OBJECTIVE: Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 (CYP) enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine.
METHODS: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose-adjusted plasma concentrations.
RESULTS: Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 203.8, P = .003). The dose-adjusted plasma concentrations were 69% lower in the comedication group (P = .001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P = .037) indicating therapeutically insufficient drug concentrations.
CONCLUSIONS: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole.

Glial cells provide physical and chemical support and protection for neurons and for the extracellular compartments of neural tissue through secretion of soluble factors, insoluble scaffolds, and vesicles. Additionally, glial cells have regenerative capacity by remodeling their physical microenvironment and changing physiological properties of diverse cell types in their proximity. Various types of aberrant glial and macrophage cells are associated with human diseases, disorders, and malignancy. We previously demonstrated that transmembrane protein, TMEM230 has tissue revascularization and regenerating capacity by its ability to secrete pro-angiogenic factors and metalloproteinases, inducing endothelial cell sprouting and channel formation. In healthy normal neural tissue, TMEM230 is predominantly expressed in glial and marcophate cells, suggesting a prominent role in neural tissue homeostasis. TMEM230 regulation of the endomembrane system was supported by co-expression with RNASET2 (lysosome, mitochondria, and vesicles) and STEAP family members (Golgi complex). Intracellular trafficking and extracellular secretion of glial cellular components are associated with endocytosis, exocytosis and phagocytosis mediated by motor proteins. Trafficked components include metalloproteins, metalloproteinases, glycans, and glycoconjugate processing and digesting enzymes that function in phagosomes and vesicles to regulate normal neural tissue microenvironment, homeostasis, stress response, and repair following neural tissue injury or degeneration. Aberrantly high sustained levels TMEM230 promotes metalloprotein expression, trafficking and secretion which contribute to tumor associated infiltration and hypervascularization of high tumor grade gliomas. Following injury of the central nervous or peripheral systems, transcient regulated upregulation of TMEM230 promotes tissue wound healing, remodeling and revascularization by activating glial and macrophage generated microchannels/microtubules (referred to as vascular mimicry) and blood vessel sprouting and branching. Our results support that TMEM230 may act as a master regulator of motor protein mediated trafficking and compartmentalization of a large class of metalloproteins in gliomas and gliosis.

Cytochrome bd-I from Escherichia coli belongs to the superfamily of prokaryotic bd-type oxygen reductases. It contains three hemes, b558, b595 and d, and couples oxidation of quinol by dioxygen with the generation of a proton-motive force. The enzyme exhibits resistance to various stressors and is considered as a target protein for next-generation antimicrobials. By using electronic absorption and MCD spectroscopy, this work shows that cyanide binds to heme d2+ in the isolated fully reduced cytochrome bd-I. Cyanide-induced difference absorption spectra display changes near the heme d2+ α-band, a minimum at 633 nm and a maximum around 600 nm, and a W-shaped response in the Soret region. Apparent dissociation constant (Kd) of the cyanide complex of heme d2+ is ∼0.052 M. Kinetics of cyanide binding is monophasic, indicating the presence of a single ligand binding site in the enzyme. Consistently, MCD data show that cyanide binds to heme d2+ but not to b5582+ or b5952+. This agrees with the published structural data that the enzyme\'s active site is not a di-heme site. The observed rate of binding (kobs) increases as the concentration of cyanide is increased, giving a second-order rate constant (kon) of ∼0.1 M-1 s-1.

Mitochondria are an essential intracellular organelle for medication targeting and delivery since they seem to create energy and conduct many other cellular tasks, and mitochondrial dysfunctions and malfunctions lead to many illnesses. Many initiatives have been taken to detect, diagnose, and image mitochondrial abnormalities, and to transport and accumulate medicines precisely to mitochondria, all because of special mitochondrial aspects of the pathophysiology of cancer. In addition to the negative membrane potential and paradoxical mitochondrial dynamics, they include high temperatures, high levels of reactive oxygen species, high levels of glutathione, and high temperatures. Neurodegenerative diseases represent a broad spectrum of debilitating illnesses. They are linked to the loss of certain groups of neurons based on an individual\'s physiology or anatomy. The mitochondria in a cell are generally accepted as the authority with respect to ATP production. Disruption of this system is linked to several cellular physiological issues. The development of neurodegenerative disorders has been linked to mitochondrial malfunction, according to pathophysiological studies. There seems to be substantial evidence connecting mitochondrial dysfunction and oxidative stress to the development of neurodegenerative disorders. It has been extensively observed that mitochondrial malfunction triggers autophagy, which plays a role in neurodegenerative disorders. In addition, excitotoxicity and mitochondrial dysfunction have been linked to the development of neurodegenerative disorders. The pathophysiology of neurodegenerative illnesses has been linked to increased apoptosis and necrosis, as well as mitochondrial malfunction. A variety of synthetic and natural treatments have shown efficacy in treating neurodegenerative illnesses caused by mitochondrial failure. Neurodegenerative illnesses can be effectively treated with existing drugs that target mitochondria, although their precise formulations are poorly understood. Therefore, there is an immediate need to focus on creating drug delivery methods specifically targeted at mitochondria in the treatment and diagnosis of neurodegenerative disorders.

Purple sulfur bacteria (PSB) are capable of anoxygenic photosynthesis via oxidizing reduced sulfur compounds and are considered key drivers of the sulfur cycle in a range of anoxic environments. In this study, we show that Allochromatium vinosum (a PSB species) is capable of autotrophic growth using pyrite as the electron and sulfur source. Comparative growth profile, substrate characterization, and transcriptomic sequencing data provided valuable insight into the molecular mechanisms underlying the bacterial utilization of pyrite and autotrophic growth. Specifically, the pyrite-supported cell cultures (\"py\"\') demonstrated robust but much slower growth rates and distinct patterns from their sodium sulfide-amended positive controls. Up to ~200-fold upregulation of genes encoding various c- and b-type cytochromes was observed in \"py,\" pointing to the high relevance of these molecules in scavenging and relaying electrons from pyrite to cytoplasmic metabolisms. Conversely, extensive downregulation of genes related to LH and RC complex components indicates that the electron source may have direct control over the bacterial cells\' photosynthetic activity. In terms of sulfur metabolism, genes encoding periplasmic or membrane-bound proteins (e.g., FccAB and SoxYZ) were largely upregulated, whereas those encoding cytoplasmic proteins (e.g., Dsr and Apr groups) are extensively suppressed. Other notable differentially expressed genes are related to flagella/fimbriae/pilin(+), metal efflux(+), ferrienterochelin(-), and [NiFe] hydrogenases(+). Characterization of the biologically reacted pyrite indicates the presence of polymeric sulfur. These results have, for the first time, put the interplay of PSB and transition metal sulfide chemistry under the spotlight, with the potential to advance multiple fields, including metal and sulfur biogeochemistry, bacterial extracellular electron transfer, and artificial photosynthesis.
OBJECTIVE: Microbial utilization of solid-phase substrates constitutes a critical area of focus in environmental microbiology, offering valuable insights into microbial metabolic processes and adaptability. Recent advancements in this field have profoundly deepened our knowledge of microbial physiology pertinent to these scenarios and spurred innovations in biosynthesis and energy production. Furthermore, research into interactions between microbes and solid-phase substrates has directly linked microbial activities to the surrounding mineralogical environments, thereby enhancing our understanding of the relevant biogeochemical cycles. Our study represents a significant step forward in this field by demonstrating, for the first time, the autotrophic growth of purple sulfur bacteria using insoluble pyrite (FeS2) as both the electron and sulfur source. The presented comparative growth profiles, substrate characterizations, and transcriptomic sequencing data shed light on the relationships between electron donor types, photosynthetic reaction center activities, and potential extracellular electron transfer in these organisms capable of anoxygenic photosynthesis. Furthermore, the findings of our study may provide new insights into early-Earth biogeochemical evolutions, offering valuable constraints for understanding the environmental conditions and microbial processes that shaped our planet\'s history.

Microorganisms are key players in the global biogeochemical sulfur cycle. Among them, some have garnered particular attention due to their electrical activity and ability to perform extracellular electron transfer. A growing body of research has highlighted their extensive phylogenetic and metabolic diversity, revealing their crucial roles in ecological processes. In this review, we delve into the electron transfer process between sulfate-reducing bacteria and anaerobic alkane-oxidizing archaea, which facilitates growth within syntrophic communities. Furthermore, we review the phenomenon of long-distance electron transfer and potential extracellular electron transfer in multicellular filamentous sulfur-oxidizing bacteria. These bacteria, with their vast application prospects and ecological significance, play a pivotal role in various ecological processes. Subsequently, we discuss the important role of the pili/cytochrome for electron transfer and presented cutting-edge approaches for exploring and studying electroactive microorganisms. This review provides a comprehensive overview of electroactive microorganisms participating in the biogeochemical sulfur cycle. By examining their electron transfer mechanisms, and the potential ecological and applied implications, we offer novel insights into microbial sulfur metabolism, thereby advancing applications in the development of sustainable bioelectronics materials and bioremediation technologies.

Recent genome-wide association studies have identified a missense variant p.A165T in mitochondrial amidoxime-reducing component 1 (mARC1) that is strongly associated with protection from all-cause cirrhosis and improved prognosis in nonalcoholic steatohepatitis. The precise mechanism of this protective effect is unknown. Substitution of alanine 165 with threonine is predicted to affect mARC1 protein stability and to have deleterious effects on its function. To investigate the mechanism, we have generated a knock-in mutant mARC1 A165T and a catalytically dead mutant C273A (as a control) in human hepatoma HepG2 cells, enabling characterization of protein subcellular distribution, stability, and biochemical functions of the mARC1 mutant protein expressed from its endogenous locus. Compared to WT mARC1, we found that the A165T mutant exhibits significant mislocalization outside of its traditional location anchored in the mitochondrial outer membrane and reduces protein stability, resulting in lower basal levels. We evaluated the involvement of the ubiquitin proteasome system in mARC1 A165T degradation and observed increased ubiquitination and faster degradation of the A165T variant. In addition, we have shown that HepG2 cells carrying the MTARC1 p.A165T variant exhibit lower N-reductive activity on exogenously added amidoxime substrates in vitro. The data from these biochemical and functional assays suggest a mechanism by which the MTARC1 p.A165T variant abrogates enzyme function which may contribute to its protective effect in liver disease.

Atom-transfer radical polymerization (ATRP) is a well-known technique for controlled polymer synthesis. However, the ATRP usually employed toxic heavy metal ionas as the catalyst and was susceptible to molecular oxygen, which made it should be conducted under strictly anoxic condition. Conducting ATRP under ambient and biocompatible conditions is the major challenge. In this study, cytochrome C was explored as an efficient biocatalyst for ATRP under biocompatible conditions. The cytochrome C catalyzed ATRP showed a relatively low polymer dispersity index of 1.19. More interestingly, the cytochrome C catalyzed ATRP showed superior oxygen resistance as it could be performed under aerobic conditions with high dissolved oxygen level. Further analysis suggested that the Fe(II) embed in the cytochrome C might serve as the catalytic center and methyl radical was responsible for the ATRP catalysis. This work explored new biocompatible catalyst for aerobic ATRP, which might open new dimension for practical ATRP and application of cytochrome C protein.

Geobacter sulfurreducens profoundly shapes Earth\'s biogeochemistry by discharging respiratory electrons to minerals and other microbes through filaments of a two-decades-long debated identity. Cryogenic electron microscopy has revealed filaments of redox-active cytochromes, but the same filaments have exhibited hallmarks of organic metal-like conductivity under cytochrome denaturing/inhibiting conditions. Prior structure-based calculations and kinetic analyses on multi-heme proteins are synthesized herein to propose that a minimum of ~7 cytochrome \'nanowires\' can carry the respiratory flux of a Geobacter cell, which is known to express somewhat more (≥20) filaments to increase the likelihood of productive contacts. By contrast, prior electrical and spectroscopic structural characterizations are argued to be physiologically irrelevant or physically implausible for the known cytochrome filaments because of experimental artifacts and sample impurities. This perspective clarifies our mechanistic understanding of physiological metal-microbe interactions and advances synthetic biology efforts to optimize those interactions for bioremediation and energy or chemical production.

The unmarked potential drug molecule azamulin has been found to be a specific inhibitor of CYP3A4 and CYP3A5 in recent years, but this molecule also shows different binding ability and affinity to the two CYP3A isoforms. In order to explore the microscopic mechanism, conventional molecular dynamics (MD) simulation methods were performed to study the dynamic interactions between two isoforms and azamulin. The simulation results show that the binding of the ligand leads to different structural properties of two CYP3A proteins. First of all, compared with apo-CYP3A4, the binding of the ligand azamulin can lead to changes in the structural flexibility of CYP3A4, i.e., holo-CYP3A4 is more flexible than apo-CYP3A4. The structural changes of CYP3A5 are just the opposite. The ligand binding increases the rigidity of CYP3A5. Furthermore, the representative structures of the production phase in the MD simulation were in details analyzed to obtain the microscopic interactions between the ligand azamulin and two CYP3A isoforms at the atomic level. It is speculated that the difference of composition and interaction of the active sites is the fundamental cause of the change of structural properties of the two proteins.Communicated by Ramaswamy H. Sarma.