Unique lipid composition maintained by extracellular blockade leads to prooncogenicity.

Lipid-mediated inflammation is involved in the development and malignancy of cancer. We previously demonstrated the existence of a novel oncogenic mechanism utilizing membrane lipids of extracellular vesicles in Epstein-Barr virus (EBV)-positive lymphomas and found that the lipid composition of lymphoma cells is skewed toward ω-3 fatty acids, which are anti-inflammatory lipids, suggesting an alteration in systemic lipid composition. The results showed that arachidonic acid (AA), an inflammatory lipid, was significantly reduced in the infected cells but detected at high levels in the sera of EBV-positive patients lead to the finding of the blockade of extracellular AA influx by downregulating FATP2, a long-chain fatty acid transporter that mainly transports AA in EBV-infected lymphoma cells. Low AA levels in tumor cells induced by downregulation of FATP2 expression confer resistance to ferroptosis and support tumor growth. TCGA data analysis and xenograft models have demonstrated that the axis plays a critical role in several types of cancers, especially poor prognostic cancers, such as glioblastoma and melanoma. Overall, our in vitro, in vivo, in silico, and clinical data suggest that several cancers exert oncogenic activity by maintaining their special lipid composition via extracellular blockade.

Corrigendum: Macrophage SREBP1 regulates skeletal muscle regeneration.

[This corrects the article DOI: 10.3389/fimmu.2023.1251784.].

Group III secreted phospholipase A2 -driven lysophospholipid pathway protects against allergic asthma.

Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of airway obstruction, hyperresponsiveness, remodeling, and eosinophilia. Phospholipase A2 s (PLA2 s), which release fatty acids and lysophospholipids from membrane phospholipids, have been implicated in exacerbating asthma by generating pro-asthmatic lipid mediators, but an understanding of the association between individual PLA2 subtypes and asthma is still incomplete. Here, we show that group III-secreted PLA2 (sPLA2 -III) plays an ameliorating, rather than aggravating, role in asthma pathology. In both mouse and human lungs, sPLA2 -III was expressed in bronchial epithelial cells and decreased during the asthmatic response. In an ovalbumin (OVA)-induced asthma model, Pla2g3-/- mice exhibited enhanced airway hyperresponsiveness, eosinophilia, OVA-specific IgE production, and type 2 cytokine expression as compared to Pla2g3+/+ mice. Lipidomics analysis showed that the pulmonary levels of several lysophospholipids, including lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidic acid (LPA), were decreased in OVA-challenged Pla2g3-/- mice relative to Pla2g3+/+ mice. LPA receptor 2 (LPA2 ) agonists suppressed thymic stromal lymphopoietin (TSLP) expression in bronchial epithelial cells and reversed airway hyperresponsiveness and eosinophilia in Pla2g3-/- mice, suggesting that sPLA2 -III negatively regulates allergen-induced asthma at least by producing LPA. Thus, the activation of the sPLA2 -III-LPA pathway may be a new therapeutic target for allergic asthma.

Lysophospholipase D from Thermocrispum limits psoriatic inflammation by hydrolyzing epidermal lysoplasmalogen produced by group IIF secreted phospholipase A2.

Epidermal lipids play important roles in skin homeostasis and diseases. Psoriasis is an inflammatory disease characterized by keratinocyte hyperproliferation and Th17 immune responses. We previously reported that ethanolamine-type lysoplasmalogen (P-LPE), preferentially produced by group IIF secreted PLA2 (sPLA2-IIF/PLA2G2F) that is expressed in the suprabasal epidermis, promotes epidermal hyperplasia in psoriatic inflammation. Herein, we show that forcible degradation of epidermal P-LPE by topical application of recombinant lysophospholipase D (LyPls-PLD) from Thermocrispum, a lysoplasmalogen-specific hydrolase, attenuated epidermal hyperplasia and inflammation in imiquimod-induced and K5.Stat3C-transgenic mouse psoriasis models. In humans, P-LPE levels were elevated in the tape-stripped stratum corneum of patients with psoriasis. Moreover, in primary cultured human epidermal keratinocytes, aberrant cell proliferation and activation by psoriatic cytokines were sPLA2-IIF/P-LPE-dependent and were suppressed by the addition of LyPls-PLD with a decrease in P-LPE. These findings confirm that the sPLA2-IIF/P-LPE axis in the epidermis indeed regulates psoriasis, that P-LPE is a lipid biomarker that predicts the severity of psoriasis, and that pharmacological removal of this bioactive lipid is useful to prevent the disease. Thus, our study may lead to the development of drug discovery and diagnostic techniques based on this pathway.

1-Oleoyl-lysophosphatidylethanolamine stimulates RORγt activity in TH17 cells.

Metabolic fluxes involving fatty acid biosynthesis play essential roles in controlling the differentiation of T helper 17 (TH17) cells. However, the exact enzymes and lipid metabolites involved, as well as their link to promoting the core gene transcriptional signature required for the differentiation of TH17 cells, remain largely unknown. From a pooled CRISPR-based screen and unbiased lipidomics analyses, we identified that 1-oleoyl-lysophosphatidylethanolamine could act as a lipid modulator of retinoid-related orphan receptor gamma t (RORγt) activity in TH17 cells. In addition, we specified five enzymes, including Gpam, Gpat3, Lplat1, Pla2g12a, and Scd2, suggestive of the requirement of glycerophospholipids with monounsaturated fatty acids being required for the transcription of Il17a. 1-Oleoyl-lysophosphatidylethanolamine was reduced in Pla2g12a-deficient TH17 cells, leading to the abolition of interleukin-17 (IL-17) production and disruption to the core transcriptional program required for the differentiation of TH17 cells. Furthermore, mice with T cell-specific deficiency of Pla2g12a failed to develop disease in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, our data indicate that 1-oleoyl-lysophosphatidylethanolamine is a lipid metabolite that promotes RORγt-induced TH17 cell differentiation and the pathogenicity of TH17 cells.

Follicular cholangitis mimicking a common bile duct cancer: a case report.

BACKGROUND: Follicular cholangitis (FC) is a benign bile duct disease that was first reported 2003. Pathologically, it is characterized by lymphoplasmacytic infiltration with multiple lymphoid follicle formations under the mucosal layer of the biliary tract. However, as this disease is extremely rare, little is known about its etiology and pathogenesis. CASE PRESENTATION: A 77-year-old woman was diagnosed with middle bile duct stenosis and potential increases in alkaline phosphatase (ALP) and γ-glutamyl transpeptidase levels (γ-GTP). Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and IgG4 levels were all within the normal limits. Contrast-enhanced computed tomography (CE-CT) and magnetic resonance imaging (MRI) revealed bile duct dilation from intrahepatic to upper common bile duct and an irregular mass lesion in distal bile duct. Additionally, multiple overlapping leaf-like folds were detected. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) did not demonstrate fluorodeoxyglucose uptake. Subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection was performed because common bile duct cancer could not be ruled out. The resected specimen showed diffuse homogeneous middle bile duct wall thickening. Microscopically, the lesion exhibited thick fibrosis with several invaded lymphoplasmacytic cells, and lymphoid follicle formations were detected under the mucosal layer. Immunohistochemical staining (IHC) revealed positive for CD3, CD4, CD20 and CD79a, and these findings led to a final diagnosis of FC. The patient has not experienced recurrence to date (42 months postoperatively). CONCLUSIONS: Currently, accurate preoperative diagnosis of FC is difficult. More cases must be accumulated to generate additional knowledge on its precise diagnosis and proper treatment.

[A Case of Myelodysplastic Syndrome Developed during Chemotherapy for Postoperative Recurrent Ovarian Cancer That Progressed to Acute Myeloid Leukemia].

Recent developments in chemotherapy for gynecologic malignancies have improved treatment results in patients and promoted long-term survival. However, various adverse events caused by long-term chemotherapy are still being observed. Here, we report a case of myelodysplastic syndrome that developed during chemotherapy for recurrent ovarian cancer and progressed to acute myeloid leukemia. However, chemotherapy for ovarian cancer was continued while maintaining the quality of life under certain conditions, such as maintenance of platelet levels in collaboration with a hematologist. A 69- year-old woman(gravida 3, para 2)was diagnosed with stage ⅢC ovarian cancer in our department. After 6 cycles of preoperative chemotherapy with paclitaxel plus carboplatin plus bevacizumab(TC plus Bev), we performed a simple abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, sigmoid colon resection, and low anterior resection. Postoperatively, 3 cycles of TC plus Bev and 6 cycles of Bev monotherapy were completed for stage ⅢC ovarian cancer (ypT3cNXM0, high-grade serous carcinoma). However, the cancer recurred, and the patient received 3 cycles of gemcitabine plus Bev and 3 cycles of doxorubicin plus Bev. Precursor cells and prolonged neutropenia were observed, and myelodysplastic syndrome was diagnosed. One month later, the condition progressed to acute myeloid leukemia. The patient's neutrophil count recovered spontaneously, and subsequently, 7 cycles of weekly paclitaxel plus Bev therapy were completed along with symptomatic treatment. Unfortunately, she died of septic shock against the background of acute myeloid leukemia. It is important to monitor the appearance of blasts for early detection of therapy-related myelodysplastic syndromes occurring during chemotherapy, as in the case in this report. Additionally, it is important to maintain platelet count and continue chemotherapy for the primary disease.

PLA2G2E-mediated lipid metabolism triggers brain-autonomous neural repair after ischemic stroke.

The brain is generally resistant to regeneration after damage. The cerebral endogenous mechanisms triggering brain self-recovery have remained unclarified to date. We here discovered that the secreted phospholipase PLA2G2E from peri-infarct neurons generated dihomo-γ-linolenic acid (DGLA) as necessary for triggering brain-autonomous neural repair after ischemic brain injury. Pla2g2e deficiency diminished the expression of peptidyl arginine deiminase 4 (Padi4), a global transcriptional regulator in peri-infarct neurons. Single-cell RNA sequencing (scRNA-seq) and epigenetic analysis demonstrated that neuronal PADI4 had the potential for the transcriptional activation of genes associated with recovery processes after ischemic stroke through histone citrullination. Among various DGLA metabolites, we identified 15-hydroxy-eicosatrienoic acid (15-HETrE) as the cerebral metabolite that induced PADI4 in peri-infarct-surviving neurons. Administration of 15-HETrE enhanced functional recovery after ischemic stroke. Thus, our research clarifies the promising potential of brain-autonomous neural repair triggered by the specialized lipids that initiate self-recovery processes after brain injury.

PLAAT1 deficiency alleviates high-fat diet-induced hepatic lipid accumulation in mice.

The phospholipase A and acyltransferase (PLAAT) family is composed of three isoforms in mice (PLAAT1, 3, and 5), all of which function as phospholipid-metabolizing enzymes exhibiting phospholipase A1 /A2 and acyltransferase activities. Plaat3-deficient (Plaat3-/- ) mice were previously reported to show lean phenotype and remarkable hepatic fat accumulation under high-fat diet (HFD) feeding, while Plaat1-/- mice have not been analyzed. In the present study, we generated Plaat1-/- mice and investigated the effects of PLAAT1 deficiency on HFD-induced obesity, hepatic lipid accumulation, and insulin resistance. After HFD treatment, PLAAT1 deficiency caused a lower body weight gain compared to wild-type mice. Plaat1-/- mice also showed reduced liver weight with negligible hepatic lipid accumulation. In accordance with these findings, PLAAT1 deficiency improved HFD-induced hepatic dysfunction and lipid metabolism disorders. Lipidomics analysis in the liver revealed that in Plaat1-/- mice, the levels of various glycerophospholipids tended to increase, while all classes of lysophospholipids examined tended to decrease, suggesting that PLAAT1 functions as phospholipase A1 /A2 in the liver. Interestingly, the HFD treatment of wild-type mice significantly increased the mRNA level of PLAAT1 in the liver. Furthermore, the deficiency did not appear to elevate the risk of insulin resistance in contrast to PLAAT3 deficiency. These results suggested that the suppression of PLAAT1 improves HFD-induced overweight and concomitant hepatic lipid accumulation.

The Roles of sPLA2s in Skin Homeostasis and Disease.

Among the phospholipase A2 (PLA2) family, the secreted PLA2 (sPLA2) family in mammals contains 11 members that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using knockout and/or transgenic mice for a nearly full set of sPLA2s, in combination with comprehensive lipidomics, have revealed the diverse pathophysiological roles of sPLA2s in various biological events. Individual sPLA2s exert specific functions within tissue microenvironments, likely through the hydrolysis of extracellular phospholipids. Lipids are an essential biological component for skin homeostasis, and disturbance of lipid metabolism by deletion or overexpression of lipid-metabolizing enzymes or lipid-sensing receptors often leads to skin abnormalities that are easily visible on the outside. Over the past decades, our studies using knockout and transgenic mice for various sPLA2s have uncovered several new aspects of these enzymes as modulators of skin homeostasis and disease. This article summarizes the roles of several sPLA2s in skin pathophysiology, providing additional insight into the research fields of sPLA2s, lipids, and skin biology.

Modulation of immunity by the secreted phospholipase A2 family.

Among the phospholipase A2 (PLA2 ) superfamily, which typically catalyzes the sn-2 hydrolysis of phospholipids to yield fatty acids and lysophospholipids, the secreted PLA2 (sPLA2 ) family contains 11 isoforms in mammals. Individual sPLA2 s have unique enzymatic specificity toward fatty acids and polar heads of phospholipid substrates and display distinct tissue/cellular distributions, suggesting their distinct physiological functions. Recent studies using knockout and/or transgenic mice for a full set of sPLA2 s have revealed their roles in modulation of immunity and related disorders. Application of mass spectrometric lipidomics to these mice has enabled to identify target substrates and products of individual sPLA2 s in given tissue microenvironments. sPLA2 s hydrolyze not only phospholipids in the plasma membrane of activated, damaged or dying mammalian cells, but also extracellular phospholipids such as those in extracellular vesicles, microbe membranes, lipoproteins, surfactants, and dietary phospholipids, thereby exacerbating or ameliorating various diseases. The actions of sPLA2 s are dependent on, or independent of, the generation of fatty acid- or lysophospholipid-derived lipid mediators according to the pathophysiological contexts. In this review, we make an overview of our current understanding of the roles of individual sPLA2 s in various immune responses and associated diseases.

The Lysophospholipase PNPLA7 Controls Hepatic Choline and Methionine Metabolism.

The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca2+-independent phospholipase A2 (iPLA2) family, as a key regulator of the production of glycerophosphocholine (GPC), a precursor of endogenous choline, whose methyl groups are preferentially fluxed into the methionine cycle in the liver. PNPLA7 deficiency in mice markedly decreases hepatic GPC, choline, and several metabolites related to choline/methionine metabolism, leading to various symptoms reminiscent of methionine shortage. Overall metabolic alterations in the liver of Pnpla7-null mice in vivo largely recapitulate those in methionine-deprived hepatocytes in vitro. Reduction of the methyl donor S-adenosylmethionine (SAM) after methionine deprivation decreases the methylation of the PNPLA7 gene promoter, relieves PNPLA7 expression, and thereby increases GPC and choline levels, likely as a compensatory adaptation. In line with the view that SAM prevents the development of liver cancer, the expression of PNPLA7, as well as several enzymes in the choline/methionine metabolism, is reduced in human hepatocellular carcinoma. These findings uncover an unexplored role of a lysophospholipase in hepatic phospholipid catabolism coupled with choline/methionine metabolism.

The phospholipase A2 superfamily as a central hub of bioactive lipids and beyond.

In essence, "phospholipase A2" (PLA2) means a group of enzymes that release fatty acids and lysophospholipids by hydrolyzing the sn-2 position of glycerophospholipids. To date, more than 50 enzymes possessing PLA2 or related lipid-metabolizing activities have been identified in mammals, and these are subdivided into several families in terms of their structures, catalytic mechanisms, tissue/cellular localizations, and evolutionary relationships. From a general viewpoint, the PLA2 superfamily has mainly been implicated in signal transduction, driving the production of a wide variety of bioactive lipid mediators. However, a growing body of evidence indicates that PLA2s also contribute to phospholipid remodeling or recycling for membrane homeostasis, fatty acid ß-oxidation for energy production, and barrier lipid formation on the body surface. Accordingly, PLA2 enzymes are considered one of the key regulators of a broad range of lipid metabolism, and perturbation of specific PLA2-driven lipid pathways often disrupts tissue and cellular homeostasis and may be associated with a variety of diseases. This review covers current understanding of the physiological functions of the PLA2 superfamily, focusing particularly on the two major intracellular PLA2 families (Ca2+-dependent cytosolic PLA2s and Ca2+-independent patatin-like PLA2s) as well as other PLA2 families, based on studies using gene-manipulated mice and human diseases in combination with comprehensive lipidomics.

Organism-Wide Analysis of Sepsis Reveals Mechanisms of Systemic Inflammation.

Sepsis is a systemic response to infection with life-threatening consequences. Our understanding of the impact of sepsis across organs of the body is rudimentary. Here, using mouse models of sepsis, we generate a dynamic, organism-wide map of the pathogenesis of the disease, revealing the spatiotemporal patterns of the effects of sepsis across tissues. These data revealed two interorgan mechanisms key in sepsis. First, we discover a simplifying principle in the systemic behavior of the cytokine network during sepsis, whereby a hierarchical cytokine circuit arising from the pairwise effects of TNF plus IL-18, IFN-γ, or IL-1ß explains half of all the cellular effects of sepsis on 195 cell types across 9 organs. Second, we find that the secreted phospholipase PLA2G5 mediates hemolysis in blood, contributing to organ failure during sepsis. These results provide fundamental insights to help build a unifying mechanistic framework for the pathophysiological effects of sepsis on the body.

Hepatic phosphatidylcholine catabolism driven by PNPLA7 and PNPLA8 supplies endogenous choline to replenish the methionine cycle with methyl groups.

Choline supplies methyl groups for regeneration of methionine and the methyl donor S-adenosylmethionine in the liver. Here, we report that the catabolism of membrane phosphatidylcholine (PC) into water-soluble glycerophosphocholine (GPC) by the phospholipase/lysophospholipase PNPLA8-PNPLA7 axis enables endogenous choline stored in hepatic PC to be utilized in methyl metabolism. PNPLA7-deficient mice show marked decreases in hepatic GPC, choline, and several metabolites related to the methionine cycle, accompanied by various signs of methionine insufficiency, including growth retardation, hypoglycemia, hypolipidemia, increased energy consumption, reduced adiposity, increased fibroblast growth factor 21 (FGF21), and an altered histone/DNA methylation landscape. Moreover, PNPLA8-deficient mice recapitulate most of these phenotypes. In contrast to wild-type mice fed a methionine/choline-deficient diet, both knockout strains display decreased hepatic triglyceride, likely via reductions of lipogenesis and GPC-derived glycerol flux. Collectively, our findings highlight the biological importance of phospholipid catabolism driven by PNPLA8/PNPLA7 in methyl group flux and triglyceride synthesis in the liver.

Hypercholesterolemic Dysregulation of Calpain in Lymphatic Endothelial Cells Interferes With Regulatory T-Cell Stability and Trafficking.

BACKGROUND: Although hypercholesterolemia reportedly counteracts lymphocyte trafficking across lymphatic vessels, the roles of lymphatic endothelial cells (LECs) in the lymphocyte regulations remain unclear. Previous studies showed that calpain-an intracellular modulatory protease-interferes with leukocyte dynamics in the blood microcirculation and is associated with hypercholesterolemic dysfunction in vascular endothelial cells. METHODS: This study investigated whether the calpain systems in LECs associate with the LEC-lymphocyte interaction under hypercholesterolemia using gene-targeted mice. RESULTS: Lipidomic analysis in hypercholesterolemic mice showed that several lysophospholipids, including lysophosphatidic acid, accumulated in the lymphatic environment. Lysophosphatidic acid enables the potentiation of calpain systems in cultured LECs, which limits their ability to stabilize regulatory T cells (Treg) without altering Th1/Th2 (T helper type1/2) subsets. This occurs via the proteolytic degradation of MEKK1 (mitogen-activated protein kinase kinase kinase 1) and the subsequent inhibition of TGF (transforming growth factor)-ß1 production in LECs. Targeting calpain systems in LECs expanded Tregs in the blood circulation and reduced aortic atherosclerosis in hypercholesterolemic mice, concomitant with the reduction of proinflammatory macrophages in the lesions. Treg expansion in the blood circulation and atheroprotection in calpain-targeted mice was prevented by the administration of TGF-ß type-I receptor inhibitor. Moreover, lysophosphatidic acid-induced calpain overactivation potentiated the IL (interleukin)-18/NF-κB (nuclear factor κB)/VCAM1 (vascular cell adhesion molecule 1) axis in LECs, thereby inhibiting lymphocyte mobility on the cells. Indeed, VCAM1 in LECs was upregulated in hypercholesterolemic mice and human cases of coronary artery disease. Neutralization of VCAM1 or targeting LEC calpain systems recovered afferent Treg transportation via lymphatic vessels in mice. CONCLUSIONS: Calpain systems in LECs have a key role in controlling Treg stability and trafficking under hypercholesterolemia.

Macrophage SREBP1 regulates skeletal muscle regeneration.

Macrophages are essential for the proper inflammatory and reparative processes that lead to regeneration of skeletal muscle after injury. Recent studies have demonstrated close links between the function of activated macrophages and their cellular metabolism. Sterol regulatory element-binding protein 1 (SREBP1) is a key regulator of lipid metabolism and has been shown to affect the activated states of macrophages. However, its role in tissue repair and regeneration is poorly understood. Here we show that systemic deletion of Srebf1, encoding SREBP1, or macrophage-specific deletion of Srebf1a, encoding SREBP1a, delays resolution of inflammation and impairs skeletal muscle regeneration after injury. Srebf1 deficiency impairs mitochondrial function in macrophages and suppresses the accumulation of macrophages at sites of muscle injury. Lipidomic analyses showed the reduction of major phospholipid species in Srebf1 -/- muscle myeloid cells. Moreover, diet supplementation with eicosapentaenoic acid restored the accumulation of macrophages and their mitochondrial gene expression and improved muscle regeneration. Collectively, our results demonstrate that SREBP1 in macrophages is essential for repair and regeneration of skeletal muscle after injury and suggest that SREBP1-mediated fatty acid metabolism and phospholipid remodeling are critical for proper macrophage function in tissue repair.

[Short-Term Outcomes of Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer].

In recent years, an increasing number of reports have demonstrated the usefulness of neoadjuvant chemoradiotherapy (NACRT). In our department, we consider cT3-4 and/or cN-positive locally advanced rectal cancer as an indication for NACRT. We have retrospectively evaluated the efficacy and safety of NACRT in 11 patients who underwent NACRT from November 2018 to July 2022. All patients were male, with a median age of 69 years, and cStage was Ⅱa: 1, Ⅱc: 1, Ⅲb: 5, Ⅲc: 3, and Ⅳa: 1. All patients completed NACRT, and there were no cases of CTCAE Grade 3 or higher adverse events or treatment interruptions. The response rate was 72.7%, and histological response grade were Grade 3: 1(9.1%), 2: 4 (36.4%), 1b: 6(54.5%), and surgical margin was negative in all cases. Pathological down stage was obtained in 45.5% of cases, and pCR was obtained in 1 case(9.1%). The median observation period was 17 months, and during the period, 2 cases(18.2%)developed recurrence, both of which were pulmonary metastases, and no local recurrence including pelvic lymph node recurrence was observed. NACRT for locally advanced rectal cancer is considered a relatively safe and highly locally controllable preoperative treatment.

[A Case of BRAF V600E-Mutant Colorectal Cancer Treated Effectively by Encorafenib, Binimetinib, and Cetuximab Triple Therapy].

A 76-year-old woman was diagnosed with left-sided transverse colon cancer invading the pancreatic tail with multiple liver metastases and peritoneal dissemination. Preoperative diagnosis was cT4b(SI)N2aM1c(H3, P1), cStage Ⅳc, harboring BRAF V600E mutation. Transverse colostomy was performed, and FOLFOXIRI plus bevacizumab(BEV)was administered. After 12 chemotherapy cycles, the primary tumor and metastatic lesions showed partial response. Because of CEA elevating after 5-FU plus LV plus BEV as maintenance therapy was changed, the regimen was switched to encorafenib plus binimetinib plus cetuximab as the second-line chemotherapy. The patient developed dermatitis around the colostomy after the start of the second-line chemotherapy, resulting in temporally cetuximab monotherapy. After improvement of dermatitis, the patient resumed encorafenib plus binimetinib, improving liver metastases. Eight months after the start of the second- line, the patient has been administered with triple therapy and had stable disease status.

Malabaricone C derived from nutmeg inhibits arachidonate 5-lipoxygenase activity and ameliorates psoriasis-like skin inflammation in mice.

As pro-inflammatory lipid mediators, leukotrienes have pathophysiological activities in several inflammatory diseases, including psoriasis. In the biosynthesis of leukotrienes from arachidonic acid, 5-lipoxygenase catalyzes the first two steps. In the present study, we showed that nutmeg (Myristica fragrans) strongly inhibited the catalytic activity of 5-lipoxygenase. To characterize the bioactive component(s) of nutmeg, we performed 5-lipoxygenase inhibitory activity-guided fractionation of aqueous ethanol extract of nutmeg, resulting in the isolation of malabaricone C having antioxidant activity. Malabaricone C exhibited potent competitive inhibition of 5-lipoxygenase with an IC50 value of 0.2 µM. In mice with imiquimod-induced psoriasis-like skin lesions, topical application of 2 mM malabaricone C significantly ameliorated hyperplasia and inflammatory cell infiltration, and suppressed the expression of the psoriasis-associated genes S100a9, Krt1, Il17a, and Il22. Lipid metabolome analysis of these psoriasis-like skin lesions showed that malabaricone C markedly decreased the level of leukotriene B4 but did not significantly increase the other pro-inflammatory lipid mediators. These findings suggest that malabaricone C decreases LTB4 by the 5-lipoxygenase inhibition and ameliorates the symptoms of psoriasis-like skin inflammation.