Hypothalamic 2-Arachidonoylglycerol Regulates Multistage Process of High-Fat Diet Preferences

In this study, we examined alterations in the hypothalamic reward system related to high-fat diet (HFD) preferences. We previously reported that hypothalamic 2-arachidonoylglycerol (2-AG) and glial fibrillary acid protein (GFAP) were increased after conditioning to the rewarding properties of a HFD. Here, we hypothesized that increased 2-AG influences the hypothalamic reward system.The conditioned place preference test (CPP test) was used to evaluate HFD preferences. Hypothalamic 2-AG was quantified by gas chromatography-mass spectrometry. The expression of GFAP was examined by immunostaining and western blotting.Consumption of a HFD over either 3 or 7 days increased HFD preferences and transiently increased hypothalamic 2-AG levels. HFD consumption over 14 days similarly increased HFD preferences but elicited a long-lasting increase in hypothalamic 2-AG and GFAP levels. The cannabinoid 1 receptor antagonist O-2050 reduced preferences for HFDs after 3, 7, or 14 days of HFD consumption and reduced expression of GFAP after 14 days of HFD consumption. The astrocyte metabolic inhibitor Fluorocitrate blocked HFD preferences after 14 days of HFD consumption.High levels of 2-AG appear to induce HFD preferences, and activate hypothalamic astrocytes via the cannabinoid system. We propose that there may be two distinct stages in the development of HFD preferences. The induction stage involves a transient increase in 2-AG, whereas the maintenance stage involves a long lasting increase in 2-AG levels and activation of astrocytes. Accordingly, hypothalamic 2-AG may influence the development of HFD preferences

Ferroptosis in health and disease.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with - or caused by - ferroptosis

Effects of FC on preferences for a HFD.

<p>Results are expressed as the mean ± S.E.M. (a) The mice were fed a HFD for 3 days before the CPP test. (Vehicle, n = 10; 0.1 nmol/site, n = 10; 1.0 nmol/site, n = 11). (b) The mice were fed a HFD for 14 days before the CPP test. (Vehicle, n = 14; 0.1 nmol/site, n = 12; 1.0 nmol/site, n = 16). ^*p<0.05 vs. Vehicle (Tukey-Kramer tests).</p

Effects of the CB₁ receptor antagonist O-2050 on HFD preferences.

<p>(a) Mice were given HFD for 3 days before CPP test. O-2050 (10 mg/kg i.p.) was administrated 1 h before the test. n = 8 for each. Results are expressed as the mean ± S.E.M. ^*<i>p</i><0.05 vs. Vehicle (Student's t-test). (b) Mice were given HFD for 14 days before CPP test. O-2050 (10 mg/kg i.p.) was administrated 1h before the test (test day) or for 14 days before the CPP test (14 days). n = 8 for each (CPP test). n = 6 for each (western blotting). Results are expressed as the mean ± S.E.M. Scale bar: 100 μm. ^*<i>p</i><0.05 vs. Vehicle (Student's t-test).</p

Preference scores and hypothalamic 2-AG after SD or HFD consumption.

<p>(a) Filled circles represent the preference score in HFD intake mice. Open circles represent the preference score in SD intake mice. Preference score represents the mean change in time (s) spent in the HFD-paired side in pre-test and test sessions. n = 8 for each. Results are expressed as the mean ± S.E.M. *<i>p</i><0.05 vs. SD consumption group (Student's t-test were performed following two-way ANOVA). (b) Mice were given HFD (+) or SD (-) before the CPP test. Hypothalamic 2-AG were quantified by GC-MS. Filled squares represents the hypothalamic 2-AG after test. Open squares represents the hypothalamic 2-AG before test. n = 8 for each. Results are expressed as the mean ± S.E.M.</p

Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib

Background: Inositol-requiring enzyme 1&alpha; (IRE1&alpha;), along with protein kinase R-like endoplasmic reticulum kinase (PERK), is a principal regulator of the unfolded protein response (UPR). Recently, the &lsquo;mono&rsquo;-specific IRE1&alpha; inhibitor, kinase-inhibiting RNase attenuator 6 (KIRA6), demonstrated a promising effect against multiple myeloma (MM). Side-stepping the clinical translation, a detailed UPR phenotype in patients with MM and the mechanisms of how KIRA8 works in MM remains unclear. Methods: We characterized UPR phenotypes in the bone marrow of patients with newly diagnosed MM. Then, in human MM cells we analyzed the possible anti-tumor mechanisms of KIRA8 and a Food and Drug Administration (FDA)-approved drug, nilotinib, which we recently identified as having a strong inhibitory effect against IRE1&alpha; activity. Finally, we performed an RNA-sequence analysis to detect key IRE1&alpha;-related molecules against MM. Results: We illustrated the dominant induction of adaptive UPR markers under IRE1&alpha; over the PERK pathway in patients with MM. In human MM cells, KIRA8 decreased cell viability and induced apoptosis, along with the induction of C/EBP homologous protein (CHOP); its combination with bortezomib exhibited more anti-myeloma effects than KIRA8 alone. Nilotinib exerted a similar effect compared with KIRA8. RNA-sequencing identified Polo-like kinase 2 (PLK2) as a KIRA8-suppressed gene. Specifically, the IRE1&alpha; overexpression induced PLK2 expression, which was decreased by KIRA8. KIRA8 and PLK2 inhibition exerted anti-myeloma effects with apoptosis induction and the regulation of cell proliferation. Finally, PLK2 was pathologically confirmed to be highly expressed in patients with MM. Conclusion: Dominant activation of adaptive IRE1&alpha; was established in patients with MM. Both KIRA8 and nilotinib exhibited anti-myeloma effects, which were enhanced by bortezomib. Adaptive IRE1&alpha; signaling and PLK2 could be potential therapeutic targets and biomarkers in MM

Clinical features and treatment strategies of febrile urinary tract infection caused by extended-spectrum beta-lactamase–producing Enterobacteriaceae in children: a multicenter retrospective observational study in Japan

Objectives: The incidence of infections caused by extended-spectrum beta-lactamase (ESBL)–producing bacteria has increased. This study aimed to clarify the risk factors and treatment strategies for febrile urinary tract infection (fUTI) caused by ESBL-producing bacteria in Japanese children. Methods: A retrospective observational study was conducted in 21 hospitals among children aged <16 years diagnosed with an fUTI between 2008 and 2017. Clinical data of children with fUTI caused by ESBL-producing and non-ESBL–producing bacteria were compared. Results: Of the 2049 cases of fUTI, 147 (7.2%) were caused by ESBL-producing bacteria. Children in the ESBL group were more likely to have a history of recent antibiotic use or prophylactic antibiotic use, and experience recurrent UTIs (P <0.001) compared with those in the non-ESBL group. Of the 124 cases of fUTI due to ESBL-producing bacteria that were reviewed, 20 and 100 had concordant and discordant antibiotic use, respectively, and four had unknown antibiotic susceptibility. The median time from the start of treatment to fever resolution was 24 hours and did not differ significantly by therapy group (P = 0.39). Conclusion: ESBL-producing bacteria should be considered in children with recurrent UTIs and recent antibiotic use. Most children with fUTI experience clinical improvement regardless of the choice of antibiotic

The International Linear Collider: Report to Snowmass 2021

The International Linear Collider (ILC) is on the table now as a new global energy-frontier accelerator laboratory taking data in the 2030s. The ILC addresses key questions for our current understanding of particle physics. It is based on a proven accelerator technology. Its experiments will challenge the Standard Model of particle physics and will provide a new window to look beyond it. This document brings the story of the ILC up to date, emphasizing its strong physics motivation, its readiness for construction, and the opportunity it presents to the US and the global particle physics community