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Journal of Translational Medicine Jun 2023Acute-on-chronic liver failure (ACLF) is a severe syndrome with high short-term mortality, but the pathophysiology still remains largely unknown. Immune dysregulation...
BACKGROUND
Acute-on-chronic liver failure (ACLF) is a severe syndrome with high short-term mortality, but the pathophysiology still remains largely unknown. Immune dysregulation and metabolic disorders contribute to the progression of ACLF, but the crosstalk between immunity and metabolism during ACLF is less understood. This study aims to depict the immune microenvironment in the liver during ACLF, and explore the role of lipid metabolic disorder on immunity.
METHODS
Single-cell RNA-sequencing (scRNA-seq) was performed using the liver non-parenchymal cells (NPCs) and peripheral blood mononuclear cells (PBMCs) from healthy controls, cirrhosis patients and ACLF patients. A series of inflammation-related cytokines and chemokines were detected using liver and plasma samples. The lipid metabolomics targeted free fatty acids (FFAs) in the liver was also detected.
RESULTS
The scRNA-seq analysis of liver NPCs showed a significant increase of monocytes/macrophages (Mono/Mac) infiltration in ACLF livers, whereas the resident Kupffer cells (KCs) were exhausted. A characterized TREM2 Mono/Mac subpopulation was identified in ACLF, and showed immunosuppressive function. Combined with the scRNA-seq data from PBMCs, the pseudotime analysis revealed that the TREM2 Mono/Mac were differentiated from the peripheral monocytes and correlated with lipid metabolism-related genes including APOE, APOC1, FABP5 and TREM2. The targeted lipid metabolomics proved the accumulation of unsaturated FFAs associated with α-linolenic acid (α-LA) and α-LA metabolism and beta oxidation of very long chain fatty acids in the ACLF livers, indicating that unsaturated FFAs might promote the differentiation of TREM2 Mono/Mac during ACLF.
CONCLUSIONS
The reprogramming of macrophages was found in the liver during ACLF. The immunosuppressive TREM2 macrophages were enriched in the ACLF liver and contributed to the immunosuppressive hepatic microenvironment. The accumulation of unsaturated FFAs in the ACLF liver promoted the reprogramming of the macrophages. It might be a potential target to improve the immune deficiency of ACLF patients through regulating lipid metabolism.
Topics: Humans; Lipid Metabolism; Acute-On-Chronic Liver Failure; Hepatitis B virus; Leukocytes, Mononuclear; Macrophages; Fatty Acid-Binding Proteins
PubMed: 37380987
DOI: 10.1186/s12967-023-04294-1 -
European Journal of Medical Research Jul 2023Flaxseed (Linum usitatissimum L) is an ancient perennial plant species regarded as a multipurpose plant owing to its richness in omega-3 polyunsaturated fatty acids... (Review)
Review
Flaxseed (Linum usitatissimum L) is an ancient perennial plant species regarded as a multipurpose plant owing to its richness in omega-3 polyunsaturated fatty acids (PUFA) including α-linolenic acid (ALA). The extensive biochemical analysis of flaxseed resulted in the identification of its bioactive, i.e., lignans with potential application in the improvement of human health. Flaxseed oil, fibers, and lignans exert potential health benefits including reduction of cardiovascular disease, atherosclerosis, diabetes, cancer, arthritis, osteoporosis, and autoimmune and neurological disorders that have led to the diversification of flaxseed plant applications. This comprehensive review focuses on flaxseed oil as the major product of flaxseed with emphasis on the interrelationship between its chemical composition and biological effects. Effects reviewed include antioxidant, anti-inflammatory, antimicrobial, anticancer, antiulcer, anti-osteoporotic, cardioprotective, metabolic, and neuroprotective. This study provides an overview of flaxseed oil effects with the reported action mechanisms related to its phytochemical composition and in comparison, to other PUFA-rich oils. This study presents the most updated and comprehensive review summarizing flaxseed oil's health benefits for the treatment of various diseases.
Topics: Humans; Linseed Oil; Flax; Cardiovascular Diseases; Antioxidants; Lignans
PubMed: 37464425
DOI: 10.1186/s40001-023-01203-6 -
Metabolites Jul 2023Phytohormones exhibit a wide range of chemical structures, though they primarily originate from three key metabolic precursors: amino acids, isoprenoids, and lipids.... (Review)
Review
Phytohormones exhibit a wide range of chemical structures, though they primarily originate from three key metabolic precursors: amino acids, isoprenoids, and lipids. Specific amino acids, such as tryptophan, methionine, phenylalanine, and arginine, contribute to the production of various phytohormones, including auxins, melatonin, ethylene, salicylic acid, and polyamines. Isoprenoids are the foundation of five phytohormone categories: cytokinins, brassinosteroids, gibberellins, abscisic acid, and strigolactones. Furthermore, lipids, i.e., α-linolenic acid, function as a precursor for jasmonic acid. The biosynthesis routes of these different plant hormones are intricately complex. Understanding of these processes can greatly enhance our knowledge of how these hormones regulate plant growth, development, and physiology. This review focuses on detailing the biosynthetic pathways of phytohormones.
PubMed: 37623827
DOI: 10.3390/metabo13080884 -
Biomolecules Aug 2023Sepsis is triggered by microbial infection, injury, or even major surgery. Both innate and adaptive immune systems are involved in its pathogenesis. Cytoplasmic presence... (Review)
Review
Sepsis is triggered by microbial infection, injury, or even major surgery. Both innate and adaptive immune systems are involved in its pathogenesis. Cytoplasmic presence of DNA or RNA of the invading organisms or damaged nuclear material (in the form of micronucleus in the cytoplasm) in the host cell need to be eliminated by various nucleases; failure to do so leads to the triggering of inflammation by the cellular cGAS-STING system, which induces the release of IL-6, TNF-α, and IFNs. These cytokines activate phospholipase A2 (PLA2), leading to the release of polyunsaturated fatty acids (PUFAs), gamma-linolenic acid (GLA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), which form precursors to various pro- and anti-inflammatory eicosanoids. On the other hand, corticosteroids inhibit PLA2 activity and, thus, suppress the release of GLA, AA, EPA, and DHA. PUFAs and their metabolites have a negative regulatory action on the cGAS-STING pathway and, thus, suppress the inflammatory process and initiate inflammation resolution. Pro-inflammatory cytokines and corticosteroids (corticosteroids > IL-6, TNF-α) suppress desaturases, which results in decreased formation of GLA, AA, and other PUFAs from the dietary essential fatty acids (EFAs). A deficiency of GLA, AA, EPA, and DHA results in decreased production of anti-inflammatory eicosanoids and failure to suppress the cGAS-STING system. This results in the continuation of the inflammatory process. Thus, altered concentrations of PUFAs and their metabolites, and failure to suppress the cGAS-STING system at an appropriate time, leads to the onset of sepsis. Similar abnormalities are also seen in radiation-induced inflammation. These results imply that timely administration of GLA, AA, EPA, and DHA, in combination with corticosteroids and anti-IL-6 and anti-TNF-α antibodies, may be of benefit in mitigating radiation-induced damage and sepsis.
Topics: Humans; Tumor Necrosis Factor-alpha; Interleukin-6; Tumor Necrosis Factor Inhibitors; Inflammation; Fatty Acids, Unsaturated; Eicosanoids; Eicosapentaenoic Acid; Arachidonic Acid; Cytokines; Docosahexaenoic Acids; Anti-Inflammatory Agents; Sepsis
PubMed: 37759732
DOI: 10.3390/biom13091332 -
International Journal of Molecular... Sep 2023Cardiovascular diseases (CVDs) represent the leading cause of global mortality with 1.7 million deaths a year. One of the alternative systems to drug therapy to minimize... (Review)
Review
Cardiovascular diseases (CVDs) represent the leading cause of global mortality with 1.7 million deaths a year. One of the alternative systems to drug therapy to minimize the risk of CVDs is represented by alpha-linolenic acid (ALA), an essential fatty acid of the omega-3 series, known for its cholesterol-lowering effect. The main purpose of this review is to analyze the effects of ALA and investigate the relevant omega-6/omega-3 ratio in order to maintain functionally beneficial effects. Concerning the lipid-lowering preventive effects, ALA may favorably affect the values of LDL-C and triglycerides in both adult and pediatric populations. Furthermore, ALA has shown protective effects against hypertension, contributing to balancing blood pressure through customary diet. According to the 2009 EFSA statement, dietary ALA may contribute to reducing the risk of CVDs, thanks to anti-hypertensive, anti-atherosclerotic and cardioprotective effects.
Topics: Adult; Child; Humans; alpha-Linolenic Acid; Fatty Acids, Omega-3; Hypertension; Antihypertensive Agents; Cardiovascular Diseases
PubMed: 37762621
DOI: 10.3390/ijms241814319 -
Journal of Personalized Medicine Feb 2024α-linolenic acid (ALA), which is a member of the n-3 polyunsaturated fatty acid (n-3 PUFA) family, has often been ignored due to a lack of information. ALA has... (Review)
Review
α-linolenic acid (ALA), which is a member of the n-3 polyunsaturated fatty acid (n-3 PUFA) family, has often been ignored due to a lack of information. ALA has gradually attracted increased attention due to its nutritional and medicinal advantages. Studies have shown that ALA exerts beneficial effects on a variety of diseases, including cancer. In this review, we summarize the antitumor effects of ALA in the context of cell biology, including the inhibition of proliferation, the induction of apoptosis, the inhibition of metastasis and angiogenesis, and antioxidant effects. In addition, studies have shown that ALA can be used as a drug carrier or exert positive clinical effects when combined with drugs. Therefore, the use of ALA in clinical treatments is very promising and valuable.
PubMed: 38541002
DOI: 10.3390/jpm14030260 -
The European Respiratory Journal Oct 2023Eicosanoids are bioactive lipids that regulate systemic inflammation and exert vasoactive effects. Specific eicosanoid metabolites have previously been associated with...
BACKGROUND
Eicosanoids are bioactive lipids that regulate systemic inflammation and exert vasoactive effects. Specific eicosanoid metabolites have previously been associated with pulmonary hypertension (PH), yet their role remains incompletely understood.
METHODS
We studied 482 participants with chronic dyspnoea who underwent clinically indicated cardiopulmonary exercise testing (CPET) with invasive haemodynamic monitoring. We performed comprehensive profiling of 888 eicosanoids and eicosanoid-related metabolites using directed non-targeted mass spectrometry, and examined associations with PH (mean pulmonary arterial pressure (mPAP) >20 mmHg), PH subtypes and physiological correlates, including transpulmonary metabolite gradients.
RESULTS
Among 482 participants (mean±sd age 56±16 years, 62% women), 200 had rest PH. We found 48 eicosanoids and eicosanoid-related metabolites that were associated with PH. Specifically, prostaglandin (11β-dhk-PGF2α), linoleic acid (12,13-EpOME) and arachidonic acid derivatives (11,12-DiHETrE) were associated with higher odds of PH (false discovery rate q<0.05 for all). By contrast, epoxide (8(9)-EpETE), α-linolenic acid (13()-HOTrE(γ)) and lipokine derivatives (12,13-DiHOME) were associated with lower odds. Among PH-related eicosanoids, 14 showed differential transpulmonary metabolite gradients, with directionality suggesting that metabolites associated with lower odds of PH also displayed pulmonary artery uptake. In individuals with exercise PH, eicosanoid profiles were intermediate between no PH and rest PH, with six metabolites that differed between rest and exercise PH.
CONCLUSIONS
Our findings highlight the role of specific eicosanoids, including linoleic acid and epoxide derivatives, as potential regulators of inflammation in PH. Of note, physiological correlates, including transpulmonary metabolite gradients, may prioritise future studies focused on eicosanoid-related pathways as important contributors to PH pathogenesis.
Topics: Humans; Female; Adult; Middle Aged; Aged; Male; Hypertension, Pulmonary; Linoleic Acid; Eicosanoids; Inflammation; Epoxy Compounds
PubMed: 37857430
DOI: 10.1183/13993003.00561-2023 -
Microbiome Dec 2023Oral infection with cysts is the main transmission route of Toxoplasma gondii (T. gondii), which leads to lethal intestinal inflammation. It has been widely recognized...
BACKGROUND
Oral infection with cysts is the main transmission route of Toxoplasma gondii (T. gondii), which leads to lethal intestinal inflammation. It has been widely recognized that T. gondii infection alters the composition and metabolism of the gut microbiota, thereby affecting the progression of toxoplasmosis. However, the potential mechanisms remain unclear. In our previous study, there was a decrease in the severity of toxoplasmosis after T. gondii α-amylase (α-AMY) was knocked out. Here, we established mouse models of ME49 and Δα-amy cyst infection and then took advantage of 16S rRNA gene sequencing and metabolomics analysis to identify specific gut microbiota-related metabolites that mitigate T. gondii-induced intestinal inflammation and analyzed the underlying mechanism.
RESULTS
There were significant differences in the intestinal inflammation between ME49 cyst- and Δα-amy cyst-infected mice, and transferring feces from mice infected with Δα-amy cysts into antibiotic-treated mice mitigated colitis caused by T. gondii infection. 16S rRNA gene sequencing showed that the relative abundances of gut bacteria, such as Lactobacillus and Bacteroides, Bifidobacterium, [Prevotella], Paraprevotella and Macellibacteroides, were enriched in mice challenged with Δα-amy cysts. Spearman correlation analysis between gut microbiota and metabolites indicated that some fatty acids, including azelaic acid, suberic acid, alpha-linolenic acid (ALA), and citramalic acid, were highly positively correlated with the identified bacterial genera. Both oral administration of ALA and fecal microbiota transplantation (FMT) decreased the expression of pro-inflammatory cytokines and restrained the MyD88/NF-κB pathway, which mitigated colitis and ultimately improved host survival. Furthermore, transferring feces from mice treated with ALA reshaped the colonization of beneficial bacteria, such as Enterobacteriaceae, Proteobacteria, Shigella, Lactobacillus, and Enterococcus.
CONCLUSIONS
The present findings demonstrate that the host gut microbiota is closely associated with the severity of T. gondii infection. We provide the first evidence that ALA can alleviate T. gondii-induced colitis by improving the dysregulation of the host gut microbiota and suppressing the production of pro-inflammatory cytokines via the MyD88/NF-κB pathway. Our study provides new insight into the medical application of ALA for the treatment of lethal intestinal inflammation caused by Toxoplasma infection. Video Abstract.
Topics: Mice; Animals; Toxoplasma; alpha-Linolenic Acid; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Myeloid Differentiation Factor 88; NF-kappa B; Toxoplasmosis; Communicable Diseases; Colitis; Cytokines; Bacteria; Inflammation; Mice, Inbred C57BL
PubMed: 38087373
DOI: 10.1186/s40168-023-01681-0 -
Diabetes, Metabolic Syndrome and... 2024Obesity is a growing global problem that causes various complications such as diabetes, cognitive dysfunction, cardiovascular diseases, and hepatobiliary disease....
BACKGROUND
Obesity is a growing global problem that causes various complications such as diabetes, cognitive dysfunction, cardiovascular diseases, and hepatobiliary disease. Alpha-linolenic acid (ALA) has been reported to exhibit multiple pharmaceutical effects. This study aimed to explore the effects of ALA on obesity-induced adipose tissue accumulation, cognitive impairment, inflammation, and colonic mucosal barrier integrity.
METHODS
Mice were fed with high-fat diet (HFD) and were treated with ALA (60 or 100 mg/kg). Body weight, adipose tissue, serum glucose and lipid levels, glucose resistance, and insulin resistance were measured. Cognitive ability was analyzed using the behavior tests. PTP1B and IRS/p-AKT/p-GSK3β/p-Tau signaling were examined to evaluate inflammation and synaptogenesis. Colon mucosal barrier integrity was examined by Alcian blue staining and expression of the tight junction proteins. The production of pro-inflammatory cytokines and liver damages were evaluated. 3T3-L1 cells were used for in vitro experiments. Cell viability, migration and invasion were detected. The levels of ROS, iron, and ferrous ions were measured to assess ferroptosis. Metabolomic analysis of adipose tissues was performed.
RESULTS
ALA treatment prevented HFD-induced adipose tissue accumulation, improved glucose and lipid homeostasis and metabolism. Administration of ALA repressed the HFD-induced increase in insulin levels and insulin resistance index. Serum and colon levels of pro-inflammatory cytokines were decreased after ALA treatment. ALA elevated mitochondrial content in brown adipose tissues. ALA ameliorated obesity-induced cognitive impairment and hippocampal inflammation, enhanced colon mucosa integrity. ALA treatment ameliorated HFD-induced liver damage and lipid accumulation and inhibited differentiation of preadipocyte 3T3-L1 cells into mature adipocytes and induces ferroptosis. Metabolomic analysis suggested that ALA may target the glycerolipid metabolism pathway to ameliorate obesity. Knockdown of AGPAT2 abolished the protective effects of ALA.
CONCLUSION
ALA treatment suppressed adipose accumulation in adipocytes, improved cognitive ability and colon integrity, and alleviated liver damage by modulating the 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2).
PubMed: 38435630
DOI: 10.2147/DMSO.S434671