Sirtuin 3 (SIRT3) is one of the most prominent deacetylases that can regulate acetylation levels in mitochondria, which are essential for eukaryotic life and inextricably linked to the metabolism of ...multiple organs. Hitherto, SIRT3 has been substantiated to be involved in almost all aspects of mitochondrial metabolism and homeostasis, protecting mitochondria from a variety of damage. Accumulating evidence has recently documented that SIRT3 is associated with many types of human diseases, including age-related diseases, cancer, heart disease and metabolic diseases, indicating that SIRT3 can be a potential therapeutic target. Here we focus on summarizing the intricate mechanisms of SIRT3 in human diseases, and recent notable advances in the field of small-molecule activators or inhibitors targeting SIRT3 as well as their potential therapeutic applications for future drug discovery.
Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and invading pathogens via the ...lysosomal system (the vacuole in plants and yeast). Autophagy is generally induced by stress, such as oxygen-, energy- or amino acid-deprivation, irradiation, drugs,
. In addition to non-selective bulk degradation, autophagy also occurs in a selective manner, recycling specific organelles, such as mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes and lipid droplets (LDs). This capability makes selective autophagy a major process in maintaining cellular homeostasis. The dysfunction of selective autophagy is implicated in neurodegenerative diseases (NDDs), tumorigenesis, metabolic disorders, heart failure,
. Considering the importance of selective autophagy in cell biology, we systemically review the recent advances in our understanding of this process and its regulatory mechanisms. We emphasize the 'cargo-ligand-receptor' model in selective autophagy for specific organelles or cellular components in yeast and mammals, with a focus on mitophagy and ER-phagy, which are finely described as types of selective autophagy. Additionally, we highlight unanswered questions in the field, helping readers focus on the research blind spots that need to be broken.
A combined strategy of building blocks recognition and molecular network construction, termed the building blocks‐based molecular network (BBMN), was first presented to facilitate the efficient ...discovery of novel natural products. By mapping the BBMN of the total alkaloid fraction of Flueggea suffruticosa, three Securinega alkaloids (SEAs) with unusual chemical architectures, suffranidines A–C (1–3), were discovered and isolated. Compound 1 characterizes an unprecedented 8/5/6/5/6/6/6/6‐fused octacyclic scaffold with a unique cage‐shaped 3‐azatricyclo6.4.0.03,11dodecane core. Compounds 2 and 3 are highly modified SEA dimers that incorporate additional C6 motifs. A hypothetical biosynthetic pathway for 1–3 was proposed. In addition, 1 significantly induced neuronal differentiation and neurite extension by upregulating eukaryotic elongation factor 2 (eEF2)‐mediated protein synthesis.
A building blocks‐based molecular network (BBMN) strategy was first presented and resulted in the discovery of three novel Securinega alkaloids. Compound 1 features an unprecedented 8/5/6/5/6/6/6/6‐fused octacyclic scaffold with a unique cage‐shaped 3‐azatricyclo6.4.0.03,11dodecane core, which also exhibited remarkable effects on neuronal differentiation and neurite extension.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Peroxidized phosphatidylethanolamine (PEox) species have been identified by liquid chromatography mass spectrometry (LC‐MS) as predictive biomarkers of ferroptosis, a new program of regulated cell ...death. However, the presence and subcellular distribution of PEox in specific cell types and tissues have not been directly detected by imaging protocols. By applying gas cluster ion beam secondary ion mass spectrometry (GCIB‐SIMS) imaging with a 70 keV (H2O)n+ (n>28 000) cluster ion beam, we were able to map PEox with 1.2 μm spatial resolution at the single cell/subcellular level in ferroptotic H9c2 cardiomyocytes and cortical/hippocampal neurons after traumatic brain injury. Application of this protocol affords visualization of physiologically relevant levels of very low abundance (20 pmol μmol−1 lipid) peroxidized lipids in subcellular compartments and their accumulation in disease conditions.
Gas cluster ion beam secondary ion mass spectrometry (GCIB‐SIMS) imaging with a 70 keV (H2O)n+ (n>28 000) cluster ion beam mapped peroxidized phosphatidylethanolamine (PEox) with 1.2 μm spatial resolution at the single cell/subcellular level. This visualized low abundance peroxidized lipids in ferroptotic H9c2 cardiomyocytes and cortical/hippocampal neurons after traumatic brain injury.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
•Natural Halloysite nanotubes (HNTs) exhibit tubular morphology with empty lumen.•The fast and high water-absorption makes HNTs blood components concentrator.•Rich negative charges of HNTs acutely ...trigger the intrinsic coagulation cascade.•Nanosized HNTs activate platelets via GPIIb/IIIa receptor pathway.•The better hemostasis performance of PET fibers arises from well-dispersion of HNTs.
Halloysite nanotubes (HNTs), a traditional mineral Chinese medicine, have been used to stop bleeding for thousands of years. However, the coagulation mechanisms of HNTs and their practical application potential have not been fully elucidated. In this study, HNTs were found to accelerate hemostasis via multiple dependent approaches: (i) absorbing water and concentrating blood due to their super-hydrophilicity and unique tubular nanostructure; (ii) triggering an intrinsic coagulation cascade by negatively charged surface interaction; and (iii) accelerating clot formation by activating and linking with platelets. To solve the difficulty in the application of powder, a HNT-coated polyester fiber dressing was designed by an impregnation method. The HNT coating enables the dressing to resist massive hemorrhaging of the liver and vessels, as well as epidermal bleeding. Moreover, the HNT-coated fiber dressings are not accompanied by burning or adhesion at the wound sites. In summary, this work provides profound insight into HNT hemostasis through the physical and biological interactions between HNTs and blood, which represents a promising strategy for effective prehospital treatment and civilian needs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Radiation colitis is the leading cause of diarrhea and hematochezia in pelvic radiotherapy patients. This work advances the pathogenesis of radiation colitis from the perspective of ...ferroptosis. An oral Pickering emulsion is stabilized with halloysite clay nanotubes to alleviate radiation colitis by inhibiting ferroptosis. Ceria nanozyme grown in situ on nanotubes can scavenge reactive oxygen species, and deferiprone was loaded into the lumen of nanotubes to relieve iron stress. These two strategies effectively inhibit lipid peroxidation and rescue ferroptosis in the intestinal microenvironment. The clay nanotubes play a critical role as either a medicine to alleviate colitis, a nanocarrier that targets the inflamed colon by electrostatic adsorption, or an interfacial stabilizer for emulsions. This ferroptosis-based strategy was effective in vitro and in vivo, providing a prospective candidate for radiotherapy protection via rational regulation of specific oxidative stress.
Because of their outstanding properties, increasing numbers of research studies and emerging applications for manufacturing products are currently in progress for halloysite nanotubes (HNTs). ...Therefore, the impact of HNTs on the environment and human health should be taken into consideration. In order to clearly show the cell uptake of HNTs and the biodistribution of HNTs in zebrafish, HNTs are labeled with fluorescein isothiocyanate (FITC-HNTs). The cytotoxicity assays showed that the cell viabilities of human umbilical vein endothelial cells (HUVECs) and human breast adenocarcinoma (MCF-7) cells were above 60% after being treated with different concentrations of HNTs (2.5-200 μg mL
) for 72 h. Confocal laser scanning microscopy (CLSM) results showed the uptake of HNTs by HUVECs and MCF-7 cells. The in vivo toxicity of HNTs was then investigated in the early development of zebrafish embryos. The percent survival of zebrafish embryos and larvae showed no significant changes at different developmental stages (24, 48, 72, 96, and 120 hpf) when treated with various concentrations of HNTs (0.25-10 mg mL
). Besides, HNTs could promote the hatchability of zebrafish embryos and did not affect the morphological development of zebrafish at a concentration of ≤25 mg mL
. HNTs could also be ingested by zebrafish larvae and accumulated predominantly in the gastrointestinal tract. The fluorescence intensity of FITC-HNTs decreased gradually with time, which suggested that HNTs could be excreted by zebrafish larvae through the gastrointestinal metabolism. Therefore, it can be concluded that HNTs are relatively biocompatible nanomaterials, which can be utilized in many fields.
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