Prostaglandin Metabolism Research Articles

Spatiotemporal endometrial transcriptome analysis revealed the luminal epithelium as key player during initial maternal recognition of pregnancy in the mare

During the period of maternal recognition of pregnancy (MRP) in the mare, the embryo needs to signal its presence to the endometrium to prevent regression of the corpus luteum and prepare for establishment of pregnancy. This is achieved by mechanical stimuli and release of various signaling molecules by the equine embryo while migrating through the uterus. We hypothesized that embryo’s signals induce changes in the endometrial gene expression in a highly cell type-specific manner. A spatiotemporal transcriptomics approach was applied combining laser capture microdissection and low-input-RNA sequencing of luminal and glandular epithelium (LE, GE), and stroma of biopsy samples collected from days 10–13 of pregnancy and the estrous cycle. Two comparisons were performed, samples derived from pregnancies with conceptuses ≥ 8 mm in diameter (comparison 1) and conceptuses ≤ 8 mm (comparison 2) versus samples from cyclic controls. The majority of gene expression changes was identified in LE and much lower numbers of differentially expressed genes (DEGs) in GE and stroma. While 1253 DEGs were found for LE in comparison 1, only 248 were found in comparison 2. Data mining mainly focused on DEGs in LE and revealed regulation of genes related to prostaglandin transport, metabolism, and signaling, as well as transcription factor families that could be involved in MRP. In comparison to other mammalian species, differences in regulation of genes involved in epithelial barrier formation and conceptus attachment and implantation reflected the unique features of equine reproduction at the time of MRP at the molecular level.

The Role of Iron and Zinc in the Treatment of ADHD among Children and Adolescents: A Systematic Review of Randomized Clinical Trials.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder common from childhood to adulthood, affecting 5% to 12% among the general population in developed countries. Potential etiological factors have been identified, including genetic causes, environmental elements and epigenetic components. Nutrition is currently considered an influencing factor, and several studies have explored the contribution of restriction and dietary supplements in ADHD treatments. Iron is an essential cofactor required for a number of functions, such as transport of oxygen, immune function, cellular respiration, neurotransmitter metabolism (dopamine production), and DNA synthesis. Zinc is also an essential trace element, required for cellular functions related to the metabolism of neurotransmitters, melatonin, and prostaglandins. Epidemiological studies have found that iron and zinc deficiencies are common nutritional deficits worldwide, with important roles on neurologic functions (poor memory, inattentiveness, and impulsiveness), finicky appetite, and mood changes (sadness and irritability). Altered levels of iron and zinc have been related with the aggravation and progression of ADHD. Objective: This is a systematic review focused on the contribution of iron and zinc in the progression of ADHD among children and adolescents, and how therapies including these elements are tolerated along with its effectiveness (according to PRISMA guidelines). Method: The scientific literature was screened for randomized controlled trials published between January 2000 to July 2021. The databases consulted were Medline, PsycINFO, Web of Science, and Google Scholar. Two independent reviewers screened studies, extracted data, and assessed quality and risk of bias (CONSORT, NICE, and Cochrane checklists used). Conclusion: Nine studies met the eligibility criteria and were selected. Evidence was obtained regarding the contribution of iron-zinc supplementation in the treatment of ADHD among young individuals. The discussion was focused on how the deficits of these elements contribute to affectation on multiple ADHD correlates, and potential mechanisms explaining the mediational pathways. Evidence also suggested that treating ADHD with diet interventions might be particularly useful for specific subgroups of children and adolescents, but further investigations of the effects of these diet interventions are needed.

Glycoprotein PTGDS promotes tumorigenesis of diffuse large B-cell lymphoma by MYH9-mediated regulation of Wnt\u2013\u03b2-catenin\u2013STAT3 signaling

Glycoprotein prostaglandin D2 synthase (PTGDS) is a member of the lipocalin superfamily and plays dual roles in prostaglandins metabolism and lipid transport. PTGDS has been involved in various cellular processes including the tumorigenesis of solid tumors, yet its role in carcinogenesis is contradictory and the significance of PTGDS in hematological malignancies is ill-defined. Here, we aimed to explore the expression and function of PTGDS in diffuse large B-cell lymphoma (DLBCL), especially the potential role of PTGDS inhibitor, AT56, in lymphoma therapy. Remarkable high expression of PTGDS was found in DLBCL, which was significantly correlated with poor prognosis. PTGDS overexpression and rhPTGDS were found to promote cell proliferation. Besides, in vitro and in vivo studies indicated that PTGDS knockdown and AT56 treatment exerted an anti-tumor effect by regulating cell viability, proliferation, apoptosis, cell cycle, and invasion, and enhanced the drug sensitivity to adriamycin and bendamustine through promoting DNA damage. Moreover, the co-immunoprecipitation-based mass spectrum identified the interaction between PTGDS and MYH9, which was found to promote DLBCL progression. PTGDS inhibition led to reduced expression of MYH9, and then declined activation of the Wnt-β-catenin-STAT3 pathway through influencing the ubiquitination and degradation of GSK3-β in DLBCL. The rescue experiment demonstrated that PTGDS exerted an oncogenic role through regulating MYH9 and then the Wnt-β-catenin-STAT3 pathway. Based on point mutation of glycosylation sites, we confirmed the N-glycosylation of PTGDS in Asn51 and Asn78 and found that abnormal glycosylation of PTGDS resulted in its nuclear translocation, prolonged half-life, and enhanced cell proliferation. Collectively, our findings identified for the first time that glycoprotein PTGDS promoted tumorigenesis of DLBCL through MYH9-mediated regulation of Wnt-β-catenin-STAT3 signaling, and highlighted the potential role of AT56 as a novel therapeutic strategy for DLBCL treatment.

ETS Family Transcription Factor Fusions in Childhood AML: Distinct Expression Networks and Clinical Implications

The ETS family of genes encode transcription factors (TFs) containing the ETS DNA binding domain, which have roles in cellular growth and development, including embryonic hematopoiesis. Dysregulation of these genes is associated with malignant transformation and tumorigenesis. In childhood acute myeloid leukemia (AML), the MNX1-ETV6 t(7;12)(q36;p13) and FUS-ERG t(16;21)(p11;q22) fusions are associated with adverse outcome. However, the biological and clinical implications of other ETS oncofusions in pediatric AML remain unknown.We identified 62 ETS gene fusions in 1,473 primary diagnostic AML samples (4.2%) using whole transcriptome RNA-sequencing and karyotype data. Four ETS family genes were identified to be involved in fusions with various partner genes: ETV6, ERG, FEV, and FLI1. Fusions with ETV6 were the most abundant (58%, 36/62) while FEV and FLI1 were the least; 21 fusion partners were identified where many function as TFs and co-activators (Figure 1A). MNX1-ETV6 (N=16) is enriched in infants (87.5% < 3 years, p < 0.001, Figure 1B), consistent with previous reports. ETV6 fusions with various partners (ETV6-Other, N=20) were likewise enriched in infants (50% < 3 years) and were significantly younger than patients without ETS fusions (median age: 3.0 vs 9.6 years, p = 0.025). FUS-ERG (N=10), HNRNPH1-ERG (N=8), and ETS fusions with various partners (ETS-Other, N=8) were primarily identified in patients 5-18 years old.Outcomes for patients with ETS fusions was determined after censoring for stem cell transplantation. Patients with ETS fusions as a collective group had adverse outcome with an EFS of 17.7% vs 39.9% (p = 0.047, Figure 1C), similar to high-risk cases in the reference group (22%), suggesting that patients with any ETS fusion may be considered high risk. Evaluation of outcomes by individual fusion groups at 3 years from diagnosis demonstrated an EFS of 0% for HNRNPH1-ERG, 18.0% for FUS-ERG, 14.2% for ETV6-Other, 20.8% for ETS-Other, and 28.4% for those with MNX1-ETV6. Twenty-one patients (37.5%) with ETS family fusions received stem cell transplant (SCT) in first complete remission, including HNRNPH1-ERG (N=5), FUS-ERG (N=3), ETV6-Other (N=5), ETS-Other (N=2), and MNX1-ETV6 (N=6). For these SCT recipients, OS at 3 years after transplant was 60.2%.We investigated whether ETS family fusions might have similar transcriptome profiles. Unsupervised uniform manifold approximation and projection (UMAP) on RNA-seq gene expression data followed by Leiden clustering found that individual fusions clustered in the same 3D space. More importantly, ETS fusion groups clustered closely to one another, indicating a shared transcriptional profile (Figure 1D, circle). Next, ETS fusion groups were each independently compared to the reference cohort (N=1421) using differential expression (DE) analysis. Intersection of DE genes revealed 17 overexpressed genes common to ETS fusions and 9/17 (52%) were also dysregulated when contrasting ETS cohorts to healthy normal marrows' transcriptome (N=68, Figure 1E). The minimal set of dysregulated genes included an adhesion molecule EDIL3, a prostaglandin (PG) enzyme HPGD, and a tyrosine phosphatase PTP4A3, which is strongly associated with progression in lymphoblastic leukemia and multiple myeloma. EDIL3 was reported to be overexpressed in MNX1-ETV6 and we found this molecule is a common feature of ETS fusions and their cellular dysregulation. The minimal set of 9 genes were further investigated using protein interaction networks defined from Pathway Commons v11. FUS-ERG and HNRNPH1-ERG both had significantly (adj. p < 0.001) activated HPGD networks; PG-E synthase and > 10 PG metabolism genes were upregulated. PG metabolism has important roles in regulating hematopoietic stem and progenitor (HSPC) functions and PG-E2 was shown to increase HSPC survival. ETV6-MXN1, ETV6-Other, and FUS-ERG had activated PTP4A3 networks and its expression was associated with sensitivity to BET inhibitors (BETi) in myeloma. They also exhibited increased activity of an ERG network with the overexpression of upstream regulators CBFA2T3 and GATA, and downstream targets like VWF and ZBTB16.Overall, we show that ETS fusions are uniformly high risk and share dysregulated cell adhesion (EDIL3) and transcriptional networks for ERG, HPGD, and PTP4A3, which provide opportunities for further research into the metabolome and therapeutics (BETi) in these fusions. [Display omitted] DisclosuresShaw: T-Cell and/or Gene Therapy for Cancer: Patents & Royalties.

Comparative proteomics elucidates the dynamics of ovarian development in the Chinese mitten crab Eriocheir sinensis

Ovarian development is a complex physiological process for crustacean reproduction that is divided into the oogonium proliferation stage, endogenous vitellogenic stage, exogenous vitellogenic stage, and oocyte maturation stage. Proteomics analysis offers a feasible approach to reveal the proteins involved in the complex physiological processes of any organism. Therefore, this study performed a comparative proteomics analysis of the ovary and hepatopancreas at three key ovarian stages, including stages I (oogonium proliferation), II (endogenous vitellogenesis) and IV (exogenous vitellogenesis), of the Chinese mitten crab Eriocheir sinensis using a label-free quantitative approach. The results showed that a total of 2,224 proteins were identified, and some key proteins related to ovarian development and nutrition metabolism were differentially expressed. The 26 key proteins were mainly involved in the ubiquitin/proteasome pathway (UPP), cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway, and mitogen-activated protein kinase (MAPK) signaling pathway during oogenesis. Fifteen differentially abundant proteins (DAPs) were found to participate in vitellogenesis and oocyte development, such as vitelline membrane outer layer protein 1 homolog, vitellogenin, vitellogenin receptor, heat shock 70 kDa protein cognate 3 and farnesyl pyrophosphate synthase. Forty-seven DAPs related to nutrition metabolism were identified, including the protein digestion, fatty acid metabolism, prostaglandin metabolism, lipid digestion and transportation, i.e. short-chain specific acyl-CoA dehydrogenase, acyl-CoA desaturase, fatty acid-binding protein, long-chain fatty acid CoA ligase 4, and hematopoietic prostaglandin D synthase. These results not only indicate proteins involved in ovarian development and nutrient deposition but also enhance the understanding of the regulatory pathways and physiological processes of crustacean ovarian development.

Thermal proteome profiling identifies PIP4K2A and ZADH2 as off‐targets of Polo‐like kinase 1 inhibitor volasertib

Polo-like kinase 1 (PLK1) is an important cell cycle kinase and an attractive target for anticancer treatments. An ATP-competitive small molecular PLK1 inhibitor, volasertib, has reached phase III in clinical trials in patients with refractory acute myeloid leukemia as a combination treatment with cytarabine. However, severe side effects limited its use. The origin of the side effects is unclear and might be due to insufficient specificity of the drug. Thus, identifying potential off-targets to volasertib is important for future clinical trials and for the development of more specific drugs. In this study, we used thermal proteome profiling (TPP) to identify proteome-wide targets of volasertib. Apart from PLK1 and proteins regulated by PLK1, we identified about 200 potential volasertib off-targets. Comparison of this result with the mass-spectrometry analysis of volasertib-treated cells showed that phosphatidylinositol phosphate and prostaglandin metabolism pathways are affected by volasertib. We confirmed that PIP4K2A and ZADH2-marker proteins for these pathways-are, indeed, stabilized by volasertib. PIP4K2A, however, was not affected by another PLK1 inhibitor onvansertib, suggesting that PIP4K2A is a true off-target of volasertib. Inhibition of these proteins is known to impact both the immune response and fatty acid metabolism and could explain some of the side effects seen in volasertib-treated patients.

MO431LIPIDOMIC ANALYSIS IN A NON-DIABETIC RAT MODEL WITH HYPERFILTRATION AND ALBUMINURIA REVEALS DYNAMIC CHANGES IN THE PROSTAGLANDIN E2 PATHWAY DURING ONSET OF ALBUMINURIA AS A POTENTIAL CAUSATIVE MECHANISM

Abstract Background and Aims We recently identified prostaglandin reductase 2 (Ptgr2) and the prostaglandin E2 (PGE2) pathway as potential causative mechanism in the Munich Wistar Frömter (MWF) non-diabetic rat model of chronic kidney disease. MWF is characterized by early onset of spontaneous albuminuria during a critical time window between 4 and 8 weeks of age, that associates with hyperfiltration, due to low nephron number, and podocyte injury. Ptgr2 plays an important role in the prostaglandin metabolism, in which PGE2 is metabolized by 15-prostaglandin dehydrogenase (15-PGDH) to 15-keto-PGE2. The latter is terminally degraded by prostaglandin reductases (PTGRs) 1, 2, and 3 to 13,14-dihydro-15-keto-PGE2. Recently, we detected elevated glomerular levels of PGE2 and 15-keto-PGE2 in MWF compared to spontaneously hypertensive rats (SHR) with no albuminuria. The aim of the present study was to characterize in detail the renal PGE2 metabolic pathway in MWF by lipidomic analysis during the time window of albuminuria onset. Method Male MWF and SHR rats were studied at week 4 and 8, respectively; 24 h-urine was collected in metabolic cages. In addition, plasma and kidney tissues including kidney cortex and isolated glomeruli were obtained from anesthetized rats. Lipidomic analysis was done by liquid chromatography electrospray ionization tandem mass spectrometry. Statistical analysis was performed by unpaired, two-tailed Student’s t-test, or otherwise the Mann-Whitney test. Results Urinary PGE2 was significantly lower (p&amp;lt;0.01), while urinary 15-keto-PGE2 and 13,14-dihydro-15-keto PGE2 levels were significantly increased in MWF compared to SHR at week 4 (p&amp;lt;0.01, respectively). All three analytes were significantly decreased in urine of MWF with increased albuminuria at week 8 (p&amp;lt;0.05 vs. SHR). The urinary metabolic ratio of 15-keto-PGE2/13,14-dihydro-15-keto-PGE2 as a surrogate for PTGRs activities was significantly increased at week 4 (p&amp;lt;0.01), whereas it was significantly decreased in MWF vs. SHR at week 8 (p&amp;lt;0.05). Plasma levels of PGE2 and 13,14-dihydro-15-keto-PGE2 did not differ between strains at both time points, while 15-keto-PGE2 was below the detection limit. Glomerular levels of PGE2 and 15-keto-PGE2 were increased in MWF at week 4 and 8 (p&amp;lt;0.01, respectively). In contrast, 13,14-dihydro-15-keto-PGE2 was only significantly higher at week 4 compared to SHR (p&amp;lt;0.01). In isolated glomeruli, the metabolic ratios of PTGRs were similar between the strains at week 4, but significantly increased in MWF compared to SHR at week 8 (p&amp;lt;0.01, respectively). In kidney cortex, 15-keto-PGE2 and 13,14-dihydro-15-keto-PGE2 were increased in MWF at week 4 (p&amp;lt;0.05 and p&amp;lt;0.01, respectively), whereas PGE2 levels were comparable to SHR. No difference for cortical levels of PGE2 and its metabolites was observed at week 8. Conclusion This study provides the first insights into age-dependent dynamic changes in the PGE2 pathway that support potential causality for the onset of albuminuria in the setting of non-diabetic hyperfiltration due to low nephron number. Notably, the increased glomerular levels of PGE2 and its downstream metabolites in 4-week-old MWF point towards an early activation of this pathway, i.e. before albuminuria occurs. This finding corroborates the hypothesis that glomerular PGE2 signaling is relevant in the early stages of hyperfiltration and suggests this pathway as a target for future therapeutics to modify the manifestation and progression of renal disease.

Pachydermoperiostosis: A Rare Masquerader of Acromegaly and Thyroid Acropachy

Background: Pachydermoperiostoasis is a rare disease of prostaglandin metabolism that presents with extensive clubbing, skin thickening, and enlargement of hands and feet, often misdiagnosed as acromegaly or thyroid acropachy. Clinical Case: A 29-year-old male presented with progressive enlargement of hands and feet for the past three years, with increased sweating, seborrhea, acne, arthralgia, and photophobia. On examination, facial furrowing and severe clubbing in all fingers and toes was noticed, with palmoplantar hyperhidrosis, tenderness and widening around distal forearms, and increased heel pad thickness. He had nodulocystic acne, injected right eye with ptosis, normal pupil, and visual field. Slit-lamp examination showed extensive pannus formation, with yellow nodules, suggestive of phlyctenular conjunctivitis, secondary to a systemic inflammatory process. No prominent supraorbital ridge, prognathism, proptosis, goiter, or pretibial myxedema. No family history of a similar condition. Labs showed normal cell counts and metabolic panel. Normal IGF-1 (112 ng/mL, n 84-250 ng/ml), TSH (3.82 mIU/L, n 0.27-4.2 mIU/L), fT4 (1.19 ng/dL, n 0.93-1.7 ng/dL), Testosterone (354 ng/dL, n 249-836 ng/dL) and Prolactin (15.2 ng/mL, n 2.1-17.7 ng/mL). Inflammatory markers were elevated with ESR of 54 mm/hr (n 0-15 mm/hr) and CRP of 12.45 mg/L (n 1-4 mg/L). ANA, RF, anti-CCP, and HLA-B27 were negative. C3 and C4 levels were normal as well. Interferon-gamma release assay was negative. Imaging showed a normal chest X-ray. Brain MRI showed normal pituitary gland and increased scalp skin thickness with cutis verticis gyrata “undulating skin sign.” X-ray of hands and feet showed diffuse periosteal reaction. A diagnosis of pachydermoperiostosis (PDP) was made based on clinical criteria (thickened skin, periosteal reaction, and finger clubbing). PDP is a genetic disorder of prostaglandin metabolism with variable expression and incomplete penetrance. It manifests after puberty and affects males more than females with a 7:1 ratio. PDP has been recently shown to go through an inflammatory phase, in which patients may benefit from immunosuppressants or NSAIDs. PDP should be distinguished from hypertrophic pulmonary osteoarthropathy, thyroid acropachy, and acromegaly. Our patient had a normal chest radiograph and normal hormone levels (TSH, T4, and IGF-1). The patient received topical steroids and antibiotics with artificial tears for his eyes, which resulted in a good response, and was referred to a rheumatology clinic for further management. Clinical Lesson: PDP can be mistaken for acromegaly or thyroid acropachy and should be considered in any patient with acromegaloid features with normal IGF-1 and no evident pituitary pathology. Awareness of this condition can help in reaching the diagnosis promptly.

A new trick for an old dog? Myocardial-specific roles for prostaglandins as mediators of ischemic injury and repair.

The small lipid-derived paracrine signaling molecules known as prostaglandins have been recognized for their ability to modulate many facets of cardiovascular physiology since their initial discovery more than 85 years ago. Although the role of prostaglandins in the vasculature has gained significant attention across time, a handful of historical studies have also directly implicated the cardiomyocyte in both prostaglandin synthesis and release. Recently, our understanding of how prostaglandin receptor modulation impacts and contributes to myocardial structure and function has gained attention while leaving most other components of myocardial prostaglandin metabolism and signaling unexplored. This mini-review highlights both the key historical studies that underpin modern prostaglandin research in the heart, while concurrently presenting the latest findings related to how prostaglandin metabolism and signaling impact myocardial injury and repair.

Fibroblast growth factor induced Ucp1 expression in preadipocytes requires PGE2 biosynthesis and glycolytic flux.

High uncoupling protein 1 (Ucp1) expression is a characteristic of differentiated brown adipocytes and is linked to adipogenic differentiation. Paracrine fibroblast growth factor 8b (FGF8b) strongly induces Ucp1 transcription in white adipocytes independent of adipogenesis. Here, we report that FGF8b and other paracrine FGFs act on brown and white preadipocytes to upregulate Ucp1 expression via a FGFR1-MEK1/2-ERK1/2 axis, independent of adipogenesis. Transcriptomic analysis revealed an upregulation of prostaglandin biosynthesis and glycolysis upon Fgf8b treatment of preadipocytes. Oxylipin measurement by LC-MS/MS in FGF8b conditioned media identified prostaglandin E2 as a putative mediator of FGF8b induced Ucp1 transcription. RNA interference and pharmacological inhibition of the prostaglandin E2 biosynthetic pathway confirmed that PGE2 is causally involved in the control over Ucp1 transcription. Importantly, impairment of or failure to induce glycolytic flux blunted the induction of Ucp1, even in the presence of PGE2 . Lastly, a screening of transcription factors identified Nrf1 and Hes1 as required regulators of FGF8b induced Ucp1 expression. Thus, we conclude that paracrine FGFs co-regulate prostaglandin and glucose metabolism to induce Ucp1 expression in a Nrf1/Hes1-dependent manner in preadipocytes, revealing a novel regulatory network in control of Ucp1 expression in a formerly unrecognized cell type.

Targeted eicosanoids profiling reveals a prostaglandin reprogramming in breast Cancer by microRNA-155

BackgroundProstaglandin is one of the key metabolites for inflammation-related carcinogenesis. Despite the microRNA-155 is implicated in various types of cancers, it’s function in prostaglandin metabolism is largely unknown.MethodsA targeted profiling of eicosanoids including prostaglandin, leukotriene and thromboxanes was performed in miR-155 deficient breast tumors and cancer cells. The molecular mechanism of miR-155-mediated prostaglandin reprogramming was investigated in primary and cancer cell lines, by analyzing key enzymes responsible for the prostaglandin production.ResultsWe found miR-155-deficient breast tumors, plasma of tumor-bearing mouse and cancer cells show altered prostaglandin level, especially for the prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Subsequent analysis in primary cancer cells, 20 triple-negative breast cancer (TNBC) specimens and breast cancer cell lines with miR-155 knockdown consistently showed a positive correlation between miR-155 level and PGE2/PGD2 ratio. Mechanistically, we reveal the miR-155 reprograms the prostaglandin metabolism by up-regulating PGE2-producing enzymes PTGES/PTGES2 while down-regulating PGD2-producing enzyme PTGDS. Further, we show the up-regulation of PTGES2 is driven by miR-155-cMYC axis, whereas PTGES is transactivated by miR-155-KLF4. Thus, miR-155 hires dual-regulatory mode for the metabolic enzyme expression to reprogram the PGE2/PGD2 balance. Lastly, we show the miR-155-driven cellular proliferation is restored by the siRNA of PTGES1/2, of which expression also significantly correlates with breast cancer patients’ survival.ConclusionsConsidering clinical trials targeting PGE2 production largely have focused on the inhibition of Cox1 or Cox2 that showed cardiac toxicity, our data suggest an alternative way for suppressing PGE2 production via the inhibition of miR-155. As the antagomiR of miR-155 (MRG-106) underwent a phase-1 clinical trial, its effect should be considered and analyzed in prostaglandin metabolism in tumor.

The Effect of Lipid Metabolism on CD4+ T Cells.

CD4+ T cells play a vital role in the adaptive immune system and are involved in the pathogenesis of many diseases, including cancer, autoimmune diseases, and chronic inflammation. As an important mechanism for energy storage, a lot of researches have clarified that metabolism imbalance interacts with immune disorder, and one leads to the other. Lipid metabolism has close relationship with CD4+ T cells. In this review, we discuss fatty acid, cholesterol, prostaglandin, and phospholipid metabolism in CD4+ T cell subsets. Fatty acid β-oxidation (FAO) is activated in Th17 cell to support the proinflammatory function. Cholesterol promotes Th1, Th2, and Treg cell differentiation. In addition to glucose metabolism, lipid metabolism is also very important for immunity. Here, it is highlighted that lipid metabolism regulates CD4+ T cell differentiation and function and is related to diseases.

SCURVY: A FORGOTTEN DISEASE LEADING TO WOUND INFECTION AND SEPTIC SHOCK

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Scurvy is a nutritional deficiency of Vitamin C, which is classically related to the ‘Age of Sail’ (1571-1862) and is considered a disease of developing countries. Here we report a patient admitted to intensive care unit (ICU) for wound infection leading to septic shock who was later diagnosed with scurvy. CASE PRESENTATION: A 63-year-old female, resident of a nursing home, having a past medical history significant for ischemic stroke with right sided residual weakness, non-verbal since her stroke for the past ten years, deep vein thrombosis on anticoagulation, was brought to the hospital for worsening encephalopathy. Her blood pressure on arrival was 80/50 mmHg, with rest of the vitals being normal. On examination, she was somnolent, having poor dental hygiene, widespread scattered petechiae on the skin, stage 3 wound on the lower back with foul smelly discharge, cold extremities with good capillary refill while having normal cardiopulmonary and abdominal examination. Lab work showed stage 2 acute kidney injury (Creatinine 1.5 mg/dl from baseline 0.7 mg/dl), sodium 154 mmol/L, INR 8.3, macrocytic anemia with hemoglobin 7.6 g/dl (baseline >10 g/dl), platelet count 37,000 K/uL (baseline >150 K/uL). CT scan of head was negative for any new or acute intracranial pathology. She was managed as per sepsis guidelines requiring blood cultures, appropriate fluid resuscitation, broad spectrum antibiotics with suspected source of sepsis being the wound infection. She required hemodynamic support with vasopressors for hypotension and was admitted to ICU. Vitamin C level was checked considering her poor dental hygiene, scattered petechiae, which came back as undetectable. She was started on optimal replacement of Vitamin C which resulted in gradual improvement of her petechiae, wound and notably her thrombocytopenia completely resolved within a week of initiation of Vitamin C. DISCUSSION: Vitamin C is essential in collagen synthesis, helping in keeping our gums, skin, bone and hair healthy. Moreover, it plays role in prostaglandin metabolism thus potentially decreasing the inflammation or even sepsis. Although considered rare nowadays, scurvy or other nutritional deficiencies can be seen in elderly population, especially people from nursing home or poor socioeconomic status. Such population is at higher risk of getting worse wounds which could result in fatal sepsis or septic shock. CONCLUSIONS: Though rare, scurvy must be kept in the differentials as it carries a higher risk of septic shock which can be fatal if not timely diagnosed and treated. Reference #1: Svirbely, J.L. and A. Szent-Gyorgyi, The chemical nature of vitamin C. Biochem J, 1933. 27(1): p. 279-85. Reference #2: Ma, N.S., C. Thompson, and S. Weston, Brief Report: Scurvy as a Manifestation of Food Selectivity in Children with Autism. J Autism Dev Disord, 2016. 46(4): p. 1464-70. DISCLOSURES: No relevant relationships by Yahya Ahmad, source=Web Response No relevant relationships by Shujaa Faryad, source=Web Response No relevant relationships by Usama Talib, source=Web Response

Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer.

Aldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives with IC50 values of 25-56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with 2j and 2l. The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide).

Diet quality and NSAIDs promote changes in formation of prostaglandins by an aquatic invertebrate

We used the freshwater insect Hydropsyche sp. to investigate the impact of diets lacking arachidonic acid (ARA) and an environmentally relevant mixture of NSAIDs (Ibuprofen, Ketoprofen, Diclofenac and Naproxen at a nominal concentration of all compounds together 16.75 μg L−1) on their metabolism of ARA and prostaglandins (PGs). The organisms were exposed for 16 days to four different treatments: a reference (FF), a diet lacking ARA (O), to NSAIDs in water (FFN) and to the combination of the two factors (ON). Mortality, biomass and bioconcentration of pharmaceuticals were investigated. The ARA and PGs levels in the organisms were monitored by utilising a targeted metabolomics approach. NSAIDs or dietary constraints did not produce significant differences in biomass or mortality of Hydropsyche sp. among treatments. In organisms exposed to NSAIDs, all pharmaceuticals were detected, except for Ketoprofen. Metabolomic approach determined the presence of PGH2, PGE1 and PGD1. Levels of ARA diminished significantly in those organisms in treatment ON. The levels of PGs responded negatively to the absence of ARA in diet: PGH2 diminished significantly with respect to the reference in treatment O while PGE1 diminished significantly in treatment ON. Regarding the effects of NSAIDs on ARA metabolism, our results suggest that it was sensitive to NSAIDs, but effects were weak and did not imply a general decrease in the PGs. We confirmed that ARA was the main substrate for the synthesis of PGs in Hydropsyche sp, their absence or poor levels of ARA in diet, produced changes in the PG levels.

Correlation of gene expression profile to identify tumors with extreme sensitivity to the alkylating agent LP184.

e21021 Background: Lantern Pharma is advancing LP184, a next generation alkylating acylfulvene class prodrug. LP184 damages DNA that is subject to preferential repair by Transcription-Coupled Nucleotide Excision Repair. LP184 efficacy in 35 cell lines from solid tumor origin with known transcriptomic profiles identifies gene expression patterns that strongly correlate with response in cell lines. This gene expression profile allows the interrogation of clinical transcriptomics datasets to identify tumors that would potentially be highly responsive to LP184. Methods: LP184 cytotoxicity in cell lines was tested in a concentration range from 14 nM to 10 uM. Cell viability readout using CellTiter Fluor reagent was measured 72h post drug addition, and IC50 value was generated using GraphPad Prism. Bioinformatic analyses were run using the Morpheus tool from the Broad Institute. CCLE microarray expression data were used for gene signature findings and TCGA patient data were used for gene signature validation. Results: LP184 showed broad anti-tumor cytotoxicity in solid tumor cell lines including liver, NSCLC, prostate, ovarian, kidney and thyroid cancers (median IC50: 358.9 nM). Across this spectrum, LP184 sensitivity was found to be most highly correlated with high transcript levels of PTGR1, and with low transcript levels of KDM4A. Analysis of top 10 sensitive cell lines showed that NSCLC cell lines had the highest representation (5 of 10). Differential sensitivity and gene expression pattern analyses on NSCLC cell lines correlated with high relative expression of PTGR1, CASP6, NAMPT, SMARCD3 and GLRX genes along with low relative expression of KMD4A, HPGD, PTPRF and KRT14 genes in the highly sensitive cell lines. The oxidoreductase activity of PTGR1 is likely involved in bioactivation of LP184 and CASP6 mediates drug-induced apoptosis. HPGD acts upstream of PTGR1 in the prostaglandin metabolism pathway in turn modulating the turnover of endogenous PTGR1 substrate. Assessing relative expression of these genes in selected clinical NSCLC data indicates that around 37% of such tumors would potentially respond with high sensitivity to LP184. Conclusions: Overall, LP184 is a novel alkylating agent with nanomolar potency in solid tumor cell lines, especially NSCLC, and can serve as a molecularly guided therapy option in multiple tumors. The correlated genes KDM4A/ HPGD that impart high sensitivity at low expression levels, suggest potential synergistic combinations of their respective inhibitors in development PKF118-310/ ML147 with LP184.

Variation in prostaglandin metabolism during growth of the diatom Thalassiosira rotula

Prostaglandins (PGs) are hormone-like mediators in many physiological and pathological processes that are present in all vertebrates, in some terrestrial and aquatic invertebrates, and have also been identified in some macroalgae. They have recently been reported also in marine microalgae but their role as chemical mediators is largely unknown. Here we studied the expression pattern of the PG biosynthetic pathway during different growth phases of the centric diatom Thalassiosira rotula and assessed the release of PGs in the surrounding environment for the first time. We show that enzymes responsible for PGs formation such as cyclooxygenase, prostaglandin E synthase 2-like and prostaglandin F synthase are mainly expressed at the end of the exponential phase and that PGs are released especially during the stationary and senescent phases, suggesting a possible signaling function for these compounds. Phylogenetic analysis of the limiting enzyme, COX, indicate the presence in diatoms of more than one enzyme related to the oxidative metabolism of fatty acids belonging to the peroxidase-cyclooxygenase superfamily. These findings suggest a more complex evolution and diversity of metabolic pathways leading to the synthesis of lipid mediators in diatoms.

Roadmap to pregnancy during the period of maternal recognition in the cow: Changes within the corpus luteum associated with luteal rescue

A viable corpus luteum (CL) producing an adequate amount of progesterone is absolutely essential for establishment and maintenance of pregnancy. One function of embryonic signaling to the mother is to ensure that the CL is maintained. In ruminants, the secretion of uterine prostaglandin F2alpha (PGF2A) is the signal that initiates luteolysis. Despite many studies to determine if PGF2A secretion from the uterus is altered in early pregnancy, conflicting interpretations have led to controversy regarding the exact mechanisms by which maternal recognition of pregnancy is achieved. In addition to alteration of uterine prostaglandin metabolism, changes within the CL itself may facilitate the establishment of a successful pregnancy. These changes include alteration of luteal blood flow, prostaglandin metabolism, sensitivity to prostaglandin actions, increased steroidogenic capacity, significant intracellular molecular changes and modification of the immune cells that are within the CL. Whether these intraluteal changes are necessary to establish pregnancy is undetermined. The focus of this review will be to provide a brief historical perspective on the utero-ovarian relationships that regulate luteal lifespan and review current knowledge of the CL of pregnancy in sheep and cattle.

Early pregnancy loss in 15-hydroxyprostaglandin dehydrogenase knockout (15-HPGD\u2212/\u2212) mice due to requirement for embryo 15-HPGD activity

Prostaglandins (PGs) have critical signaling functions in a variety of processes including the establishment and maintenance of pregnancy, and the initiation of labor. Most PGs are non-enzymatically degraded, however, the two PGs most prominently implicated in the termination of pregnancy, including the initiation of labor, prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α), are enzymatically degraded by 15-hydroxyprostaglandin dehydrogenase (15-HPGD). The role of PG metabolism by 15-HPGD in the maintenance of pregnancy remains largely unknown, as direct functional studies are lacking. To test the hypothesis that 15-PGDH-mediated PG metabolism is essential for pregnancy maintenance and normal labor timing, we generated and analyzed pregnancy in 15-HPGD knockout mice (Hpgd−/−). We report here that pregnancies resulting from matings between 15-HPGD KO mice (Hpgd−/− X Hpgd−/−KO mating) are terminated at mid gestation due to a requirement for embryo derived 15-HPGD. Aside from altered implantation site spacing, pregnancies from KO matings look grossly and histologically normal at days post coitum (dpc) 6.5 and 7.5 of pregnancy. However, virtually all of these pregnancies are resorbed by dpc 8.5. This resorption is preceded by elevation of PGF2∝ but is not preceded by a decrease in circulating progesterone, suggesting that pregnancy loss is a local inflammatory phenomenon rather than a centrally mediated phenomena. This pregnancy loss can be temporarily deferred by indomethacin treatment, but treated pregnancies are not maintained to term and indomethacin treatment increases maternal mortality. We conclude that PG metabolism to inactive products by embryo derived 15-HPGD is essential for pregnancy maintenance in mice, and may serve a similar function during human pregnancy.

Oxaliplatin induces prostaglandin E2 release in vascular endothelial cells.

Oxaliplatin (L-OHP) is known to induce adverse reactions at the injection site, including vascular pain, but the underlying mechanisms have not been clarified. Vascular pain during intravenous L-OHP administration can be inhibited by taking non-steroidal anti-inflammatory drugs (NSAIDs). In this study, we investigated the involvement of the arachidonic acid cascade and prostaglandin (PG) E2 and 15d-PGJ2 in vascular pain sensation during intravenous delivery of L-OHP. Cultured normal human umbilical cord vein endothelial cells (HUVECs) were treated with L-OHP or L-OHP + NSAID flurbiprofen for 2h and analyzed for the release of PGE2 and 15d-PGJ2 into culture supernatant by ELISA. The results showed that L-OHP significantly and dose-dependently increased PGE2 secretion by HUVECs; however, flurbiprofen effectively prevented PGE2 increase. On the other hand, cisplatin, another platinum anticancer drug, did not stimulate PGE2 production. Other PGs, including 15d-PGJ2, 6-keto PGF1α, PGF2α, and PGD2 were not increased by L-OHP or cisplatin. Protein expression analysis revealed that cyclooxygenase 1 and cytoplasmic PGE synthase involved in constitutive PG metabolism were expressed in HUVECs but not affected by L-OHP exposure. This study indicates that L-OHP treatment specifically upregulated PGE2 secretion by vascular endothelial cells, which may contribute to vascular pain, and that NSAIDs can be used to inhibit PGE2 release and attenuate L-OHP-induced hyperalgesia.