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Journal of Xenobiotics May 2024Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome... (Review)
Review
Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome P450 enzymes (CYP)s. These enzymes form a superfamily of membrane-bound hemoproteins that metabolize a wide variety of physiological, dietary, environmental, and pharmacological compounds. Modulation of CYP activity impacts the detoxification of xenobiotics as well as endogenous pathways such as steroid and fatty acid metabolism, thus playing a central role in homeostasis. This review is focused on nine main topics that include the most relevant aspects of past and current PGRMC1 research, focusing on its role in CYP-mediated drug metabolism. Firstly, a general overview of the main aspects of xenobiotic metabolism is presented (I), followed by an overview of the role of the CYP enzymatic complex (IIa), a section on human disorders associated with defects in CYP enzyme complex activity (IIb), and a brief account of cytochrome (cyt )'s effect on CYP activity (IIc). Subsequently, we present a background overview of the history of the molecular characterization of PGRMC1 (III), regarding its structure, expression, and intracellular location (IIIa), and its heme-binding capability and dimerization (IIIb). The next section reflects the different effects PGRMC1 may have on CYP activity (IV), presenting a description of studies on the direct effects on CYP activity (IVa), and a summary of pathways in which PGRMC1's involvement may indirectly affect CYP activity (IVb). The last section of the review is focused on the current challenges of research on the effect of PGRMC1 on CYP activity (V), presenting some future perspectives of research in the field (VI).
PubMed: 38804287
DOI: 10.3390/jox14020034 -
Pulmonary Circulation Apr 2024Pulmonary hypertension in sickle cell disease (SCD) is a complex phenomenon resulting from multiple overlapping etiologies, including pulmonary vasoconstriction in the...
Pulmonary hypertension in sickle cell disease (SCD) is a complex phenomenon resulting from multiple overlapping etiologies, including pulmonary vasoconstriction in the setting of chronic hemolytic anemia, diastolic dysfunction, and chronic thromboembolic disease. The presence of pulmonary hypertension of any cause in SCD confers a significant increase in mortality risk. Evidence to guide the management of patients with sickle cell disease and chronic thromboembolic pulmonary hypertension (CTEPH) is scant and largely the realm of case reports and small case series. Centered on a discussion of a complex young patient with hemoglobin hemoglobin SC who ultimately underwent treatment with pulmonary thromboendarterectomy, we review the available literature to guide management and discuss and overview of treatment of CTEPH in SCD, considering the unique considerations and challenges facing patients suffering from this multisystem disease.
PubMed: 38803827
DOI: 10.1002/pul2.12362 -
Life Science Alliance Aug 2024Cancer cells exhibit a metabolic phenotype termed “porphyrin overdrive,” characterized by dysregulated heme metabolic pathways for intermediate accumulation. This...
Cancer cells exhibit a metabolic phenotype termed “porphyrin overdrive,” characterized by dysregulated heme metabolic pathways for intermediate accumulation. This rewiring is cancer-essential and cancer-specific. Targeting this vulnerability with a “bait-and-kill” strategy shows promise in eradicating malignant cells.
PubMed: 38803226
DOI: 10.26508/lsa.202402816 -
Animal Nutrition (Zhongguo Xu Mu Shou... Jun 2024This study was to evaluate the effect of supplementing the diet of broilers with leaf extract (NCLE) on meat quality by evaluating antioxidant parameters and the...
This study was to evaluate the effect of supplementing the diet of broilers with leaf extract (NCLE) on meat quality by evaluating antioxidant parameters and the expression of genes in the p38 mitogen-activated protein kinase/nuclear factor-erythroid 2-related factor 2/antioxidant responsive element (p38 MAPK/Nrf2/ARE) signaling pathway, coupled with LC-MS-based metabolomic analysis. A total of 480 one-day-old male broilers were randomly allocated to four treatment groups-a control (CON) group, which was fed a basal diet, and three NCLE treatment groups, which were fed the basal diet supplemented with 100, 200, or 400 mg/kg NCLE (N1, N2, and N3 groups, respectively) for 42 d. Compared with the CON group, meat quality was improved in the N2 and N3 groups, as evidenced by the higher pH ( < 0.05) and lower shear force ( < 0.05) in breast muscle (BM) and lower drip loss at 48 h ( < 0.05) in leg muscle (LM). Moreover, BM antioxidant capacity was significantly enhanced in the N3 group, characterized by an increase in the total antioxidant capacity (T-AOC), the concentrations of glutathione peroxidase (GSH-Px) and catalase (CAT), and the relative mRNA expression of , extracellular-signal regulated kinase (), c-Jun N-terminal kinase (), , , and ( < 0.05). Similarly, LM in the N3 group displayed higher T-AOC, increased GSH-Px and CAT concentrations, reduced malonaldehyde contents ( < 0.05), and upregulation of the relative mRNA levels of , , heme oxygenase, , and superoxide dismutase () ( < 0.05). Metabolomics analysis revealed that D-arabinono-1,4-lactone and lyso-PAF C-16-d4 were negatively correlated with shear force and cooking loss ( < 0.05) and displayed increased abundance in BM of the N3 group. L-Serine levels were upregulated while D-fructose 1,6-diphosphate contents were downregulated in the three NCLE groups. Finally, the differential metabolites in both BM and LM were involved in amino acid metabolism pathways. Our results indicated that NCLE supplementation improved meat quality by enhancing antioxidant enzyme activities, promoting the expression of genes in the p38 MAPK/Nrf2/ARE signaling pathway, and regulating amino acid metabolism. The optimal NCLE concentration was found to be 400 mg/kg.
PubMed: 38800732
DOI: 10.1016/j.aninu.2024.01.011 -
Nutrition and Metabolic Insights 20246-Hydroxydopamine (6-OHDA) is a classic neurotoxin that has been widely used in Parkinson's disease research. 6-OHDA can increase intracellular reactive oxygen species...
6-Hydroxydopamine (6-OHDA) is a classic neurotoxin that has been widely used in Parkinson's disease research. 6-OHDA can increase intracellular reactive oxygen species (ROS) and can cause cell damage, which can be attenuated with (-)-Epigallocatechin-3-gallate (EGCG) treatment. However, the mechanism by which EGCG alters the 6-OHDA toxicity remains unclear; In this study, we found 6-OHDA (25 μM) alone increased intracellular ROS concentration in N27 cells, which was attenuated by pretreating with EGCG (100 μM). We evaluated the intracellular oxidative damage by determining the level of thiobarbituric acid reactive substances (TBARS) and protein carbonyl content. 6-OHDA significantly increased TBARS by 82.7% ( < .05) and protein carbonyl content by 47.8 ( < .05), compared to the control. Pretreatment of EGCG decreased TBARS and protein carbonyls by 36.4% ( < .001) and 27.7% ( < .05), respectively, compared to 6-OHDA alone treatment. Antioxidant effect was tested with E2-related factor 2 (Nrf2), heme oxygenase-1(HO-1) and peroxisome-proliferator activator receptor γ (PPARγ) expression. 6-OHDA increased Nrf2 expression by 69.6% ( < .001), HO-1 by 173.3% ( < .001), and PPARγ by 122.7% ( < .001), compared with untreatment. EGCG pretreatment stabilized these alterations induced by 6-OHDA. Our results suggested that the neurotoxicity of 6-OHDA in N27 cells was associated with ROS pathway, whereas pretreatment of EGCG suppressed the ROS generation and deactivated the Nrf2/HO-1 and PPARγ expression.
PubMed: 38800717
DOI: 10.1177/11786388241253436 -
Heliyon May 2024Continued widespread use of antibiotics, especially fluoroquinolones, raises environmental concerns, as its driving bacterial resistance and disrupts microbial...
Continued widespread use of antibiotics, especially fluoroquinolones, raises environmental concerns, as its driving bacterial resistance and disrupts microbial ecosystems. Here we investigate the biodegradation of ten fluoroquinolone antibiotics (six for medical use and four for veterinary use) by ligninolytic fungi, including , , , , , , , , and . The results show significant variations between strains in the efficiency of antibiotic transformation. and were the fungi that most efficiently reduced antibiotic concentrations and were able to totally degrade eight and six antibiotics, respectively, within a 15-day period. and also showed the ability to effectively degrade antibiotics. Specifically degraded six out of the ten fluoroquinolone antibiotics by more than 70 %, while degraded the tested antibiotics between 43 % and 100 %. The remaining antibiotic activity did not always correlate with a reduction in antibiotic concentrations, which points to the presence of post-transformation antimicrobial metabolites. This study also explores the potential mechanisms used by these fungi to remove selected models of fluroquinolones via enzymatic routes, such as oxidation by laccases, heme-peroxidases, and cytochrome P450, or via adsorption on fungal biomass.
PubMed: 38799738
DOI: 10.1016/j.heliyon.2024.e30611 -
Frontiers in Public Health 2024Nanoplastics, an emerging form of pollution, are easily consumed by organisms and pose a significant threat to biological functions due to their size, expansive surface...
BACKGROUND
Nanoplastics, an emerging form of pollution, are easily consumed by organisms and pose a significant threat to biological functions due to their size, expansive surface area, and potent ability to penetrate biological systems. Recent findings indicate an increasing presence of airborne nanoplastics in atmospheric samples, such as polystyrene (PS), raising concerns about potential risks to the human respiratory system.
METHODS
This study investigates the impact of 800 nm diameter-PS nanoparticles (PS-NPs) on A549, a human lung adenocarcinoma cell line, examining cell viability, redox balance, senescence, apoptosis, and internalization. We also analyzed the expression of hallmark genes of these processes.
RESULTS
We demonstrated that PS-NPs of 800 nm in diameter significantly affected cell viability, inducing oxidative stress, cellular senescence, and apoptosis. PS-NPs also penetrated the cytoplasm of A549 cells. These nanoparticles triggered the transcription of genes comprised in the antioxidant network [SOD1 (protein name: superoxide dismutase 1, soluble), SOD2 (protein name: superoxide dismutase 2, mitochondrial), CAT (protein name: catalase), Gpx1 (protein name: glutathione peroxidase 1), and HMOX1 (protein name: heme oxygenase 1)], senescence-associated secretory phenotype [Cdkn1a (protein name: cyclin-dependent kinase inhibitor 1A), IL1A (protein name: interleukin 1 alpha), IL1B (protein name: interleukin 1 beta), IL6 (protein name: interleukin 6), and CXCL8 (protein name: C-X-C motif chemokine ligand 8)], and others involved in the apoptosis modulation [BAX (protein name: Bcl2 associated X, apoptosis regulator), CASP3 (protein name: caspase 3), and BCL2 (protein name: Bcl2, apoptosis regulator)].
CONCLUSION
Collectively, this investigation underscores the importance of concentration (dose-dependent effect) and exposure duration as pivotal factors in assessing the toxic effects of PS-NPs on alveolar epithelial cells. Greater attention needs to be directed toward comprehending the risks of cancer development associated with air pollution and the ensuing environmental toxicological impacts on humans and other terrestrial mammals.
Topics: Humans; Oxidative Stress; Apoptosis; Polystyrenes; Cellular Senescence; A549 Cells; Nanoparticles; Alveolar Epithelial Cells; Cell Survival; Microplastics
PubMed: 38799687
DOI: 10.3389/fpubh.2024.1385387 -
ACS Central Science May 2024Advances in genome sequencing and bioinformatics methods have identified a myriad of biosynthetic gene clusters (BGCs) encoding uncharacterized molecules. By mining...
Advances in genome sequencing and bioinformatics methods have identified a myriad of biosynthetic gene clusters (BGCs) encoding uncharacterized molecules. By mining genomes for BGCs containing a prevalent peptide-binding domain used for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), we uncovered a new compound class involving modifications installed by a cytochrome P450, a multinuclear iron-dependent non-heme oxidative enzyme (MNIO, formerly DUF692), a cobalamin- and radical -adenosyl-l-methionine-dependent enzyme (B12-rSAM), and a methyltransferase. All enzymes were functionally expressed in sp. FERM BP-3421. Structural characterization demonstrated that the P450 enzyme catalyzed the formation of a biaryl C-C cross-link between two Tyr residues with the B12-rSAM generating β-methyltyrosine. The MNIO transformed a C-terminal Asp residue into aminopyruvic acid, while the methyltransferase acted on the β-carbon of this α-keto acid. Exciton-coupled circular dichroism spectroscopy and microcrystal electron diffraction (MicroED) were used to elucidate the stereochemical configuration of the atropisomer formed upon biaryl cross-linking. To the best of our knowledge, the MNIO featured in this pathway is the first to modify a residue other than Cys. This study underscores the utility of genome mining to isolate new macrocyclic RiPPs biosynthesized via previously undiscovered enzyme chemistry.
PubMed: 38799663
DOI: 10.1021/acscentsci.4c00088 -
Clinical Case Reports Jun 2024Heme oxygenase deficiency, a rare condition disrupting heme metabolism, has only nine reported cases. We present a 3-year-old boy with dysmorphic facies, asplenia, and...
Heme oxygenase deficiency, a rare condition disrupting heme metabolism, has only nine reported cases. We present a 3-year-old boy with dysmorphic facies, asplenia, and normal bilirubin levels despite ongoing hemolysis. Blood transfusions sustained hemoglobin while IV steroids managed inflammation.
PubMed: 38799538
DOI: 10.1002/ccr3.8986 -
Journal of Clinical Biochemistry and... May 2024Photodynamic therapy (PDT) is useful for various cancers such as high-grade glioma and cancers of other organs. However, the mechanism of tumor-specific accumulation of...
Photodynamic therapy (PDT) is useful for various cancers such as high-grade glioma and cancers of other organs. However, the mechanism of tumor-specific accumulation of porphyrin is not clear. The authors previously reported that heme carrier protein 1 (HCP1) contributes to the transport of porphyrins; specifically, we showed that the production of cancer-specific reactive oxygen species from mitochondria (mitROS) leads in turn to enhanced HCP1 expression. Indomethacin (IND), a non-steroidal anti-inflammatory drug, increases ROS production by affecting mitochondrial electron transfer system. In the present work, the authors investigated the effect of pretreatment with IND on cancer-specific porphyrin accumulation, using both a glioma cell line and a rat brain tumor model. This work demonstrated that exposure of a rat glioma cell to IND results in increased generation of cancer-specific mitROS and accumulation of HCP1 expression and porphyrin concentration. Additionally, systemic dosing of a brain tumor animal model with IND resulted in elevated cellular accumulation of porphyrin in tumor cell. This is an effect not seen with normal brain tissue. Thus, the administration of IND increases intracellular porphyrin concentrations in tumor cell without exerting harmful effects on normal brain tissue, and increased porphyrin concentration in tumor cell may lead to improved PDT effect.
PubMed: 38799142
DOI: 10.3164/jcbn.23-20