During cancer therapy, phagocytic clearance of dead cells plays a vital role in immune homeostasis. The nonapoptotic form of cell death, ferroptosis, exhibits extraordinary potential in tumor ...treatment. However, the phagocytosis mechanism that regulates the engulfment of ferroptotic cells remains unclear. Here, we establish a novel pathway for phagocytic clearance of ferroptotic cells that is different from canonical mechanisms by using diverse ferroptosis models evoked by GPX4 dysfunction/deficiency. We identified the oxidized phospholipid, 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH), as a key eat-me signal on the ferroptotic cell surface. Enriching the plasma membrane with SAPE-OOH increased the efficiency of phagocytosis of ferroptotic cells by macrophage, a process that was suppressed by lipoprotein-associated phospholipase A
. Ligand fishing, lipid blotting, and cellular thermal shift assay screened and identified TLR2 as a membrane receptor that directly recognized SAPE-OOH, which was further confirmed by TLR2 inhibitors and gene silencing studies. A mouse mammary tumor model of ferroptosis verified SAPE-OOH and TLR2 as critical players in the clearance of ferroptotic cells in vivo. Taken together, this work demonstrates that SAPE-OOH on ferroptotic cell surface acts as an eat-me signal and navigates phagocytosis by targeting TLR2 on macrophages.
Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of ...15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2β (iPLA2β, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2β averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson’s disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2β expression and a PD-relevant phenotype. Thus, iPLA2β is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.Ca2+-independent phospholipase A2β cleaves an oxidized form of phosphatidylethanolamine (PE) involved in ferroptosis such that increases in PE sensitize cells to ferroptosis. A mutant allele of the enzyme links neurodegeneration and ferroptosis.
Breast cancer is the second cause of cancer mortality in women globally. Early detection, treatment, and metastasis monitoring are of great importance to favorable prognosis. Although conventional ...diagnostic methods, such as breast X-ray mammography and image positioning biopsy, are accurate, they could cause radioactive or invasive damage to patients. Liquid biopsy as a noninvasive method is convenient for repeated sampling in clinical cancer prognostic, metastatic evaluation, and relapse monitoring. MicroRNAs encased in exosomes circulating in biofluids are promising candidate cancer biomarkers because of their cancer-specific expression profiles. Here, we report an in situ detection of microRNA-1246 (miR-1246) in human plasma exosomes as breast cancer biomarker by a nucleic acid functionalized Au nanoflare probe. Needing neither time-consuming and costly isolation of exosomes from the plasma sample nor transfection means, the Au nanoflare probe can directly enter the plasma exosomes to generate fluorescent signal quantitatively by specifically targeting miR-1246. Only 40 μL of plasma is needed to incubate 4 h with the probe, giving signal sensitive enough to distinguish samples of breast cancer to normal control. Using plasma miR-1246 level detected by our assay as a marker, we differentiated 46 breast cancer patients from 28 healthy controls with 100% sensitivity and 92.9% specificity at the best cutoff. This simple, accurate, sensitive, and cost-effective liquid biopsy by the Au nanoflare probe is potent to be developed as a noninvasive breast cancer diagnostic assay for clinical adaption.
Caffeine is a major component of xanthine alkaloids and commonly consumed in many popular beverages. Due to its occasional side effects, reduction of caffeine in a natural way is of great importance ...and economic significance. Recent studies reveal that caffeine can be converted into non-stimulatory theacrine in the rare tea plant Camellia assamica var. kucha (Kucha), which involves oxidation at the C8 and methylation at the N9 positions of caffeine. However, the underlying molecular mechanism remains unclear. Here, we identify the theacrine synthase CkTcS from Kucha, which possesses novel N9-methyltransferase activity using 1,3,7-trimethyluric acid but not caffeine as a substrate, confirming that C8 oxidation takes place prior to N9-methylation. The crystal structure of the CkTcS complex reveals the key residues that are required for the N9-methylation, providing insights into how caffeine N-methyltransferases in tea plants have evolved to catalyze regioselective N-methylation through fine tuning of their active sites. These results may guide the future development of decaffeinated drinks.
Herpes simplex virus type 1 (HSV-1) is the most common virus, with an estimated infection rate of 60⁻95% among the adult population. Once infected, HSV-1 can remain latent in the host for a lifetime ...and be reactivated in patients with a compromised immune system. Reactivation of latent HSV-1 can also be achieved by other stimuli. Though acyclovir (ACV) is a classic drug for HSV-1 infection, ACV-resistant strains have been found in immune-compromised patients and drug toxicity has also been commonly reported. Therefore, there is an urge to search for new anti-HSV-1 agents. Natural products with potential anti-HSV-1 activity have the advantages of minimal side effects, reduced toxicity, and they exert their effect by various mechanisms. This paper will not only provide a reference for the safe dose of these agents if they are to be used in humans, referring to the interrelated data obtained from in vitro experiments, but also introduce the main pharmacodynamic mechanisms of traditional Chinese medicine (TCM) against HSV-1. Taken together, TCM functions as a potential source for HSV-1 therapy by direct (blocking viral attachment/absorption/penetration/replication) or indirect (reducing the susceptibility to HSV-1 or regulating autophagy) antiviral activities. The potential of these active components in the development of anti-HSV-1 drugs will also be described.
Microbial biogeography has predominantly been studied through a taxonomic lens. However, functional properties of microbial communities are often decoupled from their taxonomic compositions, ...emphasizing the need to study the biogeography of microbial functional genes directly.
Here, using the Pearl River Estuary (PRE) sediments as a study system, we characterized the biogeographical patterns of the diversities and abundances of key microbial nitrogen‐cycling genes using metagenomic techniques.
We found that functional genes involved in denitrification and dissimilatory nitrate reduction to ammonium pathways were more diverse and abundant than genes involved in other processes (i.e. nitrogen fixation, nitrification, assimilatory nitrite reduction). The diversities and abundances of certain nitrogen‐cycling genes were, to some extent, spatially decoupled. Specifically, the diversities of narG, napA, nirK and nrfA were greater adjacent to the river outlet, whereas the abundances of narG, napA and norB were greater in the downstream of the PRE. These spatial variations were mainly driven by water depth, C/N and NH4+.
Moreover, nitrogen‐cycling genes involved in the same pathways (e.g. denitrification) showed no consistent responses to environmental changes and the main taxa involved in different nitrogen‐cycling steps were diverse, providing important clues for explaining why the abundance of single functional gene often seems not to be a reliable proxy for the specific process rate. Overall, our results demonstrate that studying the biogeography of microbial functional genes can help expand our knowledge of the nitrogen cycle from a biogeographical perspective.
A free Plain Language Summary can be found within the Supporting Information of this article.
A free Plain Language Summary can be found within the Supporting Information of this article.
Viral-encoded auxiliary metabolic genes (AMGs) are important toolkits for modulating their hosts' metabolisms and the microbial-driven biogeochemical cycles. Although the functions of AMGs have been ...extensively reported in numerous environments, we still know little about the drivers that shape the viral community-wide AMG compositions in natural ecosystems. Exploring the drivers of viral community-wide AMG compositions is critical for a deeper understanding of the complex interplays among viruses, hosts, and the environments.
Here, we investigated the impact of viral lifestyles (i.e., lytic and lysogenic), habitats (i.e., water, particle, and sediment), and prokaryotic hosts on viral AMG profiles by utilizing metagenomic and metatranscriptomic techniques. We found that viral lifestyles were the most important drivers, followed by habitats and host identities. Specifically, irrespective of what habitats viruses came from, lytic viruses exhibited greater AMG diversity and tended to encode AMGs for chaperone biosynthesis, signaling proteins, and lipid metabolism, which could boost progeny reproduction, whereas temperate viruses were apt to encode AMGs for host survivability. Moreover, the lytic and temperate viral communities tended to mediate the microbial-driven biogeochemical cycles, especially nitrogen metabolism, in different manners via AMGs. When focusing on each lifestyle, we further found clear dissimilarity in AMG compositions between water and sediment, as well the divergent AMGs encoded by viruses infecting different host orders.
Overall, our study provides a first systematic characterization of the drivers of viral community-wide AMG compositions and further expands our knowledge of the distinct interactions of lytic and temperate viruses with their prokaryotic hosts from an AMG perspective, which is critical for understanding virus-host-environment interactions in natural conditions. Video Abstract.
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder associated with
α
‐synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that psychological stress ...promotes PD progression by enhancing glucocorticoids‐related oxidative damage, however, the mechanisms involved are unknown. The present study demonstrated that plasma membrane phospholipid peroxides, as determined by phospholipidomics, triggered ferroptosis in dopaminergic neurons, which in turn contributed to stress exacerbated PD‐like motor disorder in mice overexpressing mutant human
α
‐synuclein. Using hormonomics, we identified that stress stimulated corticosteroid release and promoted 15‐lipoxygenase‐1 (ALOX15)‐mediated phospholipid peroxidation. ALOX15 was upregulated by
α
‐synuclein overexpression and acted as a fundamental risk factor in the development of chronic stress‐induced parkinsonism and neurodegeneration. Further, we demonstrated the mechanism by which corticosteroids activated the PKC pathway and induced phosphatidylethanolamine‐binding protein‐1 (PEBP1) to form a complex with ALOX15, thereby facilitating ALOX15 to locate on the plasma membrane phospholipids. A natural product isolated from herbs, leonurine, was screened with activities of inhibiting the ALOX15/PEBP1 interaction and thereby attenuating membrane phospholipid peroxidation. Collectively, our findings demonstrate that stress increases the susceptibility of PD by driving membrane lipid peroxidation of dopaminergic neurons and suggest the ALOX15/PEBP1 complex as a potential intervention target.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual loss of midbrain dopaminergic neurons in association with aggregation of α-synuclein. Oxidative damage has been ...widely implicated in this disease, though the mechanisms involved remain elusive. Here, we demonstrated that preferential accumulation of peroxidized phospholipids and loss of the antioxidant enzyme glutathione peroxidase 4 (GPX4) were responsible for vulnerability of midbrain dopaminergic neurons and progressive motor dysfunctions in a mouse model of PD. We also established a mechanism wherein iron-induced dopamine oxidation modified GPX4, thereby rendering it amenable to degradation via the ubiquitin-proteasome pathway. In conclusion, this study unraveled what we believe to be a novel pathway for dopaminergic neuron degeneration during PD pathogenesis, driven by dopamine-induced loss of antioxidant GPX4 activity.
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