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Cancer Science Dec 2023To investigate the potential of the gut microbiome as a biomarker for predicting the early recurrence of HBV-related hepatocellular carcinoma (HCC), we enrolled 124...
To investigate the potential of the gut microbiome as a biomarker for predicting the early recurrence of HBV-related hepatocellular carcinoma (HCC), we enrolled 124 patients diagnosed with HBV-associated HCC and 82 HBV-related hepatitis, and 86 healthy volunteers in our study, collecting 292 stool samples for 16S rRNA sequencing and 35 tumor tissue samples for targeted metabolomics. We performed an integrated bioinformatics analysis of gut microbiome and tissue metabolome data to explore the gut microbial-liver metabolite axis associated with the early recurrence of HCC. We constructed a predictive model based on the gut microbiota and validated its efficacy in the temporal validation cohort. Dialister, Veillonella, the Eubacterium coprostanoligenes group, and Lactobacillus genera, as well as the Streptococcus pneumoniae and Bifidobacterium faecale species, were associated with an early recurrence of HCC. We also found that 23 metabolites, including acetic acid, glutamate, and arachidonic acid, were associated with the early recurrence of HCC. A comprehensive analysis of the gut microbiome and tissue metabolome revealed that the entry of gut microbe-derived acetic acid into the liver to supply energy for tumor growth and proliferation may be a potential mechanism for the recurrence of HCC mediated by gut microbe. We constructed a nomogram to predict early recurrence by combining differential microbial species and clinical indicators, achieving an AUC of 78.0%. Our study suggested that gut microbes may serve as effective biomarkers for predicting early recurrence of HCC, and the gut microbial-tumor metabolite axis may explain the potential mechanism by which gut microbes promote the early recurrence of HCC.
Topics: Humans; Carcinoma, Hepatocellular; Gastrointestinal Microbiome; Hepatitis B virus; Liver Neoplasms; RNA, Ribosomal, 16S; Biomarkers; Acetates
PubMed: 37778742
DOI: 10.1111/cas.15983 -
BMC Microbiology Nov 2023Infantile cholestasis (IC) is the most common hepatobiliary disease in infants, resulting in elevated direct bilirubin levels. Indeed, hepatointestinal circulation...
BACKGROUND
Infantile cholestasis (IC) is the most common hepatobiliary disease in infants, resulting in elevated direct bilirubin levels. Indeed, hepatointestinal circulation impacts bile acid and bilirubin metabolism. This study evaluates changes in the gut microbiota composition in children with IC and identifies abnormal metabolite profiles associated with microbial alterations.
RESULTS
The gut microbiota in the IC group exhibits the higher abundance of Veillonella, Streptococcus and Clostridium spp. (P < 0.05), compared to healthy infants (CON) group. Moreover, the abundance of Ruminococcus, Vibrio butyricum, Eubacterium coprostanogenes group, Intestinibacter, and Faecalibacterium were lower (P < 0.05). In terms of microbiota-derived metabolites, the levels of fatty acids (palmitoleic, α-linolenic, arachidonic, and linoleic) (P < 0.05) increased and the levels of amino acids decreased in IC group. Furthermore, the abundances of Ruminococcus, Eubacterium coprostanoligenes group, Intestinibacter and Butyrivibrio are positively correlated with proline, asparagine and aspartic acid, but negatively correlated with the α-linolenic acid, linoleic acid, palmitoleic acid and arachidonic acid. For analysis of the relationship between the microbiota and clinical index, it was found that the abundance of Veillonella and Streptococcus was positively correlated with serum bile acid content (P < 0.05), while APTT, PT and INR were negatively correlated with Faecalibalum and Ruminococcus (P < 0.05).
CONCLUSION
Microbiota dysbiosis happened in IC children, which also can lead to the abnormal metabolism, thus obstructing the absorption of enteral nutrition and aggravating liver cell damage. Veillonella, Ruminococcus and Butyrivibrio may be important microbiome related with IC and need further research.
Topics: Infant; Child; Humans; Gastrointestinal Microbiome; Cholestasis; Liver; Streptococcus; Bilirubin; Bile Acids and Salts
PubMed: 37980506
DOI: 10.1186/s12866-023-03115-1 -
Frontiers in Immunology 2023The modulation of immunometabolic pathways is emerging as a promising therapeutic target for immune-mediated diseases. However, the immunometabolic features of psoriatic...
Single-cell transcriptomic landscape of immunometabolism reveals intervention candidates of ascorbate and aldarate metabolism, fatty-acid degradation and PUFA metabolism of T-cell subsets in healthy controls, psoriasis and psoriatic arthritis.
INTRODUCTION
The modulation of immunometabolic pathways is emerging as a promising therapeutic target for immune-mediated diseases. However, the immunometabolic features of psoriatic disease and the potential targets for immunometabolic intervention in the different T-cell subsets involved in its pathogenesis remain unclear.
METHODS
In this study, we analyzed circulating blood single-cell data from healthy controls (HC), psoriasis (PSO), and psoriatic arthritis (PSA) patients, and revealed their metabolic features of T-cell subsets: CD4+ central memory T cells (TCMs), CD8+ effective memory T cells (TEMs), regulatory T cells (Tregs), mucosal-associated invariant T cells (MAITs ), and γδ T cells. Pearson test was performed to determine the linkages between differential metabolic and inflammatory pathways. Based on these results, we also analyzed the potential impacts of biological antibodies on differential metabolic pathways by comparing the immunometabolism differences between PSA patients without and with biological treatment.
RESULTS
Our results suggest that upregulation of ascorbate and aldarate metabolism, as well as fatty acid degradation, may enhance the immune suppression of Tregs. Enhanced metabolism of alpha-linolenic acid, linoleic acid, and arachidonic acid may inhibit the pro-inflammatory functions of CD4+ TCMs and CD8+ TEMs in PSO and PSA, and protect the immune suppression of Tregs in PSA. We propose that supporting ascorbic acid and fatty acid metabolic pathways may be an adjunctive reprogramming strategy with adalimumab and etanercept therapy.
DISCUSSION
These findings not only provide insights into immunometabolism characteristics of psoriatic disease, but also offer preliminary options for the auxiliary treatment of psoriasis.
Topics: Humans; Arthritis, Psoriatic; Transcriptome; Psoriasis; T-Lymphocyte Subsets; Ascorbic Acid
PubMed: 37492568
DOI: 10.3389/fimmu.2023.1179877 -
MedRxiv : the Preprint Server For... Jun 2024We have shown that ω3 polyunsaturated fatty acids (PUFAs) reduce risk for heart failure, regardless of ejection fraction status. Ventricular remodeling and reduced...
BACKGROUND
We have shown that ω3 polyunsaturated fatty acids (PUFAs) reduce risk for heart failure, regardless of ejection fraction status. Ventricular remodeling and reduced ventricular performance precede overt hear failure, however there is little insight into how PUFAs contribute to maladaptive signaling over time. PUFAs are agonists for regulatory activity at g-protein coupled receptors such as Ffar4, and downstream as substrates for monooxygenases (e.g lipoxygenase, cytochrome p450, or cyclooxygenase (COX)) which mediate intracellular adaptive signaling.
METHODS
Plasma phospholipid PUFA abundance at Exam 1 as mass percent EPA, DHA, and arachidonic acid (AA) from the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated using pathway modeling to determine the association with time-dependent changes in left ventricular (LV) mass (LVM), end-diastolic LV volume (EDV), and end-systolic volume (ESV) measured by cardiac MRI at Exams 1 and 5. Ejection fraction (EF) and mass:volume (MV) were calculated posteriorly from the first three.
RESULTS
2,877 subjects had available MRI data. Participants with low AA and EPA had accelerated age-dependent declines in LVM. Males with low AA and EPA also had accelerated declines in EDV, but among females there was no PUFA association with EDV declines and exam 5 EDV status was positively associated with AA. Both sexes had nearly the same positive association of AA with changes in ESV.
CONCLUSION
Plasma phospholipid AA and EPA are prospectively associated with indices of heart remodeling, including ventricular remodeling and performance. Combined AA and EPA scarcity was associated with the most accelerated age-related changes and exam 5 status, while the greatest benefits were found among participants with both PUFAs. This suggests that both PUFAs are required for optimal slowing of age-related declines in ventricular function.
PubMed: 38883788
DOI: 10.1101/2024.06.05.24308494 -
Journal of Lipid Research Sep 2023Natural variations in the C:C ratio (carbon-13 isotopic abundance [δC]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids,... (Randomized Controlled Trial)
Randomized Controlled Trial
Natural variations in the C:C ratio (carbon-13 isotopic abundance [δC]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids, especially in the n-3 PUFA biosynthesis pathway. However, n-6 PUFA metabolism following linoleic acid (LNA) intake remains under investigation. Here, we sought to use natural variations in the δC signature of dietary oils and fatty fish to analyze n-3 and n-6 PUFA metabolism following dietary changes in LNA and eicosapentaenoic acid (EPA) + DHA in adult humans. Participants with migraine (aged 38.6 ± 2.3 years, 93% female, body mass index of 27.0 ± 1.1 kg/m) were randomly assigned to one of three dietary groups for 16 weeks: 1) low omega-3, high omega-6 (H6), 2) high omega-3, high omega-6 (H3H6), or 3) high omega-3, low omega-6 (H3). Blood was collected at baseline, 4, 10, and 16 weeks. Plasma PUFA concentrations and δC were determined. The H6 intervention exhibited increases in plasma LNA δC signature over time; meanwhile, plasma LNA concentrations were unchanged. No changes in plasma arachidonic acid δC or concentration were observed. Participants on the H3H6 and H3 interventions demonstrated increases in plasma EPA and DHA concentration over time. Plasma δC-EPA increased in total lipids of the H3 group and phospholipids of the H3H6 group compared with baseline. Compound-specific isotope analysis supports a tracer-free technique that can track metabolism of dietary fatty acids in humans, provided that the isotopic signature of the dietary source is sufficiently different from plasma δC.
Topics: Adult; Animals; Humans; Female; Male; Fatty Acids, Omega-6; Fatty Acids, Omega-3; Eicosapentaenoic Acid; Fatty Acids; Phospholipids; Docosahexaenoic Acids
PubMed: 37572791
DOI: 10.1016/j.jlr.2023.100424 -
International Journal of Molecular... Jul 2023Cancer is a significant global public health issue and, despite advancements in detection and treatment, the prognosis remains poor. Cancer is a complex disease... (Review)
Review
Cancer is a significant global public health issue and, despite advancements in detection and treatment, the prognosis remains poor. Cancer is a complex disease characterized by various hallmarks, including dysregulation in apoptotic cell death pathways. Apoptosis is a programmed cell death process that efficiently eliminates damaged cells. Several studies have indicated the involvement of polyunsaturated fatty acids (PUFAs) in apoptosis, including omega-3 PUFAs such as alpha-linolenic acid, docosahexaenoic acid, and eicosapentaenoic acid. However, the role of omega-6 PUFAs, such as linoleic acid, gamma-linolenic acid, and arachidonic acid, in apoptosis is controversial, with some studies supporting their activation of apoptosis and others suggesting inhibition. These PUFAs are essential fatty acids, and Western populations today have a high consumption rate of omega-6 to omega-3 PUFAs. This review focuses on presenting the diverse molecular mechanisms evidence in both in vitro and in vivo models, to help clarify the controversial involvement of omega-3 and omega-6 PUFAs in apoptosis mechanisms in cancer.
Topics: Humans; Fatty Acids, Unsaturated; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Docosahexaenoic Acids; Apoptosis; Neoplasms
PubMed: 37511450
DOI: 10.3390/ijms241411691 -
Bioactive Materials May 2024During skin aging, the degeneration of epidermal stem cells (EpiSCs) leads to diminished wound healing capabilities and epidermal disintegration. This study tackles this...
During skin aging, the degeneration of epidermal stem cells (EpiSCs) leads to diminished wound healing capabilities and epidermal disintegration. This study tackles this issue through a comprehensive analysis combining transcriptomics and untargeted metabolomics, revealing age-dependent alterations in the gene family and arachidonic acid (AA) metabolic networks, resulting in enhanced ferroptosis. Selenomethionine (Se-Met) could enhance GPX4 expression, thereby assisting EpiSCs in countering AA-induced mitochondrial damage and ferroptosis. Additionally, Se-Met demonstrates antioxidative characteristics and extensive ultraviolet absorption. For the sustained and controllable release of Se-Met, it was covalently grafted to UV-responsive GelMA hydrogels via AC-PEG-NHS tethers. The Se-Met@GelMA hydrogel effectively accelerated wound healing in a chronological aging mice model, by inhibiting lipid peroxidation and ferroptosis with augmented GPX4 expression. Moreover, in a photoaging model, this hydrogel significantly mitigated inflammatory responses, extracellular matrix remodeling, and ferroptosis in UV-exposed mice. These characteristics render Se-Met@GelMA hydrogel valuable in practical clinical applications.
PubMed: 38404642
DOI: 10.1016/j.bioactmat.2024.02.013 -
Lipids in Health and Disease Oct 2023Polyunsaturated fatty acids (PUFAs) have demonstrated significant therapeutic potential across a wide range of disease. The aim of this study was to investigate the...
BACKGROUND
Polyunsaturated fatty acids (PUFAs) have demonstrated significant therapeutic potential across a wide range of disease. The aim of this study was to investigate the potential impact of PUFA intake on the prevalence of erectile dysfunction (ED).
METHODS
The study included a total of 3730 participants from the National Health and Nutrition Examination Survey (NHANES) 2001-2004. Univariate analysis, multivariate regression analysis, subgroup analysis and machine learning were utilized to explore the relationship of variables to ED. Dose response curves were constructed to observe the linear or nonlinear relationship between PUFA intake and the prevalence of ED. Propensity score matching (PSM) was used for sensitivity analysis. Finally, the potential mechanistic link between PUFA intake and ED was explored.
RESULTS
Through univariate and multivariate regression analysis results before and after PSM and XGBoost algorithm model results, arachidonic acid (AA) was chosen as the main research object. The consumption of AA was found to be associated with a decreased prevalence of ED under the fully adjusted model [OR = 0.33 (0.20, 0.56), P < 0.001]. The interaction between AA and education was found in the subgroup analysis. Dose-response curves indicated a linear negative correlation between AA intake and the prevalence of ED. The above results were confirmed in the data analysis after 1:1 PSM. In addition, AA intake was associated with a decrease in inflammatory biomarkers and homocysteine.
CONCLUSIONS
The results suggest that AA intake is negatively correlated with the prevalence of ED. Further, anti-inflammatory and anti-endothelial damage may play a role in this.
Topics: Male; Humans; Erectile Dysfunction; Nutrition Surveys; Cross-Sectional Studies; Prevalence; Fatty Acids, Unsaturated; Arachidonic Acid
PubMed: 37880723
DOI: 10.1186/s12944-023-01950-9 -
Neurology Aug 2023Excessive activation of certain lipid mediator (LM) pathways plays a role in the complex pathogenesis of multiple sclerosis (MS). However, the relationship between...
BACKGROUND AND OBJECTIVES
Excessive activation of certain lipid mediator (LM) pathways plays a role in the complex pathogenesis of multiple sclerosis (MS). However, the relationship between bioactive LMs and different aspects of CNS-related pathophysiologic processes remains largely unknown. Therefore, in this study, we assessed the association of bioactive LMs belonging to the ω-3/ω-6 lipid classes with clinical and biochemical (serum neurofilament light [sNfL] and serum glial fibrillary acidic protein [sGFAP]) parameters and MRI-based brain volumes in patients with MS (PwMS) and healthy controls (HCs).
METHODS
A targeted high-performance liquid chromatography-tandem mass spectrometry approach was used on plasma samples of PwMS and HCs of the Project Y cohort, a cross-sectional population-based cohort that contains PwMS all born in 1966 in the Netherlands and age-matched HCs. LMs were compared between PwMS and HCs and were correlated with levels of sNfL, sGFAP, disability (Expanded Disability Status Scale [EDSS]), and brain volumes. Finally, significant correlates were included in a backward multivariate regression model to identify which LMs best related to disability.
RESULTS
The study sample consisted of 170 patients with relapsing remitting MS (RRMS), 115 patients with progressive MS (PMS), and 125 HCs. LM profiles of patients with PMS significantly differed from those of patients with RRMS and HCs, particularly patients with PMS showed elevated levels of several arachidonic acid (AA) derivatives. In particular, 15-hydroxyeicosatetraenoic acid (HETE) ( = 0.24, < 0.001) correlated (average = 0.2, < 0.05) with clinical and biochemical parameters such as EDSS and sNfL. In addition, higher 15-HETE levels were related to lower total brain ( = -0.24, = 0.04) and deep gray matter volumes ( = -0.27, = 0.02) in patients with PMS and higher lesion volume ( = 0.15, = 0.03) in all PwMS.
DISCUSSION
In PwMS of the same birth year, we show that ω-3 and ω-6 LMs are associated with disability, biochemical parameters (sNfL, GFAP), and MRI measures. Furthermore, our findings indicate that, particularly, in patients with PMS, elevated levels of specific products of the AA pathway, such as 15-HETE, associate with neurodegenerative processes. Our findings highlight the potential relevance of ω-6 LMs in the pathogenesis of MS.
Topics: Humans; Middle Aged; Multiple Sclerosis; Arachidonic Acid; Cross-Sectional Studies; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Patient Acuity
PubMed: 37290971
DOI: 10.1212/WNL.0000000000207459 -
Biomedicine & Pharmacotherapy =... Nov 2023Acute kidney injury (AKI) is a known complication of cisplatin administration; currently, there are no effective ways to prevent it. Therefore, it largely limited the...
BACKGROUND
Acute kidney injury (AKI) is a known complication of cisplatin administration; currently, there are no effective ways to prevent it. Therefore, it largely limited the use of cisplatin in chemotherapy in the clinic. In this study, we reported that Limonin, a triterpenoid compound extracted from citrus, alleviated cisplatin-induced AKI through metabolic reprogramming in the diseased kidneys.
METHODS
Cisplatin was employed to induce AKI in mice. Three groups were set up: Sham, cisplatin + vehicle, and cisplatin + Limonin. Using UHPLC-TOF/MS, we conducted metabolomics to profile the kidneys' endogenous metabolites and metabolic pathways. A network pharmacological method was performed to identify the targets of Limonin on AKI. The human proximal tubular epithelial cell line (HK-2) was applied for in vitro studies.
RESULTS
Limonin preserved serum creatinine and blood urea nitrogen levels after cisplatin-induced AKI. Employing metabolomics, we identified 33 endogenous differentially expressed metabolites and 7 significantly disturbed metabolic pathways in the diseased kidneys within three groups. After AKI, Limonin significantly reduced linoleic acid and its downstream product, arachidonic acid, thus exerting a protective effect on the kidney. The network pharmacological method identified CYP3A4 as a key target of Limonin in treating AKI, while CYP3A4 also serve as a mediator of arachidonic acid metabolism. In vitro, Limonin markedly reduced the level of arachidonic acid and HK-2 cell apoptosis triggered by cisplatin, mainly related to the targeted inhibition of CYP3A4-mediated arachidonic acid metabolism.
CONCLUSION
Limonin ameliorates cisplatin-induced AKI by inhibiting CYP3A4 activity to regulate arachidonic acid metabolism, ultimately preserving kidney function.
PubMed: 37741252
DOI: 10.1016/j.biopha.2023.115531