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BMC Musculoskeletal Disorders May 2024Synovitis, characterized by inflammation of the synovial membrane, is commonly induced by meniscus tears. However, significant differences in inflammatory responses and...
BACKGROUND
Synovitis, characterized by inflammation of the synovial membrane, is commonly induced by meniscus tears. However, significant differences in inflammatory responses and the key inflammatory mediators of synovium induced by different types of meniscal tears remain unclear.
METHODS
Magnetic resonance imaging (MRI) was employed to identify the type of meniscus tear, and the quantification of synovial inflammation was assessed through H&E staining assay. Transcription and expression levels of IL-1β and IL-6 were evaluated using bioinformatics, ELISA, RT-qPCR, and IHC of CD68 staining assays. The therapeutic potential of Docosapentaenoic Acid (DPA) was determined through network pharmacology, ELISA, and RT-qPCR assays. The safety of DPA was assessed using colony formation and EdU staining assays.
RESULTS
The results indicate that both IL-1β and IL-6 play pivotal roles in synovitis pathogenesis, with distinct expression levels across various subtypes. Among tested meniscus tears, oblique tear and bucket handle tear induced the most severe inflammation, followed by radial tear and longitudinal tear, while horizontal tear resulted in the least inflammation. Furthermore, in synovial inflammation induced by specific meniscus tears, the anterior medial tissues exhibited significantly higher local inflammation than the anterior lateral and suprapatellar regions, highlighting the clinical relevance and practical guidance of anterior medial tissues' inflammatory levels. Additionally, we identified the essential omega-3 fatty acid DPA as a potential therapeutic agent for synovitis, demonstrating efficacy in blocking the transcription and expression of IL-1β and IL-6 with minimal side effects.
CONCLUSION
These findings provide valuable insights into the nuanced nature of synovial inflammation induced by various meniscal tear classifications and contribute to the development of new adjunctive therapeutic agents in the management of synovitis.
Topics: Tibial Meniscus Injuries; Synovitis; Magnetic Resonance Imaging; Synovial Membrane; Humans; Fatty Acids, Unsaturated; Male; Interleukin-1beta; Animals; Interleukin-6; Female; Menisci, Tibial; Mice; Disease Models, Animal
PubMed: 38734632
DOI: 10.1186/s12891-024-07491-1 -
Molecules (Basel, Switzerland) Oct 2020Omega-3 long-chain polyunsaturated fatty acids (n-3 LC PUFAs) and vitamin D are essential components of human nutrition. A regular human diet is highly deficient in n-3...
Nutritional Enhancement of Farmed Salmon Meat via Non-GMO Nannochloropsis Gaditana: Eicosapentaenoic Acid (EPA, 20:5 n-3), Docosapentaenoic Acid (DPA, 22:5 n-3) and Vitamin D3 for Human Health.
Omega-3 long-chain polyunsaturated fatty acids (n-3 LC PUFAs) and vitamin D are essential components of human nutrition. A regular human diet is highly deficient in n-3 LC PUFAs. Fish like salmon are highly recommended in the human diet as they are a major source of high-value n-3 LC PUFAs and vitamin D The levels of these nutrients have been decreasing over the last few years in farmed salmon, whose production urgently needs sustainable sources of these nutrients. The microalga (NG) is known for its naturally high potential for the production of eicosapentaenoic (EPA, 20:5 n-3) fatty acid. A commercial diet for Atlantic salmon was supplemented with 1% and 10% of spray-dried NG grown under controlled conditions for a high EPA content. Salmon were harvested on day 49, following which, boneless and skinless salmon meat was recovered from fish and analyzed for the fatty acid profile, total fat, and vitamin D. Vitamin D, EPA, and docosapentaenoic fatty acid (DPA, 22:5 n-3) levels were significantly increased ( < 0.05) by supplementing the basal diet with 10% NG, thus, NG represents a novel, functional, natural ingredient and a sustainable source of n-3 LC-PUFAs that can raise the levels of healthy fats and vitamin D in farmed salmon meat.
Topics: Animals; Cholecalciferol; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Humans; Microalgae; Salmo salar
PubMed: 33050537
DOI: 10.3390/molecules25204615 -
Ecotoxicology and Environmental Safety Mar 202211 S, 17S-dihydroxy 7,9,13,15,19 (Z,E,Z,E,Z)-docosapentaenoic acid (DoPE) is a derivative of docosapentaenoic acid, a specialized pro-resolving mediator of inflammation...
The DPA-derivative 11S, 17S-dihydroxy 7,9,13,15,19 (Z,E,Z,E,Z)-docosapentaenoic acid inhibits IL-6 production by inhibiting ROS production and ERK/NF-κB pathway in keratinocytes HaCaT stimulated with a fine dust PM.
11 S, 17S-dihydroxy 7,9,13,15,19 (Z,E,Z,E,Z)-docosapentaenoic acid (DoPE) is a derivative of docosapentaenoic acid, a specialized pro-resolving mediator of inflammation such as lipoxins, resolvins, maresins, and protectins. PM is a fine dust particle that induces oxidative stress, DNA damage, inflammation, aging, and cancer. The anti-inflammatory mechanism of DoPE, however, has not yet been elucidated. In these studies, we investigated whether DoPE has anti-inflammatory effects in human keratinocyte HaCaT cells. We demonstrated that DoPE suppressed PM-induced expressions of IL-6 mRNA and protein in human HaCaT keratinocytes. We also investigated the modulating effects of DoPE on reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK). ROS production, extracellular signal regulated kinase (ERK) phosphorylation, and translocation of nuclear factor-kappa B (NF-kB) p65 and NF-kB activity were suppressed by DoPE in PM-stimulated HaCaT cells. Collectively, our results demonstrated that DoPE inhibited IL-6 expression by reducing ROS generation, suppressing ERK phosphorylation, and inhibiting translocation of NF-kB p65 and NF-kB activity in PM-stimulated HaCaT cells, suggesting that DoPE can be useful for the resolution of the inflammation caused by IL-6.
Topics: Dust; Extracellular Signal-Regulated MAP Kinases; Fatty Acids, Unsaturated; Humans; Interleukin-6; Keratinocytes; NF-kappa B; Reactive Oxygen Species
PubMed: 35104780
DOI: 10.1016/j.ecoenv.2022.113252 -
Environment International Mar 2024Isolated effects of single endocrine-disrupting chemicals (EDCs) on male reproductive health have been studied extensively, but their mixture effect remains...
Isolated effects of single endocrine-disrupting chemicals (EDCs) on male reproductive health have been studied extensively, but their mixture effect remains unelucidated. Previous research has suggested that consuming diet enriched in omega-3 polyunsaturated fatty acids (PUFA) might be beneficial for reproductive health, whether omega-3 PUFA could moderate the effect of EDCs mixture on semen quality remains to be explored. In this study of 155 male recruited from a reproductive health center in China, we used targeted-exposomics to simultaneously measure 55 EDCs in the urine for exposure burden. Regression analyses were restricted to highly detected EDCs (≥55%, n = 34), and those with consistently elevated risk were further screened and brought into mixture effect models (Bisphenol A, ethyl paraben, methyl paraben [MeP], benzophenone-1 [BP1], benzophenone-3, mono(3-carboxypropyl) phthalate [MCPP]). Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation (QGC) models demonstrated that co-exposure to top-ranked EDCs was related to reduced sperm total (β = -0.18, 95%CI: -0.29 - -0.07, P = 0.002) and progressive motility (β = -0.27, 95%CI: -0.43 - -0.10, P = 0.002), but not to lower semen volume. BP1, MeP and MCPP were identified as the main effect driver for deteriorated sperm motion parameters using mixture model analyses. Seminal plasma fatty acid profiling showed that high omega-3 PUFA status, notably elevated docosapentaenoic acid (DPA, C22:5n-3) status, moderated the association between MCPP and sperm motion parameters (total motility: β = 0.26, 95%CI: 0.01 - -0.51, P = 0.047; progressive motility: β = 0.64, 95%CI: 0.23 - 1.05, P = 0.003). Co-exposure to a range of EDCs is mainly associated with deteriorated sperm quality, but to a lesser extent on sperm quantity, high seminal plasma DPA status might be protective against the effect. Our work emphasizes the importance of exposomic approach to assess chemical exposures and highlighted a new possible intervention target for mitigating the potential adverse effect of EDCs on semen quality.
Topics: Male; Humans; Semen; Semen Analysis; Endocrine Disruptors; Bayes Theorem; Spermatozoa; Fatty Acids, Omega-3; Benzophenones; Fatty Acids, Unsaturated
PubMed: 38471262
DOI: 10.1016/j.envint.2024.108571 -
FASEB Journal : Official Publication of... Nov 2016In contrast to the well-characterized effects of specialized proresolving lipid mediators (SPMs) derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),...
In contrast to the well-characterized effects of specialized proresolving lipid mediators (SPMs) derived from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), little is known about the metabolic fate of the intermediary long-chain (LC) n-3 polyunsaturated fatty acid (PUFA) docosapentaenoic acid (DPA). In this double blind crossover study, shifts in circulating levels of n-3 and n-6 PUFA-derived bioactive lipid mediators were quantified by an unbiased liquid chromatography-tandem mass spectrometry lipidomic approach. Plasma was obtained from human subjects before and after 7 d of supplementation with pure n-3 DPA, n-3 EPA or placebo (olive oil). DPA supplementation increased the SPM resolvin D5 (RvD5) and maresin (MaR)-1, the DHA vicinal diol 19,20-dihydroxy-DPA and n-6 PUFA derived 15-keto-PG E (15-keto-PGE). EPA supplementation had no effect on any plasma DPA or DHA derived mediators, but markedly elevated monohydroxy-eicosapentaenoic acids (HEPEs), including the e-series resolvin (RvE) precursor 18-HEPE; effects not observed with DPA supplementation. These data show that dietary n-3 DPA and EPA have highly divergent effects on human lipid mediator profile, with no overlap in PUFA metabolites formed. The recently uncovered biologic activity of n-3 DPA docosanoids and their marked modulation by dietary DPA intake reveals a unique and specific role of n-3 DPA in human physiology.-Markworth, J. F., Kaur, G., Miller, E. G., Larsen, A. E., Sinclair, A. J., Maddipati, K. R., Cameron-Smith, D. Divergent shifts in lipid mediator profile following supplementation with n-3 docosapentaenoic acid and eicosapentaenoic acid.
Topics: Adult; Cross-Over Studies; Diet; Dietary Supplements; Eicosapentaenoic Acid; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Humans; Lipid Metabolism; Young Adult
PubMed: 27461565
DOI: 10.1096/fj.201600360R -
Marine Drugs Jan 2023Although the tumor bulk is initially reduced by 5-fluorouracil (5-FU), chemoresistance developed due to prolonged chemotherapy in colorectal cancer (CRC). The enrichment...
7,15-Dihydroxy-16,17-epoxy-docosapentaenoic Acid Overcomes Chemoresistance of 5-Fluorouracil by Suppressing the Infiltration of Tumor-Associated Macrophages and Inhibiting the Activation of Cancer Stem Cells in a Colorectal Cancer Xenograft Model.
Although the tumor bulk is initially reduced by 5-fluorouracil (5-FU), chemoresistance developed due to prolonged chemotherapy in colorectal cancer (CRC). The enrichment of cancer stem cells (CSCs) and the infiltration of tumor-associated macrophages (TAMs) contribute to chemoresistance and poor outcomes. A docosahexaenoic acid derivative developed by our group, 7,15-dihydroxy-16,17-epoxy-docosapentaenoic acid (diHEP-DPA), exerts antitumor effects against TAMs infiltration and CSCs enrichment in our previous study. The current study aimed to investigate whether diHEP-DPA was able to overcome chemoresistance to 5-FU in CRCs, together with the potential synergistic mechanisms in a CT26-BALB/c mouse model. Our results suggested that although 5-FU inhibited tumor growth, 5-FU enriched CSCs via the WNT/β-catenin signaling pathway, resulting in chemoresistance in CRCs. However, we revealed that 5-FU promoted the infiltration of TAMs via the NF-kB signaling pathway and improved epithelial-mesenchymal transition (EMT) via the signal transducer and activator of the transcription 3 (STAT3) signaling pathway; these traits were believed to contribute to CSC activation. Furthermore, supplementation with diHEP-DPA could overcome drug resistance by decreasing the CSCs, suppressing the infiltration of TAMs, and inhibiting EMT progression. Additionally, the combinatorial treatment of diHEP-DPA and 5-FU effectively enhanced phagocytosis by blocking the CD47/signal regulatory protein alpha (SIRPα) axis. These findings present that diHEP-DPA is a potential therapeutic supplement to improve drug outcomes and suppress chemoresistance associated with the current 5-FU-based therapies for colorectal cancer.
Topics: Mice; Animals; Humans; Fluorouracil; Drug Resistance, Neoplasm; Tumor-Associated Macrophages; Heterografts; Cell Line, Tumor; Colorectal Neoplasms; Wnt Signaling Pathway; Neoplastic Stem Cells
PubMed: 36827121
DOI: 10.3390/md21020080 -
Lipid Technology Apr 2015Fish oils and long-chain omega-3 fatty acids are well recognized for their critical role in human diets. Docosapentaenoic acid (DPA, 22 : 5n-3) has always been a...
Fish oils and long-chain omega-3 fatty acids are well recognized for their critical role in human diets. Docosapentaenoic acid (DPA, 22 : 5n-3) has always been a part of healthy nutrition, since infants obtain almost as much DPA as DHA from human milk. Fish oil supplements and ingredients, oily fish, and grass-fed beef can serve as the primary DPA sources for the general population. Although the DPA levels in fish oils are substantially lower than those of EPA and DHA, concentrated DPA products are now becoming commercially available, and DPA-based drugs are under development. Epidemiological studies show that similar to eicosapentaenoic (EPA, 20 : 5n-3) and docosahexaenoic (DHA, 22 : 6n-3) acids, DPA is linked to various improvements in human health, perhaps owing to its structural similarity to the other two molecules. Studies in mammals, platelets, and cell cultures have demonstrated that DPA reduces platelet aggregation, and improves lipid metabolism, endothelial cell migration, and resolution of chronic inflammation. Further, other in vivo and in vitro studies have shown that DPA can improve neural health. A human supplementation trial with 99.8% pure DPA suggested that it serves as a storage depot for EPA and DHA in the human body. Future randomized controlled human trials with purified DPA will help clarify its effects on human health. They may confirm the available evidence pointing to its nutritional and biological functions, unique or overlapping with those of EPA and DHA.
PubMed: 26097290
DOI: 10.1002/lite.201500013 -
Frontiers in Aging Neuroscience 2023Observational studies demonstrated controversial effect of polyunsaturated fatty acids (PUFAs) on Parkinson's disease (PD) with limited causality evidence. Randomized...
INTRODUCTION
Observational studies demonstrated controversial effect of polyunsaturated fatty acids (PUFAs) on Parkinson's disease (PD) with limited causality evidence. Randomized control trials showed possible improvement in PD symptoms with PUFA supplement but had small study population and limited intervention time.
METHODS
A two-sample Mendelian randomization was designed to evaluate the causal relevance between PUFAs and PD, using genetic variants of PUFAs as instrumental variables and PD data from the largest genome-wide association study as outcome. Inverse variance weighted (IVW) method was applied to obtain the primary outcome. Mendelian randomization Egger regression, weighted median and weighted mode methods were exploited to assist result analyses. Strict Mendelian randomization and multivariable Mendelian randomization (MVMR) were used to estimate direct effects of PUFAs on PD, eliminating pleiotropic effect. Debiased inverse variance weighted estimator was implemented when weak instrument bias was introduced into the analysis. A variety of sensitivity analyses were utilized to assess validity of the results.
RESULTS
Our study included 33,674 PD cases and 449,056 controls. Higher plasma level of arachidonic acid (AA) was associated with a 3% increase of PD risk per 1-standard deviation (SD) increase of AA (IVW; Odds ratio (OR)=1.03 [95% confidence interval (CI) 1.01-1.04], = 2.24E-04). After MVMR (IVW; OR=1.03 [95% CI 1.02-1.04], =6.15E-08) and deletion of pleiotropic single-nucleotide polymorphisms overlapping with other lipids (IVW; OR=1.03 [95% CI 1.01-1.05], =5.88E-04), result was still significant. Increased level of eicosapentaenoic acid (EPA) showed possible relevance with increased PD risk after adjustment of pleiotropy (MVMR; OR=1.05 [95% CI 1.01-1.08], =5.40E-03). Linoleic acid (LA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA) were found not causally relevant to PD risk. Various sensitivity analyses verified the validity of our results. In conclusion, our findings from Mendelian randomization suggested that elevated levels of AA and possibly EPA might be linked to a higher risk of PD. No association between PD risk and LA, DHA, DPA, or ALA was found.
DISCUSSION
The odds ratio for plasma AA and PD risk was weak. It is important to approach our results with caution in clinical practice and to conduct additional studies on the relationship between PUFAs and PD risk.
PubMed: 36909950
DOI: 10.3389/fnagi.2023.1123239 -
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 -
Prostaglandins, Leukotrienes, and... 2008Metabolic cascades involving arachidonic acid (AA) and docosahexaenoic acid (DHA) within brain can be independently targeted by drugs, diet and pathological conditions.... (Review)
Review
Metabolic cascades involving arachidonic acid (AA) and docosahexaenoic acid (DHA) within brain can be independently targeted by drugs, diet and pathological conditions. Thus, AA turnover and brain expression of AA-selective cytosolic phospholipase A(2) (cPLA(2)), but not DHA turnover or expression of DHA-selective Ca(2+)-independent iPLA(2), are reduced in rats given agents effective against bipolar disorder mania, whereas experimental excitotoxicity and neuroinflammation selectively increase brain AA metabolism. Furthermore, the brain AA and DHA cascades are altered reciprocally by dietary n-3 polyunsaturated fatty acid (PUFA) deprivation in rats. DHA loss from brain is slowed and iPLA(2) expression is decreased, whereas cPLA(2) and COX-2 are upregulated, as are brain concentrations of AA and its elongation product, docosapentaenoic acid (DPA). Positron emission tomography (PET) has shown that the normal human brain consumes 17.8 and 4.6 mg/day, respectively, of AA and DHA, and that brain AA consumption is increased in Alzheimer disease patients. In the future, PET could help to determine how human brain AA or DHA consumption is influenced by diet, aging or disease.
Topics: Aging; Animals; Arachidonic Acid; Bipolar Disorder; Brain; Diet; Dietary Fats; Docosahexaenoic Acids; Fatty Acids, Omega-3; Humans; Models, Biological; Positron-Emission Tomography; Rats; Up-Regulation
PubMed: 18973997
DOI: 10.1016/j.plefa.2008.09.010