Inhibiting the NLRP3 Inflammasome With MCC950 Ameliorates Isoflurane-Induced Pyroptosis and Cognitive Impairment in Aged Mice

Nod-like receptor protein 3 (NLRP3) inflammasome activation has been implicated in the pathogenesis of general anesthesia (GA)-induced neuroinflammation and cognitive impairment in aged rodents. However, the cellular basis for cognitive impairment is still not fully understood, and effective pharmacologic agents targeting the NLRP3 inflammasome during GA are lacking. This study explores the protective effects of the NLRP3 inflammasome inhibitor MCC950 on pyroptosis and cognitive impairment in aged mice exposed to isoflurane. Seventy-two 15-month-old male C57BL/6 mice were randomized to receive 2 h of 1.5% isoflurane plus 30% oxygen (O2) or 30% O2 alone, respectively. MCC950 (10 mg/kg) or vehicle was intraperitoneally administered 30 min before gas inhalation. Brain tissues were harvested for histochemical analysis and biochemical assays. Learning and memory abilities were evaluated by behavioral tests. We found that isoflurane GA caused upregulations of hippocampal NLRP3, cleaved caspase-1, interleukin-1β (IL-1β), and IL-18 and the activation of pyroptosis, which is NLRP3 inflammasome-dependent; this consequently gave rise to neuronal damage and cognitive impairment in aged mice. Interestingly, pretreatment with NLRP3 inflammasome inhibitor MCC950 not only provided a neuroprotective effect against the inflammasome activation but also ameliorated pyroptosis and cognitive impairment in aged mice exposed to isoflurane. Our data demonstrate that pyroptosis is involved in NLRP3 inflammasome-mediated isoflurane-induced cognitive impairment in aged mice and suggest that inhibiting the NLRP3 inflammasome with MCC950 may have clinically therapeutic benefits for elderly patients undertaking GA

Exogenous leucine alleviates heat stress and improves saponin synthesis in Panax notoginseng by improving antioxidant capacity and maintaining metabolic homeostasis

Panax notoginseng saponins (PNSs) are used as industrial raw materials to produce many drugs to treat cardio-cerebrovascular diseases. However, it is a heat-sensitive plant, and its large-scale artificial cultivation is impeded by high temperature stress, leading to decreases in productivity and PNSs yield. Here, we examined exogenous foliar leucine to alleviate heat stress and explored the underlying mechanism using metabolomics. The results indicated that 3 and 5 mM exogenous foliar leucine significantly alleviated heat stress in one-year- and two-year-old P. notoginseng in pots and field trials. Exogenous foliar leucine enhanced the antioxidant capacity by increasing the activities of antioxidant enzymes (POD, SOD) and the contents of antioxidant metabolites (amino acids). Moreover, exogenous foliar leucine enhanced carbohydrate metabolism, including sugars (sucrose, maltose) and TCA cycle metabolites (citric acid, aconitic acid, succinic acid and fumaric acid), in P. notoginseng leaves, stems, and fibrous roots to improve the energy supply of plants and further alleviate heat stress. Field experiments further verified that exogenous foliar leucine increased the productivity and PNSs accumulation in P. notoginseng. These results suggest that leucine application is beneficial for improving the growth and quality of P. notoginseng under heat stress. It is therefore possible to develop plant growth regulators based on leucine to improve the heat resistance of P. notoginseng and other crops

PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia

Isocitrate dehydrogenase (IDH) mutation, a known pathologic classifier, initiates metabolic reprogramming in glioma cells and has been linked to the reaction status of glioma-associated microglia/macrophages (GAMs). However, it remains unclear how IDH genotypes contribute to GAM phenotypes. Here, it is demonstrated that gliomas expressing mutant IDH determine M1-like polarization of GAMs, while archetypal IDH induces M2-like polarization. Intriguingly, IDH-mutant gliomas secrete excess cholesterol, resulting in cholesterol-rich, pro-inflammatory GAMs without altering their cholesterol biosynthesis, and simultaneously exhibiting low levels of tumoral cholesterol due to expression remodeling of cholesterol transport molecules, particularly upregulation of ABCA1 and downregulation of LDLR. Mechanistically, a miR-19a/LDLR axis-mediated novel post-transcriptional regulation of cholesterol uptake is identified, modulated by IDH mutation, and influencing tumor cell proliferation and invasion. IDH mutation-induced PERK activation enhances cholesterol export from glioma cells via the miR-19a/LDLR axis and ABCA1/APOE upregulation. Further, a synthetic PERK activator, CCT020312 is introduced, which markedly stimulates cholesterol efflux from IDH wild-type glioma cells, induces M1-like polarization of GAMs, and consequently suppresses glioma cell invasion. The findings reveal an essential role of the PERK/miR-19a/LDLR signaling pathway in orchestrating gliomal cholesterol transport and the subsequent phenotypes of GAMs, thereby highlighting a novel potential target pathway for glioma therapy

Baiji genomes reveal low genetic variability and new insights into secondary aquatic adaptations

The baiji, or Yangtze River dolphin (Lipotes vexillifer), is a flagship species for the conservation of aquatic animals and ecosystems in the Yangtze River of China; however, this species has now been recognized as functionally extinct. Here we report a high-quality draft genome and three re-sequenced genomes of L. vexillifer using Illumina short-read sequencing technology. Comparative genomic analyses reveal that cetaceans have a slow molecular clock and molecular adaptations to their aquatic lifestyle. We also find a significantly lower number of heterozygous single nucleotide polymorphisms in the baiji compared to all other mammalian genomes reported thus far. A reconstruction of the demographic history of the baiji indicates that a bottleneck occurred near the end of the last deglaciation, a time coinciding with a rapid decrease in temperature and the rise of eustatic sea level

Skeletal loading regulates breast cancer-associated osteolysis in a loading intensity-dependent fashion

Osteocytes are mechanosensitive bone cells, but little is known about their effects on tumor cells in response to mechanical stimulation. We treated breast cancer cells with osteocyte-derived conditioned medium (CM) and fluid flow-treated conditioned medium (FFCM) with 0.25 Pa and 1 Pa shear stress. Notably, CM and FFCM at 0.25 Pa induced the mesenchymal-to-epithelial transition (MET), but FFCM at 1 Pa induced the epithelial-to-mesenchymal transition (EMT). This suggested that the effects of fluid flow on conditioned media depend on flow intensity. Fluorescence resonance energy transfer (FRET)-based evaluation of Src activity and vinculin molecular force showed that osteopontin was involved in EMT and MET switching. A mouse model of tumor-induced osteolysis was tested using dynamic tibia loadings of 1, 2, and 5 N. The low 1 N loading suppressed tumor-induced osteolysis, but this beneficial effect was lost and reversed with loads at 2 and 5 N, respectively. Changing the loading intensities in vivo also led to changes in serum TGFβ levels and the composition of tumor-associated volatile organic compounds in the urine. Collectively, this study demonstrated the critical role of intensity-dependent mechanotransduction and osteopontin in tumor-osteocyte communication, indicating that a biophysical factor can tangibly alter the behaviors of tumor cells in the bone microenvironment

The enormous repetitive Antarctic krill genome reveals environmental adaptations and population insights

Antarctic krill (Euphausia superba) is Earth’smost abundant wild animal, and its enormous biomass is vital to the Southern Ocean ecosystem. Here, we report a 48.01-Gb chromosome-level Antarctic krill genome, whose large genome size appears to have resulted from inter-genic transposable element expansions. Our assembly reveals the molecular architecture of the Antarctic krill circadian clock and uncovers expanded gene families associated with molting and energy metabolism, providing insights into adaptations to the cold and highly seasonal Antarctic environment. Population-level genome re-sequencing from four geographical sites around the Antarctic continent reveals no clear population structure but highlights natural selection associated with environmental variables. An apparent drastic reduction in krill population size 10 mya and a subsequent rebound 100 thousand years ago coincides with climate change events. Our findings uncover the genomic basis of Antarctic krill adaptations to the Southern Ocean and provide valuable resources for future Antarctic research