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Cell Jun 2023Cytosolic innate immune sensors are critical for host defense and form complexes, such as inflammasomes and PANoptosomes, that induce inflammatory cell death. The sensor...
Cytosolic innate immune sensors are critical for host defense and form complexes, such as inflammasomes and PANoptosomes, that induce inflammatory cell death. The sensor NLRP12 is associated with infectious and inflammatory diseases, but its activating triggers and roles in cell death and inflammation remain unclear. Here, we discovered that NLRP12 drives inflammasome and PANoptosome activation, cell death, and inflammation in response to heme plus PAMPs or TNF. TLR2/4-mediated signaling through IRF1 induced Nlrp12 expression, which led to inflammasome formation to induce maturation of IL-1β and IL-18. The inflammasome also served as an integral component of a larger NLRP12-PANoptosome that drove inflammatory cell death through caspase-8/RIPK3. Deletion of Nlrp12 protected mice from acute kidney injury and lethality in a hemolytic model. Overall, we identified NLRP12 as an essential cytosolic sensor for heme plus PAMPs-mediated PANoptosis, inflammation, and pathology, suggesting that NLRP12 and molecules in this pathway are potential drug targets for hemolytic and inflammatory diseases.
Topics: Animals; Mice; Inflammasomes; Pathogen-Associated Molecular Pattern Molecules; Heme; Inflammation; Pyroptosis; Intracellular Signaling Peptides and Proteins
PubMed: 37267949
DOI: 10.1016/j.cell.2023.05.005 -
Annual Review of Medicine Jan 2024The porphyrias are a group of rare diseases, each resulting from a defect in a different enzymatic step of the heme biosynthetic pathway. They can be broadly divided... (Review)
Review
The porphyrias are a group of rare diseases, each resulting from a defect in a different enzymatic step of the heme biosynthetic pathway. They can be broadly divided into two categories, hepatic and erythropoietic porphyrias, depending on the primary site of accumulation of heme intermediates. These disorders are multisystemic with variable symptoms that can be encountered by physicians in any specialty. Here, we review the porphyrias and describe their clinical presentation, diagnosis, and management. We discuss novel therapies that are approved or in development. Early diagnosis is key for the appropriate management and prevention of long-term complications in these rare disorders.
Topics: Humans; Porphyrias; Heme
PubMed: 37540847
DOI: 10.1146/annurev-med-042921-123602 -
Journal of Applied Oral Science :... Jan 2019The efficacy of whitening toothpastes is questionable and controversial. Clinicians, patients and researchers have expressed concern with whitening toothpastes due to...
UNLABELLED
The efficacy of whitening toothpastes is questionable and controversial. Clinicians, patients and researchers have expressed concern with whitening toothpastes due to the risk of wearing the dental structure and the potential for disappointment if the advertised cosmetic results are not achieved.
OBJECTIVE
This study compared the whitening performance of toothpastes with different whitening technologies after initial and continued use.
MATERIAL AND METHODS
Ninety bovine incisors were stained using a concentrated solution of black tea. They were randomly distributed into 6 groups, according to the toothpaste whitening technology: activated charcoal (B&W), blue covarine (WAD), hydrogen peroxide (LWA), microbeads (Oral B 3D White Perfection - 3DW) and optimized abrasives (XW4D). They were compared to a traditional toothpaste without a whitening agent (TA - control). Specimens underwent a brushing machine with controlled pressure, time and temperature. A calibrated examiner measured the color using a VITA-Classical scale before the first brushing cycle (T0), after the first brushing cycle (TI), and after a brushing cycle that simulates continuous use (TCU). Whitening performance was evaluated by the difference of shades (ΔSGU) between T0-TI and T0-TCU timepoints, using the Kruskal-Wallis and Dunn's non-parametric test. The Wilcoxon test was used to evaluate the cumulative effect (α=0.05).
RESULTS
Statistically significant differences were observed between toothpastes in both TI and TCU (p<0.05). The time of use also had a significant effect (p<0.05).
CONCLUSION
Only WAD and 3DW showed whitening performance after the first use (TI). The greatest whitening performance after continuous use was obtained by WAD, followed by LWA and 3DW. The use of conventional toothpaste (TA) promotes no tooth whitening.
CLINICAL RELEVANCE
Microbead abrasives (3DW) and blue covarine (WAD) were the active technology tested that presented the best global tooth whitening performance.
Topics: Animals; Cattle; Charcoal; Hydrogen Peroxide; Isoindoles; Metalloporphyrins; Microspheres; Random Allocation; Reference Values; Reproducibility of Results; Surface Properties; Time Factors; Tooth; Tooth Bleaching; Tooth Bleaching Agents; Toothbrushing; Toothpastes
PubMed: 30673027
DOI: 10.1590/1678-7757-2018-0051 -
Current Opinion in Structural Biology Dec 2019Mechanisms for making and breaking the heme b cofactor (heme) are more diverse than previously expected. Biosynthetic pathways have diverged at least twice along... (Review)
Review
Mechanisms for making and breaking the heme b cofactor (heme) are more diverse than previously expected. Biosynthetic pathways have diverged at least twice along taxonomic lines, reflecting differences in membrane organization and O utilization among major groups of organisms. At least three families of heme degradases are now known, again differing in whether and how O is used by the organism and possibly the purpose for turning over the tetrapyrrole. Understanding these enzymes and pathways offers a handle for antimicrobial development and for monitoring heme use in organismal and ecological systems.
Topics: Binding Sites; Catalytic Domain; Heme; Metabolic Networks and Pathways; Models, Molecular; Molecular Conformation; Molecular Structure; Oxidation-Reduction; Protein Binding; Quantitative Structure-Activity Relationship; Sensitivity and Specificity
PubMed: 30802830
DOI: 10.1016/j.sbi.2019.01.006 -
Blood Jun 2022
Topics: Animals; Erythroid Cells; Erythropoiesis; Heme; Humans; Mice; Mice, Inbred DBA
PubMed: 35679077
DOI: 10.1182/blood.2022016341 -
Annual Review of Medicine Jan 2024Carbon monoxide (CO) poisoning leads to 50,000-100,000 emergency room visits and 1,500-2,000 deaths each year in the United States alone. Even with treatment, survivors... (Review)
Review
Carbon monoxide (CO) poisoning leads to 50,000-100,000 emergency room visits and 1,500-2,000 deaths each year in the United States alone. Even with treatment, survivors often suffer from long-term cardiac and neurocognitive deficits, highlighting a clear unmet medical need for novel therapeutic strategies that reduce morbidity and mortality associated with CO poisoning. This review examines the prevalence and impact of CO poisoning and pathophysiology in humans and highlights recent advances in therapeutic strategies that accelerate CO clearance and mitigate toxicity. We focus on recent developments of high-affinity molecules that take advantage of the uniquely strong interaction between CO and heme to selectively bind and sequester CO in preclinical models. These scavengers, which employ heme-binding scaffolds ranging from organic small molecules to hemoproteins derived from humans and potentially even microorganisms, show promise as field-deployable antidotes that may rapidly accelerate CO clearance and improve outcomes for survivors of acute CO poisoning.
Topics: Humans; United States; Carbon Monoxide Poisoning; Heme
PubMed: 37582490
DOI: 10.1146/annurev-med-052422-020045 -
Blood Sep 2021
Topics: Erythrocytes; Heme
PubMed: 34591096
DOI: 10.1182/blood.2021012875 -
Chemical Reviews Mar 2018As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive... (Review)
Review
As a result of the adaptation of life to an aerobic environment, nature has evolved a panoply of metalloproteins for oxidative metabolism and protection against reactive oxygen species. Despite the diverse structures and functions of these proteins, they share common mechanistic grounds. An open-shell transition metal like iron or copper is employed to interact with O and its derived intermediates such as hydrogen peroxide to afford a variety of metal-oxygen intermediates. These reactive intermediates, including metal-superoxo, -(hydro)peroxo, and high-valent metal-oxo species, are the basis for the various biological functions of O-utilizing metalloproteins. Collectively, these processes are called oxygen activation. Much of our understanding of the reactivity of these reactive intermediates has come from the study of heme-containing proteins and related metalloporphyrin compounds. These studies not only have deepened our understanding of various functions of heme proteins, such as O storage and transport, degradation of reactive oxygen species, redox signaling, and biological oxygenation, etc., but also have driven the development of bioinorganic chemistry and biomimetic catalysis. In this review, we survey the range of O activation processes mediated by heme proteins and model compounds with a focus on recent progress in the characterization and reactivity of important iron-oxygen intermediates. Representative reactions initiated by these reactive intermediates as well as some context from prior decades will also be presented. We will discuss the fundamental mechanistic features of these transformations and delineate the underlying structural and electronic factors that contribute to the spectrum of reactivities that has been observed in nature as well as those that have been invented using these paradigms. Given the recent developments in biocatalysis for non-natural chemistries and the renaissance of radical chemistry in organic synthesis, we envision that new enzymatic and synthetic transformations will emerge based on the radical processes mediated by metalloproteins and their synthetic analogs.
Topics: Hemeproteins; Iron; Metalloporphyrins; Models, Molecular; Oxygen; Quantum Theory; Reactive Oxygen Species
PubMed: 29286645
DOI: 10.1021/acs.chemrev.7b00373 -
Nature Chemical Biology Oct 2023Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity....
Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity. Here we show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase and directly activate the sGC-cGMP-PKG pathway without intermediacy of free NO. The NO-ferroheme species (with or without a protein carrier) efficiently relax isolated blood vessels and induce hypotension in rodents, which is greatly potentiated after the blockade of NOS activity. While free NO-induced relaxations are abolished by an NO scavenger and in the presence of red blood cells or blood plasma, a model compound, NO-ferroheme-myoglobin preserves its vasoactivity suggesting the physiological relevance of NO-ferroheme species. We conclude that NO-ferroheme behaves as a signaling entity in the vasculature.
Topics: Nitric Oxide; Erythrocytes; Heme; Signal Transduction
PubMed: 37710073
DOI: 10.1038/s41589-023-01411-5 -
Journal of Cerebral Blood Flow and... Aug 2023Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with high morbidity and mortality worldwide. We have previously shown that ferroptosis contributes to...
Spontaneous intracerebral hemorrhage (ICH) is a devastating disease with high morbidity and mortality worldwide. We have previously shown that ferroptosis contributes to neuronal loss in ICH mice. The overload of iron and dysfunction of glutathione peroxidase 4 (GPx4) promote neuronal ferroptosis post-ICH. However, how epigenetic regulatory mechanisms affect the ferroptotic neurons in ICH remains unclear. In the current study, hemin was used to induce ferroptosis in N2A and SK-N-SH neuronal cells to mimic ICH. The results showed that hemin-induced ferroptosis was accompanied by an increment of global level of trimethylation in histone 3 lysine 9 (H3K9me3) and its methyltransferase Suv39h1. Transcriptional target analyses indicated that H3K9me3 was enriched at the promoter region and gene body of transferrin receptor gene 1 () and repressed its expression upon hemin stimulation. Inhibition of H3K9me3 with inhibitor or siRNA against Suv39h1 aggravated hemin- and RSL3-induced ferroptosis by upregulating expression. Furthermore, Suv39h1-H3K9me3 mediated repression of contributes to the progression of ICH in mice. These data suggest a protective role of H3K9me3 in ferroptosis post ICH. The knowledge gained from this study will improve the understanding of epigenetic regulation in neuronal ferroptosis and shed light on future clinical research after ICH.
Topics: Mice; Animals; Ferroptosis; Hemin; Epigenesis, Genetic; Cerebral Hemorrhage; Neurons
PubMed: 36960698
DOI: 10.1177/0271678X231165653