Summary
In addition to direct activation by pathogens and antigens, immune cell functions are further modulated by factors in their environment. Recent studies have revealed that lysophospholipids ...(LPL) derived from membrane glycerophospholipids are such environmental factors. They are produced by the action of various phospholipases and modulate immune responses positively or negatively via G‐protein‐coupled receptor‐type receptors. These include lysophosphatidic acid, lysophosphatidylserine (LysoPS), and lysophosphatidylinositol. Here, we summarize what is known about the synthetic pathways, receptors, and immunomodulatory functions of these LPLs. Particular focus is given to LysoPS, which have recently been identified, and recent findings on their immunomodulatory actions are presented.
Phospholipase A1 (PLA1) is an enzyme that cleaves an ester bond at the sn-1 position of glycerophospholipids, producing a free fatty acid and a lysophospholipid. PLA1 activities have been detected ...both extracellularly and intracellularly, which are well conserved in higher eukaryotes, including fish and mammals. All extracellular PLA1s belong to the lipase family. In addition to PLA1 activity, most mammalian extracellular PLA1s exhibit lipase activity to hydrolyze triacylglycerol, cleaving the fatty acid and contributing to its absorption into the intestinal tract and tissues. Some extracellular PLA1s exhibit PLA1 activities specific to phosphatidic acid (PA) or phosphatidylserine (PS) and serve to produce lysophospholipid mediators such as lysophosphatidic acid (LPA) and lysophosphatidylserine (LysoPS). A high level of PLA1 activity has been detected in the cytosol fractions, where PA-PLA1/DDHD1/iPLA1 was responsible for the activity. Many homologs of PA-PLA1 and PLA2 have been shown to exhibit PLA1 activity. Although much has been learned about the pathophysiological roles of PLA1 molecules through studies of knockout mice and human genetic diseases, many questions regarding their biochemical properties, including their genuine in vivo substrate, remain elusive.
GPR34 is a recently identified G-protein coupled receptor, which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative ligand. Here, we report cryo-electron ...microscopy structures of human GPR34-G
complex bound with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or M1, a derivative of S3E-LysoPS in which oleic acid is substituted with a metabolically stable aromatic fatty acid surrogate. The ligand-binding pocket is laterally open toward the membrane, allowing lateral entry of lipidic agonists into the cavity. The amine and carboxylate groups of the serine moiety are recognized by the charged residue cluster. The acyl chain of S3E-LysoPS is bent and fits into the L-shaped hydrophobic pocket in TM4-5 gap, and the aromatic fatty acid surrogate of M1 fits more appropriately. Molecular dynamics simulations further account for the LysoPS-regioselectivity of GPR34. Thus, using a series of structural and physiological experiments, we provide evidence that chemically unstable 2-acyl LysoPS is the physiological ligand for GPR34. Overall, we anticipate the present structures will pave the way for development of novel anticancer drugs that specifically target GPR34.
Accumulating evidence suggests that lysophospholipids (LPL) serve as lipid mediators that exert their diverse pathophysiological functions via G protein-coupled receptors. These include ...lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), lysophosphatidylserine (LysoPS) and lysophosphatidylinositol (LPI). Unlike S1P, which is produced intracellularly and secreted from various cell types, some LPLs, such as LPA, LysoPS and LPI, are produced in lesions, especially under pathological conditions, where they positively or negatively regulate disease progression through their autacoid-like actions. Although these LPLs are minor components of the cell membrane, recent developments in mass spectrometry techniques have made it possible to detect and quantify them in a variety of biological fluids, including plasma, serum, urine and cerebrospinal fluid. The synthetic enzymes of LPA and LysoPS are also present in these biological fluids, which also can be detected by antibody-based methods. Importantly, their levels have been found to dramatically increase during various pathological conditions. Thus, LPLs and their synthetic enzymes in these biological fluids are potential biomarkers. This review discusses the potential of these LPLs and LPL-related molecules as pathological biomarkers, including methods and problems in their measurement.
Phospholipase A
(PLA
) is an enzyme that cleaves an ester bond at the
-1 position of glycerophospholipids, producing a free fatty acid and a lysophospholipid. PLA
activities have been detected both ...extracellularly and intracellularly, which are well conserved in higher eukaryotes, including fish and mammals. All extracellular PLA
s belong to the lipase family. In addition to PLA
activity, most mammalian extracellular PLA
s exhibit lipase activity to hydrolyze triacylglycerol, cleaving the fatty acid and contributing to its absorption into the intestinal tract and tissues. Some extracellular PLA
s exhibit PLA
activities specific to phosphatidic acid (PA) or phosphatidylserine (PS) and serve to produce lysophospholipid mediators such as lysophosphatidic acid (LPA) and lysophosphatidylserine (LysoPS). A high level of PLA
activity has been detected in the cytosol fractions, where PA-PLA
/DDHD1/iPLA
was responsible for the activity. Many homologs of PA-PLA
and PLA
have been shown to exhibit PLA
activity. Although much has been learned about the pathophysiological roles of PLA
molecules through studies of knockout mice and human genetic diseases, many questions regarding their biochemical properties, including their genuine in vivo substrate, remain elusive.
Objective. A new sclerosing agent for hemorrhoids, aluminum potassium sulfate and tannic acid (ALTA), is attracting attention as a curative treatment for internal hemorrhoids without resection. The ...outcome and safety of ALTA sclerotherapy using an endoscope were investigated in the present study. Materials and Methods. Subjects comprised 83 internal hemorrhoid patients (61 males and 22 females). An endoscope was inserted and retroflexed in the rectum, and a 1st-step injection was applied to the upper parts of the hemorrhoids. The retroflexed scope was returned to the normal position, and 2nd–4th-step injections were applied to the middle and lower parts of the hemorrhoids under direct vision. The effects of endoscopic ALTA sclerotherapy were determined by evaluating the condition of the hemorrhoids using an anoscope and interviewing the patient 28 days after the treatment. Results. A cure, improvement, and failure were observed in 54 (65.1%), 27 (32.5%), and 2 (2.4%) patients, respectively, treated with ALTA. Complications developed in 4 patients (mild fever in 3 and hematuria in 1). Recurrence occurred in 9.6%. Conclusions. The results of the present study suggest that endoscopic ALTA has the potential to become a useful and minimally invasive approach for ALTA sclerotherapy.
We describe an extremely rare cardiac lipoma, with electrocardiographic changes in ST segments and T waves, suggesting ischemic heart disease. The abnormal electrocardiogram was identified during a ...routine physical examination of an asymptomatic 57-year-old man. Coronary angiography showed no stenotic or occlusive lesions in the coronary arteries except that the left anterior descending artery followed a winding course in the apical region. Left ventriculography revealed a pseudoaneurysm-like mass around the apical portion. Computed tomography and magnetic resonance imaging revealed a cardiac lipoma that communicated with the left ventricle and resembled a pseudoaneurysm. After complete resection of the lipoma and left ventricle patch plasty, the postoperative course was uneventful. Histologically, the tumor was an intramyocardiac lipoma with no evidence of malignancy. To our knowledge, we are the first to describe an intramyocardiac lipoma resembling a left ventricle pseudoaneurysm.
A male patient with abdominal aortic aneurysm (AAA) and coronary artery disease was referred to our hospital. Coronary angiography showed multiple coronary lesions including the left main trunk. ...Computed tomography revealed a large AAA measuring 78 mm. To prevent aneurysmal rupture after coronary artery bypass grafting or cardiac complications after AAA repair, we performed simultaneous endovascular aneurysmal repair and coronary artery bypass grafting. The postoperative course was uneventful. Endovascular therapy and beating coronary artery bypass grafting is less invasive and may offer another promising option for the treatment of complicated case of AAA with severe coronary artery disease.
Therapy comprising 5-fluorouracil, levofolinate, and oxaliplatin is currently the most common chemotherapy for colorectal cancer. We experienced a successful case of advanced colon cancer and ...recurrent breast cancer with 5-fluorouracil, levofolinate, and oxaliplatin therapy.
A 43-year-old Japanese woman who had already undergone surgery three times for bilateral breast cancer was admitted to our hospital for the treatment of advanced transverse colon cancer. Preoperative computed tomography demonstrated a swollen lymph node at her right upper clavicle, and fine-needle aspiration biopsy of the lymph node showed that it was a metastasis from the breast cancer. A laparoscopic-assisted colectomy was performed and the pathology demonstrated that the final stage was IIIC (T4aN2aM0, Union for International Cancer Control, 7th edition). The pathological findings and immunohistochemistry showed that the transverse colon tumor was not a metastatic lesion from the breast cancer, but was a de novo colon cancer. Chemotherapy was necessary for both the recurrent breast cancer and the Stage IIIC colon cancer. Therapy of 5-fluorouracil, levofolinate, and oxaliplatin was administered; the therapy included 5-fluorouracil, which is considered to be effective for both colon and breast cancer. After two courses of 5-fluorouracil, levofolinate, and oxaliplatin, the lymph node began to shrink and almost completely disappeared after eight courses of 5-fluorouracil, levofolinate, and oxaliplatin.
We surmise that 5-fluorouracil, levofolinate, and oxaliplatin have the potential to provide a good response for tumors that are sensitive to fluorinated pyrimidine and platinum-containing anticancer drugs such as breast cancer.
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