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Aging Jul 2021Heroin addiction and withdrawal have been associated with an increased risk for infectious diseases and psychological complications. However, the changes of metabolites...
BACKGROUND
Heroin addiction and withdrawal have been associated with an increased risk for infectious diseases and psychological complications. However, the changes of metabolites in heroin addicts during withdrawal remain largely unknown.
METHODS
A total of 50 participants including 20 heroin addicts with acute abstinence stage, 15 with protracted abstinence stage and 15 healthy controls, were recruited. We performed metabolic profiling of plasma samples based on ultraperformance liquid chromatography coupled to tandem mass spectrometry to explore the potential biomarkers and mechanisms of heroin withdrawal.
RESULTS
Among the metabolites analyzed, omega-6 polyunsaturated fatty acids (linoleic acid, dihomo-gamma-linolenic acid, arachidonic acid, n-6 docosapentaenoic acid), omega-3 polyunsaturated fatty acids (docosahexaenoic acid, docosapentaenoic acid), aromatic amino acids (phenylalanine, tyrosine, tryptophan), and intermediates of the tricarboxylic acid cycle (oxoglutaric acid, isocitric acid) were significantly reduced during acute heroin withdrawal. Although majority of the metabolite changes could recover after months of withdrawal, the levels of alpha-aminobutyric acid, alloisoleucine, ketoleucine, and oxalic acid do not recover.
CONCLUSIONS
In conclusion, the plasma metabolites undergo tremendous changes during heroin withdrawal. Through metabolomic analysis, we have identified links between a framework of metabolic perturbations and withdrawal stages in heroin addicts.
Topics: Adult; Amino Acids, Aromatic; Biomarkers; Case-Control Studies; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Heroin; Heroin Dependence; Humans; Male; Metabolomics; Substance Withdrawal Syndrome; Tricarboxylic Acids
PubMed: 34282053
DOI: 10.18632/aging.203311 -
Antioxidants (Basel, Switzerland) Sep 2021Colorectal cancer is a highly malignant cancer that is inherently resistant to many chemotherapeutic drugs owing to the complicated tumor-supportive microenvironment...
7S,15R-Dihydroxy-16S,17S-Epoxy-Docosapentaenoic Acid, a Novel DHA Epoxy Derivative, Inhibits Colorectal Cancer Stemness through Repolarization of Tumor-Associated Macrophage Functions and the ROS/STAT3 Signaling Pathway.
Colorectal cancer is a highly malignant cancer that is inherently resistant to many chemotherapeutic drugs owing to the complicated tumor-supportive microenvironment (TME). Tumor-associated macrophages (TAM) are known to mediate colorectal cancer metastasis and relapse and are therefore a promising therapeutic target. In the current study, we first confirmed the anti-inflammatory effect of 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA), a novel DHA dihydroxy derivative synthesized in our previous work. We found that diHEP-DPA significantly reduced lipopolysaccharide (LPS)-induced inflammatory cytokines secretion of THP1 macrophages, IL-6, and TNF-α. As expected, diHEP-DPA also modulated TAM polarization, as evidenced by decreased gene and protein expression of the TAM markers, CD206, CD163, VEGF, and TGF-β1. During the polarization process, diHEP-DPA treatment decreased the concentration of TGF-β1, IL-1β, IL-6, and TNF-α in culture supernatants via inhibiting the NF-κB pathway. Moreover, diHEP-DPA blocked immunosuppression by reducing the expression of SIRPα in TAMs and CD47 in colorectal cancer cells. Knowing that an inflammatory TME largely serves to support epithelial-mesenchymal transition (EMT) and cancer stemness, we tested whether diHEP-DPA acted through polarization of TAMs to regulate these processes. The intraperitoneally injected diHEP-DPA inhibited tumor growth when administered alone or in combination with 5-fluorouracil (5-FU) chemotherapy in vivo. We further found that diHEP-DPA effectively reversed TAM-conditioned medium (TCCM)-induced EMT and enhanced colorectal cancer stemness, as evidenced by its inhibition of colorectal cancer cell migration, invasion and expression of EMT markers, as well as cancer cell tumorspheres formation, without damaging colorectal cancer cells. DiHEP-DPA reduced the population of aldehyde dehydrogenase (ALDH)-positive cells and expression of colorectal stemness marker proteins (CD133, CD44, and Sox2) by modulating TAM polarization. Additionally, diHEP-DPA directly inhibited cancer stemness by inducing the production of reactive oxygen species (ROS), which, in turn, reduced the phosphorylation of nuclear signal transducer and activator of transcription 3 (STAT3). These data collectively suggest that diHEP-DPA has the potential for development as an anticancer agent against colorectal cancer.
PubMed: 34573091
DOI: 10.3390/antiox10091459 -
Bioorganic Chemistry Mar 2020Cyclooxygenase-2 and several lipoxygenases convert polyunsaturated fatty acids into a large variety of products. During inflammatory processes, these enzymes form...
Cyclooxygenase-2 and several lipoxygenases convert polyunsaturated fatty acids into a large variety of products. During inflammatory processes, these enzymes form several distinct families of specialized pro-resolving lipid mediators possessing potent anti-inflammatory and pro-resolving effects. These mediators have attracted a great interest as leads in drug discovery and have recently been the subject of biosynthetic pathway studies using docosahexaenoic and n-3 docosapentaenoic acid as substrates. Herein we present enzymatic studies with cyclooxygenase-2 and 5-, 12- and 15-lipoxygenase enzymes using 3-oxa n-3 DPA as a synthetic mimic of n-3 docosapentaenoic acid. Structural elucidation based on data from RP-HPLC UV and LC/MS-MS experiments enabled the identification of novel enzymatically formed products. These findings constitute the basis for further biosynthetic studies towards understanding the mechanisms regulating substrate utilization in the biosynthesis of specialized pro-resolving lipid mediators.
Topics: Animals; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Cyclooxygenase 2; Fatty Acids, Unsaturated; Humans; Mice; Glycine max; Substrate Specificity
PubMed: 32062066
DOI: 10.1016/j.bioorg.2020.103653 -
European Journal of Nutrition Jun 2020Observational studies have suggested that polyunsaturated fatty acids (PUFAs) may decrease Alzheimer's disease (AD) risk. In the present study, we examined this...
PURPOSE
Observational studies have suggested that polyunsaturated fatty acids (PUFAs) may decrease Alzheimer's disease (AD) risk. In the present study, we examined this hypothesis using a Mendelian randomization analysis.
METHODS
We used summary statistics data for single-nucleotide polymorphisms associated with plasma levels of n-6 PUFAs (linoleic acid, arachidonic acid) and n-3 PUFAs (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid), and the corresponding data for AD from a genome-wide association meta-analysis of 63,926 individuals (21,982 diagnosed AD cases, 41,944 controls).
RESULTS
None of the genetically predicted PUFAs was significantly associated with AD risk; odds ratios (95% confidence interval) per 1 SD increase in PUFA levels were 0.98 (0.93, 1.03) for linoleic acid, 1.01 (0.98, 1.05) for arachidonic acid, 0.96 (0.88, 1.06) for alpha-linolenic acid, 1.03 (0.93, 1.13) for eicosapentaenoic acid, 1.03 (0.97, 1.09) for docosapentaenoic acid, and 1.01 (0.81, 1.25) for docosahexaenoic acid.
CONCLUSIONS
This study did not support the hypothesis that PUFAs decrease AD risk.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Fatty Acids, Unsaturated; Female; Genome-Wide Association Study; Geriatric Assessment; Humans; Male; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Risk Assessment
PubMed: 31676950
DOI: 10.1007/s00394-019-02126-x -
Prostaglandins, Leukotrienes, and... Oct 2021Treatment with high dose icosapent ethyl (IPE), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA), significantly reduced ischemic events in patients...
Treatment with high dose icosapent ethyl (IPE), an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA), significantly reduced ischemic events in patients with either cardiovascular disease (CV) or diabetes plus other risk factors (REDUCE-IT) but the mechanism is not well understood. We compared the effects of EPA, docosahexaenoic acid (DHA), and the omega-6 fatty acid arachidonic acid (AA) on bioavailability of nitric oxide (NO) and fatty acid composition. Human umbilical vein endothelial cells (HUVECs) were pretreated with EPA, DHA, or AA (10 µM). Cells were stimulated with calcium ionophore and NO and peroxynitrite (ONOO) were measured using porphyrinic nanosensors. Levels of EPA, DHA, AA and other fatty acids were measured by gas chromatography (GC). EPA treatment caused the greatest NO release (18%, p < 0.001) and reduction in ONOO (13%, p < 0.05) compared to control; the [NO]/[ ONOO] ratio increased by 35% (p < 0.001). DHA treatment increased NO levels by 12% (p < 0.01) but had no effect on ONOO release. AA did not affect either NO or ONOO release. Fatty acid treatments increased their respective levels in endothelial cells. EPA levels increased 10-fold to 4.59 mg/g protein (p < 0.001) with EPA treatment and the EPA/AA ratio increased by 10-fold (p < 0.001) compared to vehicle. Only EPA increased docosapentaenoic acid (DPA, omega-3) levels by 2-fold (p < 0.001). AA alone decreased the EPA/AA ratio 4-fold (p<0.001). These findings support a preferential benefit of EPA on endothelial function and omega-3 fatty acid content.
Topics: Arachidonic Acid; Biological Availability; Docosahexaenoic Acids; Eicosapentaenoic Acid; Endothelial Cells; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Human Umbilical Vein Endothelial Cells; Humans; Nitric Oxide; Peroxynitrous Acid
PubMed: 34464785
DOI: 10.1016/j.plefa.2021.102337 -
Therapeutic Advances in Chronic Disease 2021Fatty acids (FAs) play crucial roles in modulating and preventing diseases in humans, including early-onset coronary artery disease (EOCAD). In this study, we aimed to...
BACKGROUND
Fatty acids (FAs) play crucial roles in modulating and preventing diseases in humans, including early-onset coronary artery disease (EOCAD). In this study, we aimed to provide a profile of FAs in the serum of EOCAD patients and identify potential EOCAD-associated FAs.
METHODS
In the first stage, we analyzed the FAs profiles in pooled samples of patients with EOCAD using gas chromatography-mass spectrometry. In the second stage, the serum levels of the candidate FAs were validated in EOCAD patients.
RESULTS
A total of 128 EOCAD patients and 64 controls were included in the study. Forty-nine serum FAs were quantified in pooled samples; three ω-3 FAs were identified to be associated with EOCAD. Moreover, results from the validation stage indicated that serum levels of docosahexaenoic acid (DHA) were significantly lower in EOCAD patients (55.43 ± 33.86 µg/ml) and myocardial infarction (MI) patients (47.49 ± 28.44 μg/ml) than those in the controls (70.65 ± 43.56 µg/ml). Multivariate regression analysis revealed that elevated serum DHA level was an independent protective factor for EOCAD [odds ratio (OR) = 0.8917, 95% confidence interval (CI): 0.879-0.957] and MI (OR = 0.835, 95% CI: 0.799-0.862). Decreased serum levels of docosapentaenoic acid (DPA) and eicosapentaenoic acid (EPA) were observed in the early-onset MI group.
CONCLUSION
The study provided the serum FAs profile of EOCAD and confirmed that the decrease in serum levels of DHA, DPA, and EPA was associated with EOCAD. These findings might contribute to understanding the cardiovascular effects of FAs, particularly the protective effects of ω-3 polyunsaturated FAs.
PubMed: 34408821
DOI: 10.1177/20406223211033102 -
Journal of Dairy Science Mar 2022The specific fatty acid (FA) profile of colostrum may indicate a biological requirement for neonatal calves. The objective of this study was to characterize the FA...
The specific fatty acid (FA) profile of colostrum may indicate a biological requirement for neonatal calves. The objective of this study was to characterize the FA profile and yields in colostrum, transition milk, and mature milk in primiparous (PP) and multiparous (MP) cows. Colostrum was milked from 10 PP and 10 MP Holstein cows fed the same pre- and postpartum rations. Milkings (M) 2 to 5 and 12 were respectively termed transition and mature milk. Overall, short-chain FA (C4:0 and C6:0) were 61 and 50% lower in colostrum than mature milk, respectively. A parity by milking interaction was also present, with higher C4:0 for PP cows at M2 and for MP cows at M12. Additionally, higher concentrations of C6:0 were present for PP cows at M2 through M4 and for MP cows at M12. Palmitic (C16:0) and myristic (C14:0) acids were 16% and 27% higher in colostrum than mature milk, respectively. However, total saturated FA remained relatively stable. Branched-chain FA were 13% lower in colostrum than mature milk and higher in PP than MP cows throughout the milking period. The proportion of trans-monounsaturated FA (MUFA) was 42% higher in PP cows throughout the milking period, as well as 15% lower in colostrum than mature milk. In contrast, cis-MUFA and total MUFA were not affected by milking nor parity. Linoleic acid (LA) was 13% higher in colostrum than transition and mature milks, but α-linolenic acid (ALA) did not differ. Consequently, the ratio of LA to ALA was 23% higher in colostrum than mature milk and 25% higher in MP cows. Linoleic acid was also 13% higher in MP cows, whereas ALA was 15% higher in PP cows. Conjugated linoleic acid (CLA, cis-9,trans-11) was 63% higher in PP cows, and no differences between colostrum and mature milk were detected. Overall, polyunsaturated FA (PUFA) from the n-6 and n-3 series were over 25% higher in colostrum compared with transition and mature milk. Milking by parity interactions were present for arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), and total n-3 PUFA, translating to higher proportions in PP cows in M1 to M3, whereas proportions remained relatively stable throughout the milking period in MP cows. Despite increasing milk yields throughout the subsequent milkings, higher yields of EPA, ARA, DPA, and DHA were present in colostrum than in mature milk. Greater proportions and yields of n-3 and n-6 FA in colostrum may translate to specific requirements for newborn calves. Differences were also observed between PP and MP cows and may reflect different nutrient requirements and partitioning.
Topics: Animals; Cattle; Colostrum; Diet; Fatty Acids; Female; Lactation; Milk; Parity; Pregnancy
PubMed: 35033345
DOI: 10.3168/jds.2021-20880 -
Journal of Dairy Science May 2022The specific fatty acid (FA) profile of colostrum may indicate a biological requirement for neonatal calves. The objective of this study was to characterize the FA...
The specific fatty acid (FA) profile of colostrum may indicate a biological requirement for neonatal calves. The objective of this study was to characterize the FA profile and yields in colostrum, transition milk, and mature milk in primiparous (PP) and multiparous (MP) cows. Colostrum was milked from 10 PP and 10 MP Holstein cows fed the same pre- and postpartum rations. Milkings (M) 2 to 5 and 12 were respectively termed transition and mature milk. Overall, short-chain FA (C4:0 and C6:0) were 61 and 50% lower in colostrum than mature milk, respectively. A parity by milking interaction was also present, with higher C4:0 for PP cows at M2 and for MP cows at M12. Additionally, higher concentrations of C6:0 were present for PP cows at M2 through M4 and for MP cows at M12. Palmitic (C16:0) and myristic (C14:0) acids were 38% and 19% higher in colostrum than mature milk, respectively. However, total saturated FA remained relatively stable. Branched-chain FA were 13% lower in colostrum than mature milk and higher in PP than MP cows throughout the milking period. The proportion of trans-monounsaturated FA (MUFA) was 72% higher in PP cows throughout the milking period, as well as 13% lower in colostrum than mature milk. In contrast, cis-MUFA and total MUFA were not affected by milking nor parity. Linoleic acid (LA) was 25% higher in colostrum than transition and mature milks, but α-linolenic acid (ALA) did not differ. Consequently, the ratio of LA to ALA was 29% higher in colostrum than mature milk and 33% higher in MP cows. Linoleic acid was also 15% higher in MP cows, whereas ALA was 15% higher in PP cows. Conjugated linoleic acid (CLA, cis-9,trans-11) was 2.7-fold higher in PP cows, and no differences between colostrum and mature milk were detected. Overall, polyunsaturated FA (PUFA) from the n-6 and n-3 series were over 40% higher in colostrum compared with transition and mature milk. Milking by parity interactions were present for arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), and total n-3 PUFA, translating to higher proportions in PP cows in M1 to M3, whereas proportions remained relatively stable throughout the milking period in MP cows. Despite increasing milk yields throughout the subsequent milkings, higher yields of EPA, ARA, DPA, and DHA were present in colostrum than in mature milk. Greater proportions and yields of n-3 and n-6 FA in colostrum may translate to specific requirements for newborn calves. Differences were also observed between PP and MP cows and may reflect different nutrient requirements and partitioning.
Topics: Animals; Cattle; Colostrum; Docosahexaenoic Acids; Fatty Acids; Female; Lactation; Milk; Parity; Pregnancy
PubMed: 35473965
DOI: 10.3168/jds.2022-20880a -
Allergy Aug 2020Maternal dietary exposures are considered to influence the development of infant allergies through changes in the composition of breast milk. Cohort studies have shown...
BACKGROUND
Maternal dietary exposures are considered to influence the development of infant allergies through changes in the composition of breast milk. Cohort studies have shown that ω3 polyunsaturated fatty acids (PUFAs) in breast milk may have a beneficial effect on the preventing of allergies in infants; however, the underlying mechanisms remain to be investigated. We investigated how the maternal intake of dietary ω3 PUFAs affects fatty acid profiles in the breast milk and their pups and reduced the incidence of allergic diseases in the pups.
METHODS
Contact hypersensitivity (CHS) induced by 2,4-dinitrofluorobenzene (DNFB) and fluorescein isothiocyanate was applied to the skin in pups reared by mother maintained with diets mainly containing ω3 or ω6 PUFAs. Skin inflammation, immune cell populations, and expression levels of immunomodulatory molecules in pups and/or human cell line were investigated by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. ω3 PUFA metabolites in breast milk and infant's serum were evaluated by lipidomics analysis using LC-MS/MS.
RESULTS
We show that maternal intake of linseed oil, containing abundant ω3 α-linolenic acid, resulted in the increased levels of ω3 docosapentaenoic acid (DPA) and its 14-lipoxygenation products in the breast milk of mouse dams; these metabolites increased the expression of TNF-related apoptosis-inducing ligand (TRAIL) on plasmacytoid dendritic cells (pDCs) in their pups and thus inhibited infant CHS. Indeed, the administration of DPA-derived 14-lipoxygenation products to mouse pups ameliorated their DNFB CHS.
CONCLUSION
These findings suggest that an inhibitory mechanism in infant skin allergy is induced through maternal metabolism of dietary ω3 PUFAs in mice.
Topics: Animals; Chromatography, Liquid; Dendritic Cells; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Mice; TNF-Related Apoptosis-Inducing Ligand; Tandem Mass Spectrometry
PubMed: 32027039
DOI: 10.1111/all.14217 -
Neurology Feb 2020To examine the association between prediagnostic plasma polyunsaturated fatty acids levels (PUFA) and amyotrophic lateral sclerosis (ALS).
OBJECTIVE
To examine the association between prediagnostic plasma polyunsaturated fatty acids levels (PUFA) and amyotrophic lateral sclerosis (ALS).
METHODS
We identified 275 individuals who developed ALS while enrolled in 5 US prospective cohorts, and randomly selected 2 controls, alive at the time of the case diagnosis, matched on cohort, birth year, sex, ethnicity, fasting status, and time of blood draw. We measured PUFA, expressed as percentages of total fatty acids, using gas liquid chromatography and used conditional logistic regression to estimate risk ratios (RR) and 95% confidence intervals (CI) for the association between PUFA and ALS.
RESULTS
There was no association between total, n-3, and n-6 PUFA, eicosapentaenoic acid, or docosapentaenoic acid levels and ALS. Higher plasma α-linolenic acid (ALA) in men was associated with lower risk of ALS in age- and matching factor-adjusted analyses (top vs bottom quartile: RR = 0.21 [95% CI 0.07, 0.58], for trend = 0.004). In women, higher plasma arachidonic acid was associated with higher risk (top vs bottom quartile: RR = 1.65 [95% CI 0.99, 2.76], for trend = 0.052). Multivariable adjustment, including correlated PUFA, did not change the findings for ALA and arachidonic acid. In men and women combined, higher plasma docosahexaenoic acid (DHA) was associated with higher risk of ALS (top vs bottom quartile: RR = 1.56 [95% CI 1.01, 2.41], for trend = 0.054), but in multivariable models the association was only evident in men.
CONCLUSIONS
The majority of individual PUFAs were not associated with ALS. In men, ALA was inversely and DHA was positively related to risk of ALS, while in women arachidonic acid was positively related. These findings warrant confirmation in future studies.
Topics: Aged; Amyotrophic Lateral Sclerosis; Biomarkers; Fatty Acids, Unsaturated; Female; Humans; Male; Middle Aged; Prodromal Symptoms; Risk Factors; Sex Factors
PubMed: 31796528
DOI: 10.1212/WNL.0000000000008676