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Background: Although low-level laser therapy (LLLT) is a widely used noninvasive treatment because of photobiomodulation effects, its application for xerostomia remained uncertain. Tight junctions (TJs), mainly composed of claudins, occludin, and ZO family members, are crucial structures that determine material transport through paracellular pathway in salivary gland epithelial cells. This work aimed to investigate whether LLLT affected salivary secretion through epithelial TJs. Methods: Transepithelial electrical resistance (TER) measurement and paracellular permeability assay were applied to evaluate paracellular permeability in submandibular gland (SMG)-C6 cells after irradiation with 540 nm green light. Immunofluorescence and western blot were used to detect the expression of TJ proteins. Quantitative phosphoproteomics were performed to explore possible intracellular signals. Results: We found that irradiation with 540 nm green light significantly decreased TER values while increased paracellular transport in SMG-C6 cells. 540 nm green light-induced redistribution of claudin-1, -3, and -4, but not occludin or ZO-1. Moreover, above phenomena were abolished by preincubation with capsazepine, an antagonist of transient receptor potential vanilloid subtype 1. Notably, irradiation with 540 nm green light on the skin covering the whole submandibular gland regions promoted salivary secretion and attenuated lymphocytic infiltration in 21-week-old non-obese diabetic mice (n = 5 per group), a xerostomia animal model for Sjögren's syndrome. Through in-depth bioinformatics analysis and expression verification, ERK1/2 and EphA2 served as potential canonical and noncanonical signals underlying 540 nm green light. Conclusions: Our findings uncovered the novel therapeutic effects of 540 nm green light on xerostomia through regulation on the expression and distribution of TJs.
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Enzymatically derived selenium-enriched peptides from Cardamine violifolia (CV) can serve as valuable selenium supplements. However, the industrial application of free enzyme is impeded by its limited stability and reusability. Herein, this study explores the application of co-immobilized enzymes (Alcalase and Dispase) on amino resin for hydrolyzing CV proteins to produce selenium-enriched peptides. The successful enzyme immobilization was confirmed through scanning electron microscopy (SEM), energy dispersive X-ray (EDX), and Fourier-transform infrared spectroscopy (FTIR). Co-immobilized enzyme at a mass ratio of 5:1 (Alcalase/Dispase) exhibited the smallest pore size (7.065 nm) and highest activity (41 U/mg), resulting in a high degree of hydrolysis of CV protein (27.2%), which was obviously higher than the case of using free enzymes (20.7%) or immobilized Alcalase (25.8%). In addition, after a month of storage, the co-immobilized enzyme still retained a viability level of 41.93%, showing fairly good stability. Encouragingly, the selenium-enriched peptides from co-immobilized enzyme hydrolysis exhibited uniform distribution of selenium forms, complete amino acid fractions and homogeneous distribution of molecular weight, confirming the practicality of using co-immobilized enzymes for CV protein hydrolysis.
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MAIN CONCLUSION: Genome-wide identification revealed 79 BpNAC genes belonging to 16 subfamilies, and their gene structures and evolutionary relationships were characterized. Expression analysis highlighted their importance in plant selenium stress responses. Paper mulberry (Broussonetia papyrifera), a deciduous arboreal plant of the Moraceae family, is distinguished by its leaves, which are abundant in proteins, polysaccharides, and flavonoids, positioning it as a novel feedstock. NAC transcription factors, exclusive to plant species, are crucial in regulating growth, development, and response to biotic and abiotic stress. However, extensive characterization of the NAC family within paper mulberry is lacking. In this study, 79 BpNAC genes were identified from the paper mulberry genome, with an uneven distribution across 13 chromosomes. A comprehensive, genome-wide analysis of BpNACs was performed, including investigating gene structures, promoter regions, and chromosomal locations. Phylogenetic tree analysis, alongside comparisons with Arabidopsis thaliana NACs, allowed for categorizing these genes into 16 subfamilies in alignment with gene structure and motif conservation. Collinearity analysis suggested a significant homologous relationship between the NAC genes of paper mulberry and those in Morus notabilis, Ficus hispida, Antiaris toxicaria, and Cannabis sativa. Integrating transcriptome data and Se content revealed that 12 BpNAC genes were associated with selenium biosynthesis. Subsequent RT-qPCR analysis corroborated the correlation between BpNAC59, BpNAC62 with sodium selenate, and BpNAC55 with sodium selenite. Subcellular localization experiments revealed the nuclear functions of BpNAC59 and BpNAC62. This study highlights the potential BpNAC transcription factors involved in selenium metabolism, providing a foundation for strategically breeding selenium-fortified paper mulberry.
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Broussonetia , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Selênio , Fatores de Transcrição , Arabidopsis/genética , Arabidopsis/metabolismo , Broussonetia/genética , Broussonetia/metabolismo , Genoma de Planta , Estudo de Associação Genômica Ampla , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Selênio/metabolismo , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Key Clinical Message: CHARGE syndrome is a rare genetic disorder characterized by several distinct features. The presence of fetal ear abnormalities could be the early indicator of CHARGE syndrome. Subsequent prenatal diagnosis is essential to confirm the disorder. This is significant because the patient may receive genetic counseling and appropriate disposal based on the accurate diagnosis. Abstract: CHARGE syndrome is a rare genetic disorder with multiple specific clinical features. The prenatal diagnosis is crucial but rarely achieved. We report a fetus with fetal external ear abnormality detected by ultrasound at 22nd week of gestation. Postnatal examination revealed an external ear abnormality, a mild atrial septal defect, and other clinical signs of CHARGE syndrome. A de novo pathogenic nonsense mutation in the CHD7 gene (c.406C > T, p.Q136X in exon 2) was identified to cause the disorder. Our study demonstrated that prenatal diagnosis and genetic testing were recommended to obtain a solid diagnosis of CHARGE syndrome when fetal external ear abnormality was detected by ultrasound examination.
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In this study, we investigated the protective effect of selenium (Se)-enriched peptide isolated from Cardamine violifolia (SPE) against ethanol-induced liver injury. Cell proliferation assays show that different concentrations of SPE protect human embryonic liver L-02 cells against ethanol-induced injury in a dose-dependent manner. Treatment with 12 µmol/L Se increases the cell survival rate (82.44%) and reduces the release of alanine aminotransferase, aspartate transaminase, lactate dehydrogenase, and apoptosis rate. SPE treatment with 12 µmol/L Se effectively reduces the concentration of intracellular reactive oxygen species and increases the contents of intracellular superoxide dismutase (51.64 U/mg), catalase (4.41 U/mg), glutathione peroxidase (1205.28 nmol/g), and glutathione (66.67 µmol/g), thereby inhibiting the effect of ethanol-induced oxidative damage. The results of the transcriptomic analysis show that the glutathione metabolism and apoptotic pathway play significant roles in the protection of L-02 hepatocytes by SPE. Real-time qPCR analysis shows that SPE increases the mRNA expression of GPX1 and NGFR. The results of this study highlight the protective effects of SPE against ethanol-induced liver injury.
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Oxidative stress occurs in the process of egg storage. Antioxidants as feed additives can enhance egg quality and extend the shelf life of eggs. Selenium-enriched Cardamine violifolia (SEC) has strongly antioxidant properties. The objective of this study was to assess the effects of dietary supplementation with SEC on egg quality and the yolk antioxidant capacity of eggs stored at 4 °C and 25 °C. Four hundred fifty 65-week-old, Roman hens that were similar in laying rate (90.79 ± 1.69%) and body weight (2.19 ± 0.23 kg) were divided into 5 groups. The birds were fed diets supplemented with 0 mg/kg selenium (Se) (CON), 0.3 mg/kg Se from sodium selenite (SS), 0.3 mg/kg Se from Se-enriched yeast (SEY), 0.3 mg/kg Se for selenium-enriched Cardamine violifolia (SEC) or 0.3 mg/kg Se from Se-enriched Cardamine violifolia and 0.3 mg/kg Se from Se-enriched yeast (SEC + SEY) for 8 weeks. The eggs were collected on the 8th week and were analyzed for egg quality and oxidative stability of yolk during storage at 4 °C or 25 °C for 0, 2, 4, or 6 weeks. Dietary SEC and SEC + SEY supplementation increased the Haugh unit (HU) and albumen foam stability in eggs stored at 4 °C and 25 °C (p < 0.05). SS and SEC supplementation increased the yolk index in eggs stored at 25 °C (p < 0.05). SEC or SEC + SEY slowed down an increase in albumen pH and gel firmness in eggs stored at 4 °C and 25 °C (p < 0.05). Moreover, SEC or SEC + SEY alleviated the increase in malonaldehyde (MDA), and the decrease in total antioxidant capacity (T-AOC) level and total superoxide dismutase (T-SOD) activity in yolks stored at 4 °C and 25 °C (p < 0.05). These results indicate that SEC mitigated egg quality loss and improved the antioxidant capacity of yolks during storage. SEC supplementation would be advantageous to extend the shelf life of eggs.
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Broussonetia papyrifera, a valuable feed resource, is known for its fast growth, wide adaptability, high protein content and strong selenium enrichment capacity. Selenomethionine (SeMet), the main selenium form in selenium fortification B. papyrifera, is safe for animals and this enhances its nutritional value as a feed resource. However, the molecular mechanisms underlying SeMet synthesis remain unclear. This study identified three homocysteine S-methyltransferase genes from the B. papyrifera genome. The phylogenetic tree demonstrated that BpHMTs were divided into two classes, and BpHMT2 in the Class 2-D subfamily evolved earlier and possesses more fundamental functions. On the basis of the correlation between gene expression levels and selenium content, BpHMT2 was identified as a key candidate gene associated with selenium tolerance. Subcellular localization experiments confirmed the targeting of BpHMT2 in nucleus, cell membrane and chloroplasts. Moreover, three BpHMT2 overexpression Arabidopsis thaliana lines were confirmed to enhance plant selenium tolerance and SeMet accumulation. Overall, our finding provides insights into the molecular mechanisms of selenium metabolism in B. papyrifera, highlighting the potential role of BpHMT2 in SeMet synthesis. This research contributes to our understanding of selenium-enriched feed resources, with increased SeMet content contributing to the improved nutritional value of B. papyrifera as a feed resource.
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Broussonetia , Selênio , Animais , Selênio/metabolismo , Broussonetia/genética , Broussonetia/metabolismo , Filogenia , Selenometionina/metabolismoRESUMO
Inherited cardiac arrhythmias are a group of genetic diseases predisposing to sudden cardiac arrest, mainly resulting from variants in genes encoding cardiac ion channels or proteins involved in their regulation. Currently available therapeutic options (pharmacotherapy, ablative therapy and device-based therapy) can not preclude the occurrence of arrhythmia events and/or provide complete protection. With growing understanding of the genetic background and molecular mechanisms of inherited cardiac arrhythmias, advancing insight of stem cell technology, and development of vectors and delivery strategies, gene therapy and stem cell therapy may be promising approaches for treatment of inherited cardiac arrhythmias. Recent years have witnessed impressive progress in the basic science aspects and there is a clear and urgent need to be translated into the clinical management of arrhythmic events. In this review, we present a succinct overview of gene and cell therapy strategies, and summarize the current status of gene and cell therapy. Finally, we discuss future directions for implementation of gene and cell therapy in the therapy of inherited cardiac arrhythmias.
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Arritmias Cardíacas , Morte Súbita Cardíaca , Humanos , Arritmias Cardíacas/terapia , Arritmias Cardíacas/tratamento farmacológico , Canais Iônicos/genética , Terapia Baseada em Transplante de Células e TecidosRESUMO
Inadequate Se intake can enhance vulnerability to certain health risks, with supplementation lessening these risks. This study investigated the bioavailability of Se and Se species in five Se compounds and in Se-rich Cardamine violifolia using in vitro digestion coupled with a Caco-2 cell monolayer model, which enabled the study of Se transport and uptake. Translocation results showed that SeCys2 and MeSeCys had high translocation rates in C. violifolia leaves (CVLs). The uptake rate of organic Se increased with time, and MeSeCys exhibited a higher uptake rate than that for SeCys2 and SeMet. The translocation mechanisms of SeMet, Se(IV), and Se(VI) were passive transport, whereas those of SeCys2 and MeSeCys were active transport. The bioavailability of organic Se was higher than that of inorganic Se, with a total Se bioavailability in CVLs of 49.11 %. This study would provide a theoretical basis for the application of C. violifolia in the functional food.
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Cardamine , Compostos de Selênio , Selênio , Humanos , Células CACO-2 , Disponibilidade Biológica , DigestãoRESUMO
With increased awareness of dry eye disease (DED), a multitude of therapeutic options have become available. Nevertheless, the treatment of severe DED remains difficult. In a patient whose DED is related to the loss of lacrimal function without severe destruction of the salivary glands, autologous transplantation of the latter as functioning exocrine tissue to rebuild a stable tear film is an attractive idea. All three major and minor salivary glands have been used for such transplantation. Due to the complications associated with and unfavorable prognosis of parotid duct and sublingual gland transplantation, surgeons now prefer to use the submandibular gland (SMG) for such procedures. The transplantation of the SMG not only has a high survival rate, but also improves dry eye symptoms and signs for more than 20 years post-surgery. The regulation of the secretion of the transplanted SMG is critical because the denervated SMG changes its mechanism of secretion. Innovative procedures have been developed to stimulate secretion in order to prevent the obstruction of the Wharton's duct and to decrease secretion when postoperative "epiphora" occurs. Among the minor salivary glands, the transplantation of the labial salivary glands is the most successful in the long-term. The measurement of the flow rates of minor salivary glands and donor-site selection are critical steps before surgery.
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Selenium-enriched Cardamine violifolia (SEC), a cruciferous plant, exerts excellent antioxidant and anti-inflammatory capacity, but its effect on hepatic function is unclear. This study investigated the effect and potential mechanism of SEC on hepatic injury induced by lipopolysaccharide (LPS). Twenty-four weaned piglets were randomly allotted to treatment with SEC (0.3 mg/kg Se) and/or LPS (100 µg/kg). After 28 days of the trial, pigs were injected with LPS to induce hepatic injury. These results indicated that SEC supplementation attenuated LPS-induced hepatic morphological injury and reduced aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities in plasma. SEC also inhibited the expression of pro-inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) after the LPS challenge. In addition, SEC improved hepatic antioxidant capacity via enhancing glutathione peroxidase (GSH-Px) activity and decreasing malondialdehyde (MDA) concentration. Moreover, SEC downregulated the mRNA expression of hepatic myeloid differentiation factor 88 (MyD88) and nucleotide-binding oligomerization domain proteins 1 (NOD1) and its adaptor molecule receptor interacting protein kinase 2 (RIPK2). SEC also alleviated LPS-induced hepatic necroptosis by inhibiting RIPK1, RIPK3, and mixed-lineage kinase domain-like (MLKL) expression. These data suggest that SEC potentially mitigates LPS-induced hepatic injury via inhibiting Toll-like receptor 4 (TLR4)/NOD2 and necroptosis signaling pathways in weaned piglets.
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Cardamine , Hepatopatias , Selênio , Suínos , Animais , Lipopolissacarídeos , Selênio/farmacologia , Receptor 4 Toll-Like/metabolismo , Cardamine/metabolismo , Antioxidantes/farmacologia , Necroptose , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológicoRESUMO
Tight junctions (TJs) are cell-cell interactions that localize at the most apical portion of epithelial/endothelial cells. One of the predominant functions of TJs is to regulate material transport through paracellular pathway, which serves as a selective barrier. In recent years, the expression and function of TJs in salivary glands has attracted great interest. The characteristics of multiple salivary gland TJ proteins have been identified. During salivation, the activation of muscarinic acetylcholine receptor and transient receptor potential vanilloid subtype 1, as well as other stimuli, promote the opening of acinar TJs by inducing internalization of TJs, thereby contributing to increased paracellular permeability. Besides, endothelial TJs are also redistributed with leakage of blood vessels in cholinergic-stimulated submandibular glands. Furthermore, under pathological conditions, such as Sjögren's syndrome, diabetes mellitus, immunoglobulin G4-related sialadenitis, and autotransplantation, the integrity and barrier function of TJ complex are impaired and may contribute to hyposalivation. Moreover, in submandibular glands of Sjögren's syndrome mouse model and patients, the endothelial barrier is disrupted and involved in hyposecretion and lymphocytic infiltration. These findings enrich our understanding of the secretory mechanisms that link the importance of epithelial and endothelial TJ functions to salivation under both physiological and pathophysiological conditions.
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Sialorreia , Síndrome de Sjogren , Camundongos , Animais , Humanos , Junções Íntimas/metabolismo , Junções Íntimas/patologia , Síndrome de Sjogren/patologia , Células Endoteliais , Glândulas Salivares/patologia , Saliva/metabolismo , Glândula Submandibular/metabolismoRESUMO
Aims: To investigate the effects of M-CSF on myocardial injury in mice after MI by regulating different types of cardiac macrophages through the P2X7R/NLRP3/IL-1ß signal pathway. Methods: A total of 60 C57BL/6J WT mice were used, with the Sham Group subjected to ligation without ligation through the LAD, the MI model was prepared by ligation of the LAD in the MC Group and MM Group, with the M-CSF reagent (500 µg/kg/d) being given an intraperitoneal injection for the first 5 days after surgery in the MM Group. All mice were fed in a barrier environment for 1 week. After the study, myocardial tissues were collected and IL-4, IL-6, IL-10, TNF-α, MCP-1, IFN-α, ANP, BNP, ß-MHC, Collage I, Collage III, P2X7R, NLRP3, IL-1ß, Bax, Caspase 3, C-Casp 3, Bcl-2, M1/2 macrophage, the apoptosis of cardiomyocytes, and the collagen deposition were detected. Results: The inflammatory response was significantly lower in the MM Group, the cardiomyocyte apoptosis, fibrosis, and hypertrophy were inhibited compared to the MC Group, and the levels of P2X7R, NLRP3, and IL-1ß were also statistically lower in the MM Group. Additionally, the expression of M2 macrophages increased in the MM Group while the M1 macrophages statistically decreased compared to the MC Group. Conclusion: M-CSF can significantly increase the expression of M2 macrophage and reduce the level of M1 macrophage by inhibiting the levels of NLRP3/IL-1ß-related proteins, thereby inhibiting inflammation, ameliorating reducing myocardial hypertrophy, apoptosis, and fibrosis, improve myocardial injury in mice after MI.
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To evaluate and compare the safety of four selenium supplements, namely Se-enriched peptides (SeP), yeast selenium (SeY), L-Se-methylselenocysteine (L-SeMc) and sodium selenite (Na2SeO3), the subchronic toxicity study was designed by 90-day gavage administration in Sprague-Dawley rats. The doses of SeP, SeY, L-SeMc and Na2SeO3 were 0.15, 0.30 and 0.60 mg/kg bw/day, with additional dose of 0.45 mg/kg L-SeMc (All dose calculated as Se). Symptoms like growling, hair loss and significant weight loss were found at 0.60 mg/kg of L-SeMc, but not in other groups. At the dose of 0.60 mg/kg, females in Na2SeO3, SeY and L-SeMc groups showed significant elevations in ALT and/or ALP. Pathologic manifestations such as bile duct hyperplasia and cholestasis were predominantly found in females at 0.6 mg/kg of L-SeMc and SeY groups, and in males at same dose of L-SeMc group showed marked testicular atrophy. 0.60 mg/kg of SeY and Na2SeO3, and 0.30, 0.45, 0.60 mg/kg of L-SeMc induced significant reductions in sperm motility rates, rapid movement and amount. In conclusion, the NOAEL of SeP, SeY, L-SeMc, Na2SeO3 was all 0.30 mg/kg for female, and 0.60, 0.30, 0.15 and 0.30 mg/kg for male respectively. Liver and reproductive organs are possible toxic target organs of hyper selenium.
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Selênio , Masculino , Feminino , Ratos , Animais , Ratos Sprague-Dawley , Selênio/toxicidade , Motilidade dos Espermatozoides , Suplementos Nutricionais/toxicidade , Selenito de Sódio/toxicidade , Saccharomyces cerevisiaeRESUMO
Due to its inversion-broken triple helix structure and the nature of Weyl semiconductor, 2D Tellurene (2D Te) is promising to possess a strong nonlinear optical response in the infrared region, which is rarely reported in 2D materials. Here, a giant nonlinear infrared response induced by large Berry curvature dipole (BCD) is demonstrated in the Weyl semiconductor 2D Te. Ultrahigh second-harmonic generation response is acquired from 2D Te with a large second-order nonlinear optical susceptibility (χ(2) ), which is up to 23.3 times higher than that of monolayer MoS2 in the range of 700-1500 nm. Notably, distinct from other 2D nonlinear semiconductors, χ(2) of 2D Te increases extraordinarily with increasing wavelength and reaches up to 5.58 nm V-1 at ≈2300 nm, which is the best infrared performance among the reported 2D nonlinear materials. Large χ(2) of 2D Te also enables the high-intensity sum-frequency generation with an ultralow continuous-wave (CW) pump power. Theoretical calculations reveal that the exceptional performance is attributed to the presence of large BCD located at the Weyl points of 2D Te. These results unravel a new linkage between Weyl semiconductor and strong optical nonlinear responses, rendering 2D Te a competitive candidate for highly efficient nonlinear 2D semiconductors in the infrared region.
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The interactions between charges and excitons involve complex many-body interactions at high densities. The exciton-polaron model has been adopted to understand the Fermi sea screening of charged excitons in monolayer transition metal dichalcogenides. The results provide good agreement with absorption measurements, which are dominated by dilute bright exciton responses. Here we investigate the Fermi sea dressing of spin-forbidden dark excitons in monolayer WSe2. With a Zeeman field, the valley-polarized dark excitons show distinct p-doping dependence in photoluminescence when the carriers reach a critical density. This density can be interpreted as the onset of strongly modified Fermi sea interactions and shifts with increasing exciton density. Through valley-selective excitation and dynamics measurements, we also infer an intervalley coupling between the dark trions and exciton-polarons mediated by the many-body interactions. Our results reveal the evolution of Fermi sea screening with increasing exciton density and the impacts of polaron-polaron interactions, which lay the foundation for understanding electronic correlations and many-body interactions in 2D systems.
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Diatoms are typical marine biofouling organisms that secrete extracellular polymers (EPS) to achieve strong underwater adhesion. Here, we report a diatom-inspired bionic hydrophilic polysaccharide adhesive composed of diatom biosilica (DB) and bletilla striata polysaccharide (BSP) for rapid sealing hemostasis. The hierarchical porous structure of DB with rich surface silanol groups provides a strong anchored interface effect for BSP, which can significantly enhance cross-linking density and interaction strength of the hydrophilic macromolecular network. BSP/DB adhesive offers 6 times greater mechanical strength and viscosity over BSP under different temperature conditions. The aggregation effect of DBs interface for BSP avoided the washout of BSP/DB adhesive during application in a wet environment before cross-linking occurs. This strengthened the adhesion ability of BSP/DB adhesive to biological tissue that brought out complete sealing hemostasis without blood loss in a rat liver injury model. The dry BSP/DB prepared by lyophilization inherited excellent clotting ability of BSP/DB adhesive, which could realize rapidly the cruor of anticoagulant whole blood within 1 min. The results of animal studies confirmed that dry BSP/DB exhibited superior hemostatic performance over silicate-based inorganic Quikclot, in terms of hemostatic rate, blood loss, dosage, and multiscroll wound closure.
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Here, we developed a Ca2+ modified diatom biosilica-based hemostat (DBp-Ca2+) with a full scale hierarchical porous structure (pore sizes range from micrometers to nanometers). The unique porous size in stepped arrangement of DBp-Ca2+give it selective adsorption capacity during coagulation process, resulted in rapid hemorrhage control. Based on in vitro and in vivo studies, it was confirmed that the primary micropores of DBp-Ca2+gave it high porosity to hold water (water absorption: 78.46 ± 1.12 %) and protein (protein absorption: 83.7 ± 1.33 mg/g). Its secondary mesopores to macropores could reduce of water diffusion length to accelerate blood exchange (complete within 300 ms). The tertiary stacking pores of DBp-Ca2+ could absorb platelets and erythrocytes to reduce more than 50 % of thrombosis time, and provided enough contact between Ca active site and coagulation factors for triggering clotting cascade reaction. This work not only developed a novel DBs based hemostat with efficient hemorrhage control, but also provided new insights to study procoagulant mechanism of inorganic hemostat with hierarchical porous structure from selective adsorption to rapid hemostasis.
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Diatomáceas , Humanos , Porosidade , Diatomáceas/química , Adsorção , Hemostasia , Hemorragia , Água/químicaRESUMO
To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that Gs-biased signaling, but not Gi activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-Gi, EP4-Gs, and EP4-Gi in complex with endogenous prostaglandin E2 (PGE2)or two synthetic agonists and comparing with PGE2-EP2-Gs structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the Gs/Gi transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their Gs/Gi coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for Gs/Gi coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.