Brown adipose tissue (BAT) dysfunction in aging and obesity has been related to chronic unresolved inflammation, which could be mediated by an impaired production of specialized proresolving lipid mediators (SPMs), such as Lipoxins‐LXs, Resolvins‐Rvs, Protectins‐PDs, and Maresins‐MaRs. Our aim was to characterize the changes in BAT SPMs signatures and their association with BAT dysfunction during aging, especially under obesogenic conditions, and their modulation by a docosahexaenoic acid (DHA)‐rich diet. Lipidomic, functional, and molecular studies were performed in BAT of 2‐ and 18‐month‐old lean (CT) female mice and in 18‐month‐old diet‐induced obese (DIO) mice fed with a high‐fat diet (HFD), or a DHA‐enriched HFD. Aging downregulated Prdm16 and UCP1 levels, especially in DIO mice, while DHA partially restored them. Arachidonic acid (AA)‐derived LXs and DHA‐derived MaRs and PDs were the most abundant SPMs in BAT of young CT mice. Interestingly, the sum of LXs and of PDs were significantly lower in aged DIO mice compared to young CT mice. Some of the SPMs most significantly reduced in obese‐aged mice included LXB ₄ , MaR2, 4S,14S‐diHDHA, 10S,17S‐diHDHA (a.k.a. PDX), and RvD6. In contrast, DHA increased DHA‐derived SPMs, without modifying LXs. However, MicroPET studies showed that DHA was not able to counteract the impaired cold exposure response in BAT of obese‐aged mice. Our data suggest that a defective SPMs production could underlie the decrease of BAT activity observed in obese‐aged mice, and highlight the relevance to further characterize the physiological role and therapeutic potential of specific SPMs on BAT development and function.

Drug-resistant Plasmodium falciparum parasites have swept across Southeast Asia and now threaten Africa. By implementing a P. falciparum genetic cross using humanized mice, we report the identification of key determinants of resistance to artemisinin (ART) and piperaquine (PPQ) in the dominant Asian KEL1/PLA1 lineage. We mapped k13 as the central mediator of ART resistance in vitro and identified secondary markers. Applying bulk segregant analysis, quantitative trait loci mapping using 34 recombinant haplotypes, and gene editing, our data reveal an epistatic interaction between mutant PfCRT and multicopy plasmepsins 2/3 in mediating high-grade PPQ resistance. Susceptibility and parasite fitness assays implicate PPQ as a driver of selection for KEL1/PLA1 parasites. Mutant PfCRT enhanced susceptibility to lumefantrine, the first-line partner drug in Africa, highlighting a potential benefit of opposing selective pressures with this drug and PPQ. We also identified that the ABCI3 transporter can operate in concert with PfCRT and plasmepsins 2/3 in mediating multigenic resistance to antimalarial agents.

Remodeling of the microenvironment by tumor cells can activate pathways that favor cancer growth. Molecular delineation and targeting of such malignant-cell nonautonomous pathways may help overcome resistance to targeted therapies. Herein we leverage genetic mouse models, patient-derived xenografts, and patient samples to show that acute myeloid leukemia (AML) exploits peripheral serotonin signaling to remodel the endosteal niche to its advantage. AML progression requires the presence of serotonin receptor 1B (HTR1B) in osteoblasts and is driven by AML-secreted kynurenine, which acts as an oncometabolite and HTR1B ligand. AML cells utilize kynurenine to induce a proinflammatory state in osteoblasts that, through the acute-phase protein serum amyloid A (SAA), acts in a positive feedback loop on leukemia cells by increasing expression of IDO1—the rate-limiting enzyme for kynurenine synthesis—thereby enabling AML progression. This leukemia–osteoblast cross-talk, conferred by the kynurenine–HTR1B–SAA–IDO1 axis, could be exploited as a niche-focused therapeutic approach against AML, opening new avenues for cancer treatment. Significance: AML remains recalcitrant to treatments due to the emergence of resistant clones. We show a leukemia-cell nonautonomous progression mechanism that involves activation of a kynurenine–HTR1B–SAA–IDO1 axis between AML cells and osteoblasts. Targeting the niche by interrupting this axis can be pharmacologically harnessed to hamper AML progression and overcome therapy resistance. This article is highlighted in the In This Issue feature, p. 873

Obesity and aging are associated to non-alcoholic fatty liver disease (NAFLD) development. Here, we investigate whether long-term feeding with a docosahexaenoic acid (DHA)-enriched diet and aerobic exercise, alone or in combination, are effective in ameliorating NAFLD in aged obese mice. Two-month-old female C57BL/6J mice received control or high fat diet (HFD) for 4 months. Then, the diet-induced obese (DIO) mice were distributed into four groups: DIO, DIO + DHA (15% dietary lipids replaced by a DHA-rich concentrate), DIO + EX (treadmill running), and DIO + DHA + EX up to 18 months. The DHA-rich diet reduced liver steatosis in DIO mice, decreasing lipogenic genes (Dgat2, Scd1, Srebp1c), and upregulated lipid catabolism genes (Hsl/Acox) expression. A similar pattern was observed in the DIO + EX group. The combination of DHA + exercise potentiated an increase in Cpt1a and Ppara genes, and AMPK activation, key regulators of fatty acid oxidation. Exercise, alone or in combination with DHA, significantly reversed the induction of proinflammatory genes (Mcp1, Il6, Tnfα, Tlr4) in DIO mice. DHA supplementation was effective in preventing the alterations induced by the HFD in endoplasmic reticulum stress-related genes (Ern1/Xbp1) and autophagy markers (LC3II/I ratio, p62, Atg7). In summary, long-term DHA supplementation and/or exercise could be helpful to delay NAFLD progression during aging in obesity.

Multidrug-resistant Plasmodium falciparum parasites have emerged in Cambodia and neighboring countries in Southeast Asia, compromising the efficacy of first-line antimalarial combinations. Dihydroartemisinin + piperaquine (PPQ) treatment failure rates have risen to as high as 50% in some areas in this region. For PPQ, resistance is driven primarily by a series of mutant alleles of the P. falciparum chloroquine resistance transporter (PfCRT). PPQ resistance was reported in China three decades earlier, but the molecular driver remained unknown. Herein, we identify a PPQ-resistant pfcrt allele (China C) from Yunnan Province, China, whose genotypic lineage is distinct from the PPQ-resistant pfcrt alleles currently observed in Cambodia. Combining gene editing and competitive growth assays, we report that PfCRT China C confers moderate PPQ resistance while re-sensitizing parasites to chloroquine (CQ) and incurring a fitness cost that manifests as a reduced rate of parasite growth. PPQ transport assays using purified PfCRT isoforms, combined with molecular dynamics simulations, highlight differences in drug transport kinetics and in this transporter’s central cavity conformation between China C and the current Southeast Asian PPQ-resistant isoforms. We also report a novel computational model that incorporates empirically determined fitness landscapes at varying drug concentrations, combined with antimalarial susceptibility profiles, mutation rates, and drug pharmacokinetics. Our simulations with PPQ-resistant or -sensitive parasite lines predict that a three-day regimen of PPQ combined with CQ can effectively clear infections and prevent the evolution of PfCRT variants. This work suggests that including CQ in combination therapies could be effective in suppressing the evolution of PfCRT-mediated multidrug resistance in regions where PPQ has lost efficacy.