastic phenotype group. Prolonged neutrophil aplasia thus occurs in patients with systemic immune dysregulation at baseline with subsequently impaired CAR-T expansion and myeloid-related inflammatory changes. The association between neutrophil recovery and survival outcomes highlights critical interactions between host hematopoiesis and the immune state stimulated by CAR-T infusion.PMID:37738350 | DOI:10.1126/sciadv.adg3919

Sci Adv. 2023 Sep 22;9(38):eadh8228. doi: 10.1126/sciadv.adh8228. Epub 2023 Sep 22.ABSTRACTBreakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mitochondrial proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPRmt's role in maintaining proteostasis during stress. We find essential roles for the UPRmt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPRmt. Transcriptome analyses together with MitoPQ reveal that UPRmt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPRmt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPRmt failed. Collectively, this study defines the network of proteostasis mediated by the UPRmt and highlights the value of functional proteomics in decoding stressed proteomes.PMID:37738349 | DOI:10.1126/sciadv.adh8228

Sleep. 2023 Sep 20:zsad246. doi: 10.1093/sleep/zsad246. Online ahead of print.ABSTRACTSTUDY OBJECTIVES: Insufficient sleep is a concerning hallmark of modern society because sleep deprivation (SD) is a risk factor for neurodegenerative and cardiometabolic disorders. SD imparts an aging-like effect on learning and memory, although little is known about possible common molecular underpinnings of SD and aging. Here, we examine this question by profiling metabolic features across different tissues after acute sleep deprivation in young adult and aged mice.METHODS: Young adult and aged mice were subjected to acute SD for five hours. Blood plasma, hippocampus and liver samples were subjected to UPLC-MS/MS based metabolic profiling.RESULTS: SD preferentially impacts peripheral plasma and liver profiles (e.g., ketone body metabolism) whereas the hippocampus is more impacted by aging. We further demonstrate that aged animals exhibit SD-like metabolic features at baseline. Hepatic alterations include parallel changes in nicotinamide metabolism between aging and SD in young animals. Overall, metabolism in young adult animals is more impacted by SD, which in turn induces aging-like features. A set of nine metabolites classifies (79% correct) based on age and sleep status across all four groups.CONCLUSION: Our metabolic observations demonstrate striking parallels to previous observations in studies of learning and memory and define a molecular metabolic signature of sleep loss and aging.PMID:37738102 | DOI:10.1093/sleep/zsad246

Environ Sci Pollut Res Int. 2023 Sep 22. doi: 10.1007/s11356-023-29925-4. Online ahead of print.ABSTRACTCopper (Cu) is an essential element for mammals, but excess intake can have detrimental health consequences. However, Cu is no longer present in the "Limit of Contaminants in Foods" promulgated in 2022. The potential impact of different Cu (II) concentrations on human health remains unclear. In this study, a strain of lactic acid bacteria (LAB), namely, Lactiplantibacillus plantarum CICC 23121 (L23121), was selected as a prebiotic indicator strain to indirectly assess the effects of food-limited Cu (II) concentrations (issued by Tolerance limit of copper in foods in 1994) on the functions of intestinal microbes. We used non-target metabolomics, automatic growth curve detector, scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR) to investigate the effects of Cu (II) on L23121. The study revealed shows that the 50% minimum inhibitory concentration (MIC50) of Cu (II) for most lactic acid bacteria was 4 mg/L. At low Cu (II) concentrations (≤ 4 mg/L), the pentose phosphate pathway and pyrimidine metabolism of the lactic acid bacteria were affected, resulting in a decrease in the content of beneficial secondary metabolites and a significant decrease in the cell activity. As Cu (II) concentrations increase (≥ 6 mg/L), the key amino acid and lipid metabolisms were affected, leading to the inhibition of growth and primary metabolite production of the bacteria. Under high concentration of Cu (II) (6 mg/L), the surface adhesion of the bacteria was distorted and covered with significantly large particles, and the functional groups of the cells were significantly shifted. As a probiotic, the abundance of lactic acid bacteria in the intestine is significantly reduced, which will inevitably seriously damage intestinal homeostasis. Thus, to protect human intestinal microbes' health, it is recommended to limit the concentration of Cu in food to less than 4 mg/L.PMID:37737949 | DOI:10.1007/s11356-023-29925-4

J Agric Food Chem. 2023 Sep 22. doi: 10.1021/acs.jafc.3c01900. Online ahead of print.ABSTRACTBacillus licheniformis has been widely utilized in the food industry as well as various agricultural industries. In particular, it is a main microorganism of fermented soybeans. In this study, the changes of the metabolome and transcriptome of B. licheniformis KACC15844, which had been isolated from fermented soybeans, were investigated depending on alkaline pH (BP) and a high salt concentration (BS) using an integrated-omics technology, focusing on leucine metabolism. Overall, carbohydrate (glycolysis, sugar transport, and overflow) and amino acid (proline, glycine betaine, and serine) metabolisms were strongly associated with BS, while fatty acid metabolism, malate utilization, and branched-chain amino acid-derived volatiles were closely related to BP, in both gene and metabolic expressions. In particular, in leucine metabolism, the formation of 3-methylbutanoic acid, which has strong cheesy odor notes, was markedly increased in BP compared to the other samples. This study provided information on how specific culture conditions can affect gene expressions and metabolite formations in B. licheniformis using an integrated-omics approach.PMID:37737871 | DOI:10.1021/acs.jafc.3c01900

Am J Physiol Heart Circ Physiol. 2023 Sep 22. doi: 10.1152/ajpheart.00436.2023. Online ahead of print.ABSTRACTHeart failure (HF) is the end stage of most cardiovascular diseases and remains a significant health problem globally. We aimed to assess whether patients with left ventricular ejection fraction ≤45% had alterations in both the gut microbiome profile and production of associated metabolites when compared to a healthy cohort. We also examined the associated inflammatory, metabolomic, and lipidomic profiles of HF patients. This single centre, observational study, recruited 73 HF patients and 59 healthy volunteers. Blood and stool samples were collected at baseline and 6-month follow-up, along with anthropometric and clinical data. Compared to healthy controls, HF patients had reduced gut bacterial alpha diversity at follow-up (p =0.004) but not at baseline. The stool microbiota of HF patients was characterized by a depletion of operational taxonomic units representing commensal Clostridia at both baseline and follow-up. HF patients also had significantly elevated baseline plasma acetate (p =0.007), plasma TMAO (p =0.003), serum sCD14 (p =0.005) and sCD163 (p =0.004) levels compared to healthy controls. Furthermore, HF patients had a distinct metabolomic and lipidomic profile at baseline when compared to healthy controls. Differences in the composition of the gut microbiome and the levels of associated metabolites were observed in patients with HF when compared to a healthy cohort. This was also associated with an altered metabolomic and lipidomic profile. Our study identifies microorganisms and metabolites that could represent new therapeutic targets and diagnostic tools in the pathogenesis of HF.PMID:37737730 | DOI:10.1152/ajpheart.00436.2023

Indian J Pediatr. 2023 Sep 22. doi: 10.1007/s12098-023-04819-y. Online ahead of print.ABSTRACTChronic liver disease (CLD) is a persistent public health burden, with over one billion cases reported worldwide. In most cases, the progression of CLD is slow and undulating with end-stage liver disease developing at variable time points depending on the underlying etiology of the disease. The concept of reversibility or halting progression to end stage liver disease is recent and various medications are in the pipeline which influence the progression of CLD. Non-invasive tests for monitoring of CLD may have the potential to avoid the morbidity and mortality related to invasive procedures. However, their applicability and validation in pediatrics requires further development and a coordinated effort by large pediatric liver centres. Recent advances in metabolomics and modern molecular technologies have led to an understanding of the interaction between gut microbiome liver axis and gut dysbiosis contributing to liver diseases. In the future, modifying the gut microbiome has the potential to change the outcome and significantly reduce the morbidity associated with CLD. This article focuses on newer modalities and concepts in the management of CLD, which may help develop strategies to prevent its progression to end-stage liver disease and associated morbidity/mortality.PMID:37737559 | DOI:10.1007/s12098-023-04819-y

Cancer Causes Control. 2023 Sep 22. doi: 10.1007/s10552-023-01793-w. Online ahead of print.ABSTRACTPURPOSE OF THE STUDY: Breast density is an established risk factor for breast cancer. However, little is known about metabolic influences on breast density phenotypes. We conducted untargeted serum metabolomics analyses to identify metabolic signatures associated with breast density phenotypes among young women.METHODS: In a cross-sectional study of 173 young women aged 25-29 who participated in the Dietary Intervention Study in Children 2006 Follow-up Study, 449 metabolites were measured in fasting serum samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. Multivariable-adjusted mixed-effects linear regression identified metabolites associated with magnetic resonance imaging measured breast density phenotypes: percent dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute non-dense breast volume (ANDBV). Metabolite results were corrected for multiple comparisons using a false discovery rate adjusted p-value (q).RESULTS: The amino acids valine and leucine were significantly inversely associated with %DBV. For each 1 SD increase in valine and leucine, %DBV decreased by 20.9% (q = 0.02) and 18.4% (q = 0.04), respectively. ANDBV was significantly positively associated with 16 lipid and one amino acid metabolites, whereas no metabolites were associated with ADBV. Metabolite set enrichment analysis also revealed associations of distinct metabolic signatures with %DBV, ADBV, and ANDBV; branched chain amino acids had the strongest inverse association with %DBV (p = 0.002); whereas, diacylglycerols and phospholipids were positively associated with ANDBV (p ≤ 0.002), no significant associations were observed for ADBV.CONCLUSION: Our results suggest an inverse association of branched chain amino acids with %DBV. Larger studies in diverse populations are needed.PMID:37737303 | DOI:10.1007/s10552-023-01793-w

JCI Insight. 2023 Sep 22;8(18):e166860. doi: 10.1172/jci.insight.166860.ABSTRACTLung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelial cells (AEC) drives the acute inflammatory response following LC and GA. Metabolomic profiling and metabolic flux of Type II AEC following LC revealed marked increases in glycolytic and TCA intermediates in vivo and in vitro that were HIF-1α dependent. GLUT-1/4 expression was also increased in HIF-1α+/+ mice, suggesting that increased glucose entry may contribute to increased intermediates. Importantly, lactate incubation in vitro on Type II cells did not significantly increase the inflammatory byproduct IL-1β. Contrastingly, succinate had a direct proinflammatory effect on human small AEC by IL-1β generation in vitro. This effect was reversed by dimethylmalonate, suggesting an important role for succinate dehydrogenase in mediating HIF-1α effects. We confirmed the presence of the only known receptor for succinate binding, SUCNR1, on Type II AEC. These results support the hypothesis that succinate drives HIF-1α-mediated airway inflammation following LC. This is the first report to our knowledge of direct proinflammatory activation of succinate in nonimmune cells such as Type II AEC in direct lung injury models.PMID:37737265 | DOI:10.1172/jci.insight.166860

Sci Rep. 2023 Sep 22;13(1):15798. doi: 10.1038/s41598-023-42786-8.ABSTRACTConventional chemotherapy methods have adverse off-target effects and low therapeutic efficiencies of drug release in target tumors. In this study, we proposed a combination therapy of doxorubicin (DOX)-loaded ultrasound (US)-sensitive liposomal nanocarriers (IMP301), microbubbles (MBs) under focused US exposure using convex acoustic lens-attached US (LENS) to tumor treatment. The therapeutic effects of each treatment in a murine melanoma model were evaluated using contrast-enhanced US (CEUS) and micro-computed tomography (micro-CT) imaging, bioluminescence and confocal microscopy imaging, and liquid chromatography-mass spectroscopy (LC/MS) analysis. Tumor-bearing mice were randomly assigned to one of the following groups: (1) G1: IMP301 only (n = 9); (2) G2: IMP301 + LENS (n = 9); (3) G3: IMP301 + MB + LENS (n = 9); (4) G4: DOXIL only (n = 9); and (5) G5: IMP301 without DOXIL group as a control group (n = 4). Ten days after tumor injection, tumor-bearing mice were treated according to each treatment strategy on 10th, 12th, and 14th days from the day of tumor injection. The CEUS images of the tumors in the murine melanoma model clearly showed increased echo signal intensity from MBs as resonant US scattering. The relative tumor volume of the G2 and G3 groups on the micro-CT imaging showed inhibited tumor growth than the reference baseline of the G5 group. DOX signals on bioluminescence and confocal microscopy imaging were mainly located at the tumor sites. LC/MS showed prominently higher intratumoral DOX concentration in the G3 group than in other treated groups. Therefore, this study effectively demonstrates the feasibility of the synergistic combination of IMP301, MBs, and LENS-application for tumor-targeted treatment. Thus, this study can enable efficient tumor-targeted treatment by combining therapy such as IMP301 + MBs + LENS-application.PMID:37737248 | DOI:10.1038/s41598-023-42786-8

Methods Protoc. 2023 Aug 29;6(5):77. doi: 10.3390/mps6050077.ABSTRACTFungi are well-known producers of chemically diverse and biologically active secondary metabolites. However, their production yields through fermentation may hamper structural analysis and biological activity downstream investigations. Herein, a systematic experimental design that varies multiple cultivation parameters, followed by chemometrics analysis on HPLC-UV-MS or UHPLC-HRMS/MS data, is presented to enhance the production yield of fungal natural products. The overall procedure typically requires 3-4 months of work when first developed, and up to 3 months as a routine procedure.PMID:37736960 | DOI:10.3390/mps6050077

Neurogastroenterol Motil. 2023 Sep 22:e14681. doi: 10.1111/nmo.14681. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Disorders of gut-brain interaction (DGBI) are complex conditions that result in decreased quality of life and a significant cost burden. Linaclotide, a guanylin cyclase C (GCC) receptor agonist, is approved as a DGBI treatment. However, its efficacy has been limited and variable across DGBI patients. Microbiota and metabolomic alterations are noted in DGBI patients, provoking the hypothesis that the microbiota may impact the GCC response to current therapeutics.METHODS: Human-derived intestinal organoids were grown from pediatric DGBI, non-IBD colon biopsies (colonoids). Colonoids were treated with 250 nM linaclotide and assayed for cGMP to develop a model of GCC activity. Butyrate was administered to human colonoids overnight at a concentration of 1 mM. Colonoid lysates were analyzed for cGMP levels by ELISA. For the swelling assay, colonoids were photographed pre- and post-treatment and volume was measured using ImageJ. Principal coordinate analyses (PCoA) were performed on the Bray-Curtis dissimilarity and Jaccard distance to assess differences in the community composition of short-chain fatty acid (SCFA) producing microbial species in the intestinal microbiota from pediatric patients with IBS and healthy control samples.KEY RESULTS: Linaclotide treatment induced a significant increase in [cGMP] and swelling of patient-derived colonoids, demonstrating a human in vitro model of linaclotide-induced GCC activation. Shotgun sequencing analysis of pediatric IBS patients and healthy controls showed differences in the composition of commensal SCFA-producing bacteria. Butyrate exposure significantly dampened linaclotide-induced cGMP levels and swelling in patient-derived colonoids.CONCLUSIONS & INFERENCES: Patient-derived colonoids demonstrate that microbiota-derived butyrate can dampen human colonic responses to linaclotide. This study supports incorporation of microbiota and metabolomic assessment to improve precision medicine for DGBI patients.PMID:37736865 | DOI:10.1111/nmo.14681