Joint effects of one year of marine omega-3 fatty acid supplementation and participant dietary fish intake upon circulating lipid mediators of inflammation resolution in a randomized controlled trial.

OBJECTIVES: We assessed the joint effects of omega (n)-3 fatty acid supplementation and dietary fish intake on systemic lipid mediators of inflammation among adults. METHODS: Within VITAL, a double-blind randomized controlled trial, adults were randomized to ω-3 fatty acids (460 mg EPA + 380 mg DHA/d) or placebo. We selected participants who reported low (<1 serving/mo) baseline dietary fish intake and matched them by age, sex, race, and trial arm to participants with self-reported highest fish intake (≥3.9 servings/wk). Baseline and 1-y plasma samples were tested for 9 ω-3 fatty acid-derived lipid mediators. Multivariable linear models assessed lipid mediator changes and joint effects of ω-3 fatty acid supplementation and dietary fish intake. RESULTS: Forty-eight participants with low baseline fish intake were matched to 48 with high fish intake. Mean age was 64.6 (±7.26), 50% were female, and 85% non-Hispanic white. One-year lipid mediator changes in expected directions were observed in those receiving ω-3 fatty acids versus placebo: reductions in proinflammatory mediators, PGD2, 5-HETE, and 12-HETE; increases in proresolving mediators, EPA and DHA. Larger 1-y lipid biomarker changes were seen in those with low baseline fish intake randomized to active ω-3 fatty acids for DHA, EPA, PGD2, Resolvin D1, and Resolvin D4 were observed, although no significant multiplicative interactions were detected. DISCUSSION: Beneficial changes in circulating proresolving and proinflammatory mediators were found with 1-y of ω-3 fatty acid supplementation versus placebo for all participants, with a trend toward larger effects among those with low baseline fish intake, although interactions were not significant.

Hemorrhoid laser dearterialization: systematic review and meta-analysis.

Hemorrhoidal disease is a common and troublesome condition. Excisional hemorrhoidectomy can assure the best chance of cure but it is hampered by postoperative pain and potential long-term morbidity therefore minimally invasive techniques have been developed. Since 2009 a doppler-guided hemorrhoidal dearterialization with laser (the hemorrhoidal laser procedure; HeLP) has been proposed to control symptoms without significant sequelae. The aim of this systematic review is to analyze the benefits and disadvantages of HeLP for symptomatic hemorrhoids. The Medline/PubMed, Embase, and Cochrane library databases were searched from January 2010 to March 2022, language was restricted to English and documents to the full text. Randomized and non-randomized, prospective and retrospective cohort studies were included. Risk of bias assessment was performed using the Risk of bias for non-randomized studies (ROBINS-I) and the RoB2 Tool for randomized clinical trial. Primary outcome was to assess the efficacy of HeLP on symptoms' resolution. Secondary objectives were postoperative pain and complications, comparison with other interventional techniques, and evaluation of long-term recurrence. Whenever possible, a meta-analysis was conducted. The GRADE approach was employed to assess the certainty of evidence. We included six non-randomized and one randomized study. HeLP improved or resolved preoperative symptoms in 83.6 to 100% of patients during follow-up. In the randomized study symptoms resolved in 90% of patients after HeLP and 53.3% after rubber band ligation as comparator. Published data indicate that HeLP is effective, relatively safe, with limited recurrence rate, after a short to medium follow-up. The quality of evidence was however low. There is a paucity of studies assessing the benefits or harms of laser dearterialization for the treatment of hemorrhoids and randomized trials are furthermore rare, therefore trials with adequate power and proper design, assessing the advantages and disadvantages of HeLP versus other minimally invasive techniques, are needed. Furthermore, studies evaluating long-term follow-up are wanted.

Reflecting on the COVID-19 Surgical Literature Surge: A Scoping Review of Pandemic Otolaryngology Publications.

OBJECTIVE: To assess the high-volume 2020 COVID-19-related surgical literature, with special attention to otolaryngology articles in regard to content, level of evidence, citations, and public attention. STUDY DESIGN: A scoping literature review was performed with PubMed and Web of Science, including articles pertaining to COVID-19 and surgical specialties (March 20-May 19, 2020) or otolaryngologic subspecialties (March 20-December 31, 2020). SETTING: Scoping literature review. METHODS: Otolaryngology-specific COVID-19-related articles were reviewed for publication date, county of origin, subspecialty, content, level of evidence, and Altmetric Attention Score (a weighted approximation of online attention received). Data were analyzed with Pearson correlation coefficients, analysis of variance, independent t tests, and univariable and logistic regressions. RESULTS: This review included 773 early COVID-19 surgical articles and 907 otolaryngology-specific COVID-19-related articles from 2020. Otolaryngology was the most represented surgical specialty within the early COVID-19-related surgical literature (30.4%). The otolaryngology-specific COVID-19 surgical literature responsively reflects the unique concerns within each otolaryngologic subspecialty. Although this literature was largely based on expert opinion (64.5%), articles with stronger levels of evidence received significantly more citations (on Web of Science and Google Scholar, P < .001 for both) and public attention (according to Altmetric Attention Scores, P < .001). CONCLUSION: Despite concerns of a surge in underrefereed publications during the COVID-19 pandemic, our review of the surgical literature offers some degree of reassurance. Specifically, the COVID-19 otolaryngology literature responsively reflects the unique concerns and needs of the field, and more scholarly citations and greater online attention have been given to articles offering stronger levels of scientific evidence.

Prognostic role of ultrasonography staging in patients with anal cancer.

BACKGROUND: Carcinomas of the anal canal are staged according to the size and extent of the disease; however, we propose including a novel ultrasound (US) staging system, based on depth of tumor invasion. In this study the clinical American Joint Committee on Cancer (AJCC) staging guidelines and the US classificationss in patients with anal cancer were compared. AIM: To evaluate the prognostic role of the US staging system in patients with anal cancer. METHODS: The data of 48 patients with anal canal squamous cells carcinoma, observed at our University Hospital between 2007 and 2017, who underwent pre-treatment assessment with pelvic magnetic resonance imaging (MRI), total body computed tomography (CT) scan and endoanal US were retrospectively reviewed. Anal canal tumors were clinically staged according to AJCC, determined by MRI by measurement of the longest tumor diameter, and CT scan. Endoanal US was performed with a high multi-frequency (9-16 MHz), 360° rotational mechanical probe; US classification was based on depth of tumor penetration through the anal wall, according to Giovannini's study. All patients were treated with definitive radiation combined with 5-fluorouracile and Mitomycin-C. After treatment patients were followed-up regularly. RESULTS: At baseline there were 30 and 32 T1-2, 18 and 16 T3-4, 31 and 19 N+ patients classified according to the clinical AJCC and US staging system respectively. After a mean follow-up of 98 months, 38 patients (79.1%) are alive and 28 (58.3%) are disease free. During follow up 20 patients (41.6%) experienced recurrences. After univariate analysis, American Society of Anesthesiologists (ASA) score (P = 0.00000001) and US staging (P = 0.009) were significantly related to disease-free survival (DFS). When overall survival and DFS functions were compared, a statistically significant difference was observed for DFS survival when the US staging was applied with respect to the clinical AJCC staging. By combining the 2 significant prognostic variables, namely the US staging with the ASA score, four risks groups with different prognoses were identified. CONCLUSION: Our findings suggest that US staging may be superior to traditional clinical staging, since it is significantly associated with DFS in anal cancer patients.

Adipocytes promote ovarian cancer chemoresistance.

Ovarian cancer (OvCa), while accounting for only 3% of all women's cancer, is the fifth leading cause of cancer death among women. One of the most significant obstacles to successful OvCa treatment is chemoresistance. The current lack of understanding of the driving mechanisms underlying chemoresistance hinders the development of effective therapeutics against this obstacle. Adipocytes are key components of the OvCa microenvironment and have been shown to be involved in OvCa cell proliferation, however, little is known about their impact on OvCa chemoresistance. In the current study, we found that adipocytes, of both subcutaneous and visceral origin, secrete factors that enhance the resistance of OvCa cells against chemotherapeutic drugs by activating the Akt pathway. Importantly, we have demonstrated that secreted lipids mediate adipocyte-induced chemoresistance. Through a comprehensive lipidomic analysis, we have identified this chemo-protective lipid mediator as arachidonic acid (AA). AA acts on OvCa cells directly, not through its downstream derivatives such as prostaglandins, to activate Akt and inhibit cisplatin-induced apoptosis. Taken together, our study has identified adipocytes and their secreted AA as important mediators of OvCa chemoresistance. Strategies that block the production of AA from adipocytes or block its anti-apoptotic function may potentially inhibit chemoresistance in OvCa patients.

The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells.

Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight into the mechanisms by which this worm suppresses inflammatory responses, an active component was purified from T. suis soluble products (TsSPs) that suppress---- TNF and IL-12 secretion from LPS-activated human dendritic cells (DCs). Analysis by liquid chromatography tandem mass spectrometry identified this compound as prostaglandin (PG)E2. The purified compound showed similar properties compared with TsSPs and commercial PGE2 in modulating LPS-induced expression of many cytokines and chemokines and in modulating Rab7B and P2RX7 expression in human DCs. Furthermore, the TsSP-induced reduction of TNF secretion from DCs is reversed by receptor antagonists for EP2 and EP4, indicating PGE2 action. T. suis secretes extremely high amounts of PGE2 (45-90 ng/mg protein) within their excretory/secretory products but few related lipid mediators as established by metabololipidomic analysis. Culture of T. suis with several cyclooxygenase (COX) inhibitors that inhibit mammalian prostaglandin synthesis affected the worm's motility but did not inhibit PGE2 secretion, suggesting that the worms can synthesize PGE2 via a COX-independent pathway. We conclude that T. suis secretes PGE2 to suppress proinflammatory responses in human DCs, thereby modulating the host's immune response.-Laan, L. C., Williams, A. R., Stavenhagen, K., Giera, M., Kooij, G., Vlasakov, I., Kalay, H., Kringel, H., Nejsum, P., Thamsborg, S. M., Wuhrer, M., Dijkstra, C. D., Cummings, R. D., van Die, I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells.

Identification and Actions of the Maresin 1 Metabolome in Infectious Inflammation.

Maresin 1 (MaR1) is an immunoresolvent that governs resolution of acute inflammation, and its local metabolism in the context of infectious inflammation is of interest. In this study, we investigated the MaR1 metabolome in infectious exudates and its bioactions in regulating leukocyte responses in the context of bacterial infection. In Escherichia coli infectious exudates, MaR1 was temporally regulated with maximal levels at 4 h (2.2 ± 0.4 pg/lavage). In these exudates we also identified two novel products, and their structure elucidation gave 22-hydroxy-MaR1 and 14-oxo-MaR1. Using human primary leukocytes, we found that neutrophils primarily produced 22-OH-MaR1, whereas the main macrophage product was 14-oxo-MaR1. Both 22-OH-MaR1 and 14-oxo-MaR1 incubated with human primary macrophages gave dose-dependent increases in macrophage phagocytosis of ∼75% at 1 pM 22-OH-MaR1 and ∼25% at 1 pM 14-oxo-MaR1, whereas 14-oxo-MaR1 was less active than MaR1 at higher concentrations. Together these findings establish the temporal regulation of MaR1 during infectious inflammation, and elucidate the structures and actions of two novel MaR1 further metabolites that carry bioactivities.

Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages.

Macrophages are central in coordinating immune responses, tissue repair, and regeneration, with different subtypes being associated with inflammation-initiating and proresolving actions. We recently identified a family of macrophage-derived proresolving and tissue regenerative molecules coined maresin conjugates in tissue regeneration (MCTR). Herein, using lipid mediator profiling we identified MCTR in human serum, lymph nodes, and plasma and investigated MCTR biosynthetic pathways in human macrophages. With human recombinant enzymes, primary cells, and enantiomerically pure compounds we found that the synthetic maresin epoxide intermediate 13S,14S-eMaR (13S,14S-epoxy- 4Z,7Z,9E,11E,16Z,19Z-docosahexaenoic acid) was converted to MCTR1 (13R-glutathionyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) by LTC4S and GSTM4. Incubation of human macrophages with LTC4S inhibitors blocked LTC4 and increased resolvins and lipoxins. The conversion of MCTR1 to MCTR2 (13R-cysteinylglycinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid) was catalyzed by γ-glutamyl transferase (GGT) in human macrophages. Biosynthesis of MCTR3 was mediated by dipeptidases that cleaved the cysteinyl-glycinyl bond of MCTR2 to give 13R-cysteinyl, 14S-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Z-docosahexaenoic acid. Of note, both GSTM4 and GGT enzymes displayed higher affinity to 13S,14S-eMaR and MCTR1 compared with their classic substrates in the cysteinyl leukotriene metabolome. Together these results establish the MCTR biosynthetic pathway and provide mechanisms in tissue repair and regeneration.

DHA but Not EPA Emulsions Preserve Neurological and Mitochondrial Function after Brain Hypoxia-Ischemia in Neonatal Mice.

BACKGROUND AND PURPOSE: Treatment with triglyceride emulsions of docosahexaenoic acid (tri-DHA) protected neonatal mice against hypoxia-ischemia (HI) brain injury. The mechanism of this neuroprotection remains unclear. We hypothesized that administration of tri-DHA enriches HI-brains with DHA/DHA metabolites. This reduces Ca2+-induced mitochondrial membrane permeabilization and attenuates brain injury. METHODS: 10-day-old C57BL/6J mice following HI-brain injury received tri-DHA, tri-EPA or vehicle. At 4-5 hours of reperfusion, mitochondrial fatty acid composition and Ca2+ buffering capacity were analyzed. At 24 hours and at 8-9 weeks of recovery, oxidative injury, neurofunctional and neuropathological outcomes were evaluated. In vitro, hyperoxia-induced mitochondrial generation of reactive oxygen species (ROS) and Ca2+ buffering capacity were measured in the presence or absence of DHA or EPA. RESULTS: Only post-treatment with tri-DHA reduced oxidative damage and improved short- and long-term neurological outcomes. This was associated with increased content of DHA in brain mitochondria and DHA-derived bioactive metabolites in cerebral tissue. After tri-DHA administration HI mitochondria were resistant to Ca2+-induced membrane permeabilization. In vitro, hyperoxia increased mitochondrial ROS production and reduced Ca2+ buffering capacity; DHA, but not EPA, significantly attenuated these effects of hyperoxia. CONCLUSIONS: Post-treatment with tri-DHA resulted in significant accumulation of DHA and DHA derived bioactive metabolites in the HI-brain. This was associated with improved mitochondrial tolerance to Ca2+-induced permeabilization, reduced oxidative brain injury and permanent neuroprotection. Interaction of DHA with mitochondria alters ROS release and improves Ca2+ buffering capacity. This may account for neuroprotective action of post-HI administration of tri-DHA.

Synthesis of the 16S,17S-Epoxyprotectin Intermediate in the Biosynthesis of Protectins by Human Macrophages.

The n-3 polyunsaturated fatty acids act as substrates during the resolution phase of acute inflammation for the biosynthesis of specialized pro-resolving lipid mediators. One premier example is the C22-dihydroxy-polyunsaturated fatty acid protectin D1 (1). The human 15-lipoxygenase type I, via stereoselective processes and with docosahexaenoic acid as the substrate, enables the formation of this specialized pro-resolving lipid mediator. Herein, based on results from LC/MS-MS metabololipidomics, support is presented for the apprehended biosynthesis of 1 in human macrophages occurring via the intermediate 16S,17S-epoxyprotectin (5). Stereochemically pure 5 was obtained using the Katsuki-Sharpless epoxidation protocol, establishing the chirality at the C16 and C17 atoms, one Z-selective reduction, and E- and Z-stereoselective Wittig reactions. In addition, information on the nonenzymatic aqueous hydrolysis products and the half-life of 16S,17S-epoxyprotectin (5) is presented.