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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 -
Frontiers in Endocrinology 2022The pathogenesis of the progressive loss of beta cell function latent autoimmune diabetes in adults (LADA) remains still elusive. We aim to study the fatty acid (FA)...
BACKGROUND
The pathogenesis of the progressive loss of beta cell function latent autoimmune diabetes in adults (LADA) remains still elusive. We aim to study the fatty acid (FA) profile in LADA.
SUBJECTS AND METHODS
Data from 116 patients with diabetes and GADA and 249 diabetes controls without GADA selected by Propensity Score Matching were collected. FA was analyzed with liquid chromatography-tandem mass spectrometry analysis.
RESULTS
Principal factor analysis found component 1 explains 82.6% of total variance contained fatty acids from a mixed of lard oil, seafood, and vegetable diet, followed by diet predominantly from vegetable oil, a diet of high fat diet, and a diet of seafood diet. The FA heatmap looked clearly different among the three groups with more similar type 1 (t1dm) and LADA fatty acid profile. n-3 α-linolenic acid (ALA), n-3 long chain polyunsaturated fatty acid (n-3 LC-PUFA), such as Eicosapentaenoic Acid and Docosapentaenoic Acid, n-3/n-6 ratio and triene/tetraene ratio were higher in patients with type 2 diabetes (t2dm) compared with LADA and t1dm. Saturated FAs were lower in t2dm than t1dm and LADA. Arachidic acid and n-6 LC-PUFAs were lower in t2dm than in t1dm and LADA. The characteristics of FAs in LADA were in between of classical t1dm and t2dm. Patients were classified into 6 clusters by FA clusters. Only cluster 2, 3, 5 contained enough patients to be analyzed. Cluster 5 showed an insulin deficient phenotype containing more than 60% of patients with t1dm and LADA and only 12.8% of t2dm. Cluster 2 and 3 were similar. β cell function and glycemic control was better in cluster 3 homing 25% of t2dm. Cluster 2 held 28% of t1dm and LADA, in this cluster more than 60% of patients was t2dm. n-3 linolenic acid, n-3 LC-PUFAs, some n-6 LC-PUFAs, n-3/n-6 ratio and triene/tetraene ratio were negatively associated with GADA positivity while n-6 Arachidonic Acid was associated positively with GADA. Similar findings were found for insulin sensitivity and beta cell function.
CONCLUSION
PUFA are associated with insulin sensitivity and beta cell function, and like other clinical features, FA profile distributed differently, but could not be used as makers to differentiate LADA from t1dm and t2dm.
ETHICS AND DISSEMINATION
This study has been approved by the Ethical Review Committee of Second Hospital of Dalian Medical University (approval number: 2021-005).
CLINICAL TRIAL REGISTRATION
none.
Topics: Autoantibodies; Autoimmunity; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fatty Acids; Glucose Intolerance; Glutamate Decarboxylase; Humans; Insulin Resistance; Latent Autoimmune Diabetes in Adults
PubMed: 35846301
DOI: 10.3389/fendo.2022.916981 -
Molecular Medicine Reports Sep 2022Ulcerative colitis (UC) is difficult to eradicate as it leads to chronic inflammation in the digestive tract due to immune system malfunction. The present study...
Ulcerative colitis (UC) is difficult to eradicate as it leads to chronic inflammation in the digestive tract due to immune system malfunction. The present study demonstrated the protective effect of 7S,15R‑dihydroxy‑16S,17S‑epoxy‑docosapentaenoic acid (diHEP‑DPA), which had been previously synthesized, on a dextran sulfate sodium (DSS)‑induced BALB/c mouse model of UC. UC was induced with 4% DSS drinking water for 7 days. Initially, the anti‑inflammatory effect of diHEP‑DPA was confirmed by demonstrating that lipopolysaccharide‑stimulated THP1 cells treated with diHEP‑DPA decreased IL‑6, TNF‑α and nitrite levels by fluorescence‑activated cell sorting (FACS) and Griess reagent kit. The results indicated that the administration of diHEP‑DPA at 20 µg/kg significantly reduced the severity of colitis, as determined by hematoxylin and eosin staining. The levels of TNF‑α, IL‑6 and IL‑1β in the colon tissue and serum were significantly reduced in the diHEP‑DPA + DSS‑treated group compared with in the control group, as determined by FACS and ELISA kit. It was also observed that diHEP‑DPA decreased myeloperoxidase (MPO) and nitrite levels in the colon tissues of diHEP‑DPA + DSS‑treated mice, as indicated using commercial MPO and nitric oxide kits. The diHEP‑DPA+DSS‑treated mice also exhibited decreased expression levels of phosporylated (p)‑inhibitor κB protein, p‑p65 and inducible nitric oxide synthase in the colon tissue by inhibiting inflammation, which were measured by reverse transcription‑quantitative PCR and weatern blot analysis. Overall, the present study demonstrated the protective effect of diHEP‑DPA against a severe colitis condition .
Topics: Animals; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Disease Models, Animal; Fatty Acids, Unsaturated; Inflammation; Interleukin-6; Mice; Mice, Inbred BALB C; NF-kappa B; Nitrites; Tumor Necrosis Factor-alpha
PubMed: 35856414
DOI: 10.3892/mmr.2022.12794 -
The Chinese Journal of Physiology 2023Regular moderate physical exercise is beneficial for the cardiovascular system. Our prior study has demonstrated a long-term moderate exercise (4-week of 60-min 74.0%...
Regular moderate physical exercise is beneficial for the cardiovascular system. Our prior study has demonstrated a long-term moderate exercise (4-week of 60-min 74.0% V̇O treadmill running) is optimal in protecting from exhaustive exercise-induced cardiac ischemic injury. This study is aimed to investigate the effect of long-term moderate exercise on myocardial metabolome in rats. Thirteen male Sprague-Dawley rats were randomly assigned into the control group (C) and the long-term moderate exercise group (E). The targeted metabolomics of the myocardium was analyzed by ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system. Results showed that the metabolites categories of bile acids (BAs), fatty acids (FAs), and phenylpropanoic acids were significantly decreased. The biosynthesis of unsaturated FAs pathway was significantly downregulated. The altered metabolites in the E Group included decreased FAs (pentadecanoic acid, 10Z-heptadecenoic acid, dihomo-gamma-linolenic acid, docosahexaenoic acid, docosapentaenoic acid, and 10Z-nonadecenoic acid), decreased BAs (chenodeoxycholic acid and beta-muricholic acid), decreased organic acids (glycolic acid and 2-hydroxyglutaric acid), decreased carbohydrate (N-acetylneuraminic acid, Neu5Ac), decreased amino acids (α-aminobutyric acid and norvaline), decreased phenylpropanoic acids (hydroxyphenyllactic acid), and benzoic acids (4-hydroxybenzoic acid and phthalic acid). The results indicated that long-term moderate exercise has promoted lipids utilization in myocardium while exerted little influence on carbohydrate metabolism and diminished many detrimental metabolites. Notably, decrease of myocardial carbohydrate Neu5Ac after long-term moderate exercise might predict a prospective metabolomics biomarker for cardioprotection. This research has displayed the effect of long-term moderate exercise on myocardial metabolomic profiling in rats and indicated some promising metabolites which can be applied for exercise benefits in future.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; Chromatography, Liquid; Prospective Studies; Tandem Mass Spectrometry; Metabolome; Myocardium; Carbohydrates
PubMed: 38149568
DOI: 10.4103/cjop.CJOP-D-23-00126 -
Cancer Epidemiology, Biomarkers &... Oct 2023Previous epidemiologic studies found inconsistent associations between fish consumption and renal cell carcinoma (RCC). Although the consumption of n-3 polyunsaturated...
BACKGROUND
Previous epidemiologic studies found inconsistent associations between fish consumption and renal cell carcinoma (RCC). Although the consumption of n-3 polyunsaturated fatty acids (PUFA) was reported to protect against the development of some types of cancer, little is known regarding its association with RCC.
METHODS
We investigated the association between fish and n-3 PUFA consumption and RCC risk using the Japan Public Health Center-based Prospective Study. We examined data from 84,063 eligible Japanese participants aged 45 to 74 years who responded to a validated food frequency questionnaire for Cohort I in 1995 and Cohort II in 1998. The participants were followed-up until 2013. HRs and 95% confidence intervals (CI) were estimated using a multivariable-adjusted Cox proportional hazard model, and the exposure level was categorized into quartiles.
RESULTS
Among the 1,272,298 person-years of follow-up, 262 cases of newly diagnosed RCC were identified. The multivariate-adjusted HRs for the highest vs. lowest quartile of fish, including shellfish, were (HR = 1.43; 95% CI, 0.98-2.07) and the individual marine n-3 PUFAs were (HR = 1.56; 95% CI, 1.07-2.28; Ptrend = 0.09) for eicosapentenoic acid, (HR = 1.81; 95% CI, 1.27-2.59; Ptrend = 0.01) for docosapentaenoic acid, and (HR = 1.56; 95% CI, 1.07-2.27; Ptrend = 0.09) for docosahexaenoic acid. RCC were further categorized on the basis of diagnosis methods and cancer stage, and the positive correlation did not change substantially.
CONCLUSIONS
We demonstrated that high consumption of n-3 PUFA is associated with RCC risk.
IMPACT
The positive association between n-3 PUFA and RCC risk was observed in Japanese who consume higher amounts of fish than Western populations.
PubMed: 37530751
DOI: 10.1158/1055-9965.EPI-23-0269 -
Scientific Reports Apr 2023Breast cancer is the most common malignant tumor and one of the leading causes of cancer-related death in women throughout the world. This study is a parallel,... (Randomized Controlled Trial)
Randomized Controlled Trial
Anti-inflammatory effect of combining fish oil and evening primrose oil supplementation on breast cancer patients undergoing chemotherapy: a randomized placebo-controlled trial.
Breast cancer is the most common malignant tumor and one of the leading causes of cancer-related death in women throughout the world. This study is a parallel, randomized, double-blind, controlled, 12-week supplementation trial, investigating the anti-inflammatory effects of dietary intake of fish oil and evening primrose oil (EPO), in patients with breast cancer undergoing chemotherapy. The primary outcomes were changes in the nutritional status and inflammatory cytokines of patients during the study. The secondary outcomes were changes in hematological and biochemical parameters and fatty acid profile. Of the 32 eligible patients, half of them is randomly assigned to a treatment arm with fish oil and EPO (n = 16), or a control arm (n = 16) with mineral oil as a placebo. The intervention group was taking 2 gel capsules of fish oil and 3 gel capsules of EPO (400 mg eicosapentaenoic acid, 600 mg docosahexaenoic acid, and 351 mg gamma-linolenic acid) fish oil and evening primrose oil for 12 weeks, during their chemotherapy. The control/placebo group was taking 5 gel capsules of 1g of mineral oil. One of the patients dropped out due to discontinuation of the treatment (in the placebo group) and two did not show up at the post-treatment measurements (in the intervention group), thus, 29 women completed the study. The results showed an increase in plasma levels of docosapentaenoic acid (22:5n-3), docosahexaenoic acid (22:6n-3), total n-3PUFA, vaccenic acid (18:1n-7), and a decrease in n-6/n-3 PUFA ratio in the intervention group. An increase in the plasma level of dihomo-gamma-linolenic acid (20:3n-6) was observed in the placebo group. There was no difference in plasma levels of interleukin (IL) IL-8, IL-10, and tumor necrosis factor-alpha, while the level of IL-6 decreased in both groups and was significantly lower in the intervention group at the end of the study. In conclusion, this supplementation improved the PUFA status and decreased the level of IL-6 in breast cancer patients undergoing chemotherapy. Consequently, this treatment may help reduce cancer complications resulting from impaired lipid metabolism and inflammation. ClinicalTrials.gov Identifier: NCT03516253. Date of registration 04/05/2018.
Topics: Female; Animals; Fish Oils; gamma-Linolenic Acid; Docosahexaenoic Acids; Interleukin-6; Mineral Oil; Fatty Acids, Omega-3; Dietary Supplements; Anti-Inflammatory Agents; Double-Blind Method; Neoplasms
PubMed: 37081029
DOI: 10.1038/s41598-023-28411-8 -
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... Jun 2021Omega-3 fatty acids have been suggested as a complement in cancer treatment, but doses are not established. We performed a dose-finding study in 33 children in remission... (Clinical Trial)
Clinical Trial
Omega-3 fatty acids have been suggested as a complement in cancer treatment, but doses are not established. We performed a dose-finding study in 33 children in remission from cancer. Participants were allocated to a body surface area (BSA) adjusted dose (mg/m) of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (40:60), ranging 233-3448 mg/m daily for 90 days. Fatty acid concentration in plasma phospholipids and red blood cells were determined by GC. Supplementation was well tolerated and correlated strongly with blood ω3-fatty acid concentrations and EPA showed the highest increase. Using the ω3-index disregards docosapentaenoic acid (DPA), which increased 30-43% in our study motivating an EDD-index (∑EPA,DPA,DHA). The ratio between arachidonic acid and EPA or DHA showed negative exponential trends. Dose per BSA enabled an individualized omega-3 supplementation decreasing the variation referred to interindividual differences. Based on our results, we suggest a dose of 1500 mg/m BSA for further studies.
Topics: Adolescent; Body Surface Area; Child; Child, Preschool; Chromatography, Gas; Docosahexaenoic Acids; Drug Administration Schedule; Drug Dosage Calculations; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Female; Humans; Male; Neoplasms
PubMed: 33964665
DOI: 10.1016/j.plefa.2021.102285 -
Journal of Functional Biomaterials Apr 2023The implantation of a biomaterial will lead to the immediate onset of an acute inflammatory response, which is of key importance in shaping the quality of the repair... (Review)
Review
The implantation of a biomaterial will lead to the immediate onset of an acute inflammatory response, which is of key importance in shaping the quality of the repair process. However, the return to homeostasis is critical to prevent a chronic inflammatory response that may impair the healing process. The resolution of the inflammatory response is now recognized as an active and highly regulated process, being described as specialized immunoresolvents that have a fundamental role in the termination of the acute inflammatory response. These mediators collectively coined as specialized pro-resolving mediators (SPMs) are a family of endogenous molecules that include lipoxins (Lx), resolvins (Rv), protectins (PD), maresins (Mar), Cysteinyl-SPMs (Cys-SPMs) and n-3 docosapentaenoic acid-derived SPMs (n-3 DPA-derived SPMs). SPMs have important anti-inflammatory and pro-resolutive actions such as decreasing the recruitment of polymorphonuclear leukocytes (PMNs), inducing the recruitment of anti-inflammatory macrophages, and increasing macrophage clearance of apoptotic cells through a process known as efferocytosis. Over the last years, the trend in biomaterials research has shifted towards the engineering of materials that are able to modulate the inflammatory response and thus stimulate appropriate immune responses, the so-called immunomodulatory biomaterials. These materials should be able to modulate the host immune response with the aim of creating a pro-regenerative microenvironment. In this review, we explore the potential of using of SPMs in the development of new immunomodulatory biomaterials and we propose insights for future research in this field.
PubMed: 37103313
DOI: 10.3390/jfb14040223 -
Nutritional conditions of the novel freshwater Coccomyxa AP01 for versatile fatty acids composition.Journal of Applied Microbiology Jan 2022This study was to analyse the biomass production and fatty acids (FAs) profiles in a newly isolated chlorophyte, namely Coccomyxa AP01, under nutritionally balanced (NB)...
AIMS
This study was to analyse the biomass production and fatty acids (FAs) profiles in a newly isolated chlorophyte, namely Coccomyxa AP01, under nutritionally balanced (NB) conditions (comparing nitrate and urea as nitrogen sources) and nitrogen or phosphate deprivation.
METHODS AND RESULTS
Lipid yields was about 30%-40% of dried biomasses in all examined nutritional conditions. Under NB conditions, lipids were principally constituted by monounsaturated FAs, mainly represented by oleic acid, and saturated and polyunsaturated FAs at similar concentrations. Nutrients deprivation induced remarkable changes in FAs profiles, with the highest amounts of saturated (42%-46%), followed by similar amounts of monounsaturated and polyunsaturated, and the emergence of rare long-chain FAs. Under phosphate deprivation, biomass yield was similar to NB conditions, with the highest yield of saturated (mainly palmitic acid) and of polyunsaturated FAs (33%) (mainly linoleic and linolenic acids).
CONCLUSIONS
Balanced or deprived nutritional conditions in Coccomyxa AP01 induced a selective production and composition of FAs. The phosphate-deprivation condition concomitantly provided high biomass yield and the production of high value saturated and polyunsaturated FAs with industrial interest.
SIGNIFICANCE AND IMPACT OF THE STUDY
Coccomyxa AP01 could be considered a promising source of different FAs, including also docosapentaenoic acid, for several commercial purposes spanning from biodiesel production, pharmaceutical and cosmetic applications to innovative aquaculture fish feeds.
Topics: Animals; Biomass; Chlorophyta; Fatty Acids; Fresh Water; Lipids
PubMed: 34260800
DOI: 10.1111/jam.15223