Secreted Phospholipase PLA2G2D Contributes to Metabolic Health by Mobilizing ω3 Polyunsaturated Fatty Acids in WAT

Polyunsaturated fatty acids (PUFAs) confer health benefits by preventing inflammation and obesity and by increasing thermogenesis in brown and beige adipocytes. As well as being supplied exogenously as nutrients, PUFAs are largely stored in membrane glycerophospholipids and released by phospholipase A2s (PLA2s). However, the molecular identity of the PLA2 subtype(s) that supplies endogenous PUFAs for metabolic homeostasis remains unclear. Here we show that PLA2G2D, a secreted PLA2 isoform, is constitutively expressed in M2-type macrophages in white adipose tissue (WAT) and shows a reciprocal correlation with obesity. Studies using global and macrophage-specific Pla2g2d-deficient mice reveal that PLA2G2D increases energy expenditure and thermogenesis by facilitating adipocyte browning, thereby ameliorating diet-induced obesity, insulin resistance, and WAT inflammation. Mechanistically, PLA2G2D constitutively supplies a pool of PUFAs, ω3 in particular, in WAT. Thus, our present findings underscore the contribution of the macrophage-driven PLA2G2D-ω3 PUFA axis to metabolic health

Five Prognostic Factors for Readmission in Patients Over 75 Years Old with Worsening Heart Failure

Heart failure （HF） is a common disease in elderly patients, particularly in those presenting as readmission for worsening HF. While recent studies have revealed mortality-associated factors in this population, little is known about prognostic factors associated with worsening HF. To investigate this clinical evidence gap in patients aged over 75 years, we retrospectively investigated 165 patients hospitalized for HF at Showa University Hospital, of whom 65 （39.4％） were readmitted for worsening HF. We extracted the candidate variables based on univariate analysis, and then elucidated the independent prognostic factors by multivariate analysis. Compared with non-readmitted patients, readmitted patients with worsening HF had lower left ventricular ejection fraction （LVEF） （39％ vs. 50％, P＝0.002） and body mass index （BMI） （19.9kg/m2 vs. 21.4kg/m2, P＝0.007）, higher levels of B-type natriuretic peptide （BNP） （478pg/ml vs. 198pg/ml, P＜0.001）, and heart rate （HR） （71.0 beats/min vs. 67.0 beats/min, P＝0.021） upon discharge during the primary admission. Multivariate logistic analysis identified LVEF ＜40％, BMI ＜21kg/m2, BNP ≥500pg/ml, Charlson score ≥3, and HR ≥70 beats/min upon initial discharge as independent prognostic factors. Based on these factors, readmission for worsening HF was more frequent in those with our proposed risk score of ≥3.0 than in those with a risk score ＜3.0 （P＜0.001）, and we suggested five prognostic factors for HF patients over 75 years old. Our proposed risk score combines these factors and might predict readmission for worsening HF in the elderly population

Risk of Drug-Induced Accidents and Injuries in Elderly Patients Treated with Specific Drugs Rather than Polypharmacy : Analyses of the Japanese Adverse Drug Event Report Database

One of the reasons the health care system requires long-term nursing care for elderly patients is the risk of falls and fractures. In this study, we sought to identify risk factors for drug-induced falls and fractures in elderly patients in Japan. Risk factors for drug-induced falls and fractures in the elderly were analyzed by searching for the Standardised Medical Dictionary for Regulatory Activities （MedDRA） query （SMQ） “accidents/injuries” in the Japanese Adverse Drug Event Report database （JADER）, as this SMQ was the most well suited for evaluating data on falls and fractures. For elderly patients in Japan, the risk factors for drug-induced accidents/injuries include age ≥ 70 years old, female sex, and treatment with specific drugs, but not polypharmacy. Among the risk factors with the 10 highest reporting odds ratios （RORs） were treatment with: anti-osteoporosis agents such as bisphosphonates （e.g., minodronic acid）, eldecalcitol and bazedoxifene; dementia therapeutic agents such as rivastigmine and memantine; antiparkinsonian agents such as entacapone and pramipexole; and neuropathic pain relievers such as pregabalin. Although various geriatric syndromes were generally caused by polypharmacy, it has been posited that individual medications such as those mentioned above have a more significant association with drug-induced accidents and injuries in the elderly than polypharmacy. These drugs should be used cautiously while considering drug interruption, dose reductions, and switching to alternative therapies with lower risks. An association between accidents/injuries and drugs targeting the central nervous system （such as hypnotics, sedatives, anxiolytics, and antidepressants） has previously been reported. However, in the present study, no elevated risks in association with triazolam, zopiclone, flunitrazepam, diazepam, rilmazafone, estazolam, etizolam, or paroxetine were detected. Using RORs for risk detection for drugs in the JADER database is accessible and useful, and enables sensitive risk detection

Group III phospholipase A2 promotes colitis and colorectal cancer

Lipid mediators play pivotal roles in colorectal cancer and colitis, but only a limited member of the phospholipase A2 (PLA2) subtypes, which lie upstream of various lipid mediators, have been implicated in the positive or negative regulation of these diseases. Clinical and biochemical evidence suggests that secreted PLA2 group III (sPLA2-III) is associated with colorectal cancer, although its precise role remains obscure. Here we have found that sPLA2-III-null (Pla2g3−/−) mice are highly resistant to colon carcinogenesis. Furthermore, Pla2g3−/− mice are less susceptible to dextran sulfate-induced colitis, implying that the amelioration of colonic inflammation by sPLA2-III ablation may underlie the protective effect against colon cancer. Lipidomics analysis of the colon revealed significant reduction of pro-inflammatory/pro-tumorigenic lysophosholipids as well as unusual steady-state elevation of colon-protective fatty acids and their oxygenated metabolites in Pla2g3−/− mice. Overall, our results establish a role of sPLA2-III in the promotion of colorectal inflammation and cancer, expand our understanding of the divergent roles of multiple PLA2 enzymes in the gastrointestinal tract, and point to sPLA2-III as a novel druggable target for colorectal diseases

Blockade and reversal of spinal morphine tolerance by peptide and non-peptide calcitonin gene-related peptide receptor antagonists

1. This study examined the effects of the peptide CGRP receptor antagonist CGRP(8-37) and the newly-developed non-peptide CGRP receptor antagonist BIBN4096BS for their potential to both inhibit the development and reverse tolerance to the antinociceptive action of morphine. 2. Repeated administration of intrathecal morphine (15 μg), once daily, produced a progressive decline of antinociceptive effect and an increase in the ED(50) value in the tailflick and paw pressure tests. Co-administration of CGRP(8-37) (4 μg) or BIBN4096BS (0.05, 0.1 μg) with morphine (15 μg) prevented the decline of antinociceptive effect and increase in ED(50) value in the tailflick test. Intrathecal administration of the CGRP receptor antagonists did not alter the baseline responses in either tests. Acute CGRP(8-37) also did not potentiate the acute actions of spinal morphine. 3. In animals rendered tolerant to intrathecal morphine, subsequent administration of CGRP(8-37) (4 μg) with morphine (15 μg) partially restored the antinociceptive effect and ED(50) value of acute morphine, reflecting the reversal of tolerance. 4. Animals tolerant to intrathecal morphine expressed increased CGRP and substance P-like immunostaining in the dorsal horn of the spinal cord. The increase in CGRP, but not substance P-like immunostaining, was blocked by a co-treatment with CGRP(8-37) (4 μg). In animals already tolerant to morphine, the increase in CGRP but not substance P-like immunostaining was partially reversed by CGRP(8-37) (4 μg). 5. These data suggest that activation of spinal CGRP receptors contributes to both the development and expression of spinal opioid tolerance. CGRP receptor antagonists may represent a useful therapeutic approach for preventing as well as reversing opioid tolerance