Exercise reduces pro-inflammatory lipids and preserves resolution mediators that calibrate macrophage-centric immune metabolism in spleen and heart following obesogenic diet in aging mice.

The study investigated the role of volunteer exercise and an obesogenic diet (OBD) in mice, focusing on the splenocardiac axis and inflammation-resolution signaling. Male C57BL/6J mice (2 months old) were assigned to control (CON) or OBD groups for ten months, then randomized into sedentary (Sed) or exercise (Exe) groups for two weeks. Leukocytes, heart function, structure, and spleen tissue examined for inflammation-resolution mediators and macrophage-centric gene transcripts. After two weeks of volunteer exercise, cardiac function shows limited changes, but structural changes were notable in the heart and spleen. Exercise induced cardiac nuclear hyperplasia observed in both CON and OBD groups. OBD-Sed mice showed splenic changes and increased neutrophils, whereas increased neutrophils were noted in the CON post exercise. OBD-Sed increased pro-inflammatory lipid mediators in the heart, reduced by exercise in OBD-Exe, while CON-Exe preserved resolution mediators. Chronic OBD-Sed depletes long chain fatty acids (DHA/EPA) in the heart and spleen, while exercise independently regulates lipid metabolism genes in both organs, affecting macrophage-centric lipid and lipoprotein pathways. Chronic obesity amplified cardiac inflammation, countered by exercise that lowered pro-inflammatory bioactive lipid mediators in the heart. OBD sustained inflammation in the heart and spleen, while exercise conserved resolution mediators in CON mice. In summary, these findings emphasize the interplay of diet with exercise and highlight the intricate connection of diet, exercise, inflammation-resolution signaling in splenocardiac axis and immune health.

Macrophage Specific Lipoxygenase Deletion Amplify Cardiac Repair Activating Tregs in Chronic Heart Failure.

Splenic leukocytes, particularly macrophage-expressed lipoxygenases, facilitate the biosynthesis of resolution mediators essential for cardiac repair. Next, we asked whether deletion of 12/15 lipoxygenase (12/15LOX) in macrophages impedes the resolution of inflammation following myocardial infarction (MI). Using 12/15flox/flox and LysMcre scheme, we generated macrophage-specific 12/15LOX (Mɸ-12/15LOX-/-) mice. Young C57BL/6J wild-type and Mɸ-12/15LOX-/- male mice were subjected to permanent coronary ligation micro-surgery. Mice were monitored at day (d)1-d5 (as acute HF; AHF) and to d56 (chronic HF; CHF) post-MI, maintaining no-MI as d0 naïve controls. Post-ligation, Mɸ-12/15LOX-/- mice showed increased survival (88%vs56%) and limited heart dysfunction compared with WT. In AHF, Mɸ-12/15LOX-/- mice have increased biosynthesis of epoxyeicosatrienoic acid (EETs) by 30%, with the decrease in D-series resolvins, protectin, and maresin by 70% in the infarcted heart. Overall, myeloid cell profiling from the heart and spleen indicated that Mɸ-12/15LOX-/- mice showed higher immune cells with reparative Ly6Clow macrophages during AHF. In addition, the detailed immune profiling revealed reparative macrophage phenotype (Ly6Clow) in Mɸ-12/15LOX-/- mice in a splenocardiac manner post-MI. Mɸ-12/15LOX-/- mice showed an increase in myeloid population that coordinated increase of Tregs (CD4+/Foxp3+) in the spleen and injured heart at CHF compared with WT. Thus, macrophage-specific deletion of 12/15LOX directs reparative macrophage phenotype to facilitate cardiac repair. The presented study outlines the complex role of 12/15LOX in macrophage plasticity, and Treg signaling that indicates resolution mediators are viable targets to facilitate cardiac repair in heart failure post-MI.

Macrophage-derived bioactive lipids promote the safe clearance of inflammation (resolution), thus modulating macrophage-specific 12/15 lipoxygenase restores structure, function, and survival after heart attack in mice.

Targeted and untargeted lipidomics with integration of liver dynamics and microbiome after dietary reversal of obesogenic diet targeting inflammation-resolution signaling in aging mice.

Obesity, a global epidemic linked to around 4 million deaths yearly, arises from lifestyle imbalances impacting inflammation-related conditions like non-alcoholic fatty liver disease and gut dysbiosis. But the long-term effects of inflammation caused by lifestyle-related dietary changes remain unexplained. In this study, we used young male C57Bl/6 mice which were fed either an obesogenic diet (OBD) or a control diet (CON) for six months. Later, a group of mice from the OBD group were intervened to the CON diet (OBD-R) for four months, while another OBD group remained on the OBD diet. The OBD induced distinct changes in gut microbial, notably elevating Firmicutes and Actinobacteria, while reducing Bacteroidetes and Tenericutes. OBD-R restored microbial abundance like CON. Analyzing liver, plasma, and fecal samples revealed OBD-induced alterations in various structural and bioactive lipids, which were normalized to CON in the OBD-R, showcasing lipid metabolism flexibility and adaptability to dietary shifts. OBD increased omega 6 fatty acid, Arachidonic Acid (AA) and decreased omega 3-derived lipid mediators in the OBD mimicking non-alcoholic fatty liver disease thus impacting inflammation-resolution pathways. OBD also induced hepatic inflammation via increasing alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and proinflammatory markers CCR2, TNF-α, and IL-1ß in liver. Transitioning from OBD to CON mitigated inflammatory gene expression and restored lipid and cholesterol networks. This study underscores the intricate interplay between lifestyle-driven dietary changes, gut microbiota, lipid metabolism, and liver health. Notably, it suggests that shift from an OBD (omega-6 enriched) to CON partially alleviates signs of chronic inflammation during aging. Understanding these microbial, lipidomic, and hepatic inflammatory dynamics reveals potential therapeutic avenues for metabolic disorders induced by diet, emphasizing the pivotal role of diet in sustaining metabolic health.

Measurement of Δ9THC and metabolites in the brain and peripheral tissues after intranasal instillation of a nanoformulation.

BACKGROUND: Comparative bioavailability of cannabinoids following their administration by dosing routes has been studied previously, but there are no quantitative reports of distribution of Δ9THC, nor its metabolites, across various brain regions following intranasal (i.n.) administration. The aim of the present study was to determine the time course of Δ9THC transport from nose to brain and to quantify the distribution of Δ9THC and its metabolites in four brain regions. METHODS: Δ9THC was formulated as a lipophilic nano-emulsion and instilled i.n. to three groups of adult mice and euthanized after 2, 4, and 8 h. Brains were dissected into 4 regions. Sensitive analytical methods (HPLC-MS) were utilized to quantify levels of Δ9THC and metabolites in brain regions and peripheral tissues. Data was expressed as mean concentrations (± SEM) of Δ9THC and metabolites in brain regions, blood, plasma, urine, and liver. Two-way analysis of variance was performed followed by post hoc multiple comparisons. RESULTS: Peak concentrations of Δ9THC were reached at 2 h in the brain (15.9 ng/mg), blood (4.54 µg/mL), and plasma (4.56 µg /mL). The percentage of administered dose of Δ9THC transported to the brain (5.9%) was greater than in blood (1.7%), plasma (1.6%), urine (0.4%), and liver (0.1%). Concentrations of Δ9THC and its THC-COOH metabolite in the liver reached their highest levels at 8 h. DISCUSSION: The present study is the first to report the uptake and distribution across brain regions of Δ9THC and its principal metabolites following i.n. administration. The systemic bioavailability (absorption into the blood) of intranasal Δ9THC was 1.7% of the administered dose, much lower than that reported by others after oral ingestion (7-10%) and inhalation (20-35%), but those prior studies did not measure the transport of Δ9THC into brain regions. Others have reported Δ9THC in the whole brain following i.n. instillation in a different species (rats) to be twice (5.9%) that following i.p. injections, while metabolites of Δ9THC in rat brain were lower after i.n. administration. CONCLUSIONS: The intranasal route of a Δ9THC nanoformulation is an effective way to deliver cannabinoids to the brain, especially in those who cannot take the medication orally. Going forward, a metered dosing nasal spray will provide accurate and consistent doses.