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1.
Cell ; 2024 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-39389057

RESUMEN

Current metagenomic tools can fail to identify highly divergent RNA viruses. We developed a deep learning algorithm, termed LucaProt, to discover highly divergent RNA-dependent RNA polymerase (RdRP) sequences in 10,487 metatranscriptomes generated from diverse global ecosystems. LucaProt integrates both sequence and predicted structural information, enabling the accurate detection of RdRP sequences. Using this approach, we identified 161,979 potential RNA virus species and 180 RNA virus supergroups, including many previously poorly studied groups, as well as RNA virus genomes of exceptional length (up to 47,250 nucleotides) and genomic complexity. A subset of these novel RNA viruses was confirmed by RT-PCR and RNA/DNA sequencing. Newly discovered RNA viruses were present in diverse environments, including air, hot springs, and hydrothermal vents, with virus diversity and abundance varying substantially among ecosystems. This study advances virus discovery, highlights the scale of the virosphere, and provides computational tools to better document the global RNA virome.

2.
Nature ; 604(7907): 771-778, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35418677

RESUMEN

Adhesion G protein-coupled receptors (aGPCRs) constitute an evolutionarily ancient family of receptors that often undergo autoproteolysis to produce α and ß subunits1-3. A tethered agonism mediated by the 'Stachel sequence' of the ß subunit has been proposed to have central roles in aGPCR activation4-6. Here we present three cryo-electron microscopy structures of aGPCRs coupled to the Gs heterotrimer. Two of these aGPCRs are activated by tethered Stachel sequences-the ADGRG2-ß-Gs complex and the ADGRG4-ß-Gs complex (in which ß indicates the ß subunit of the aGPCR)-and the other is the full-length ADGRG2 in complex with the exogenous ADGRG2 Stachel-sequence-derived peptide agonist IP15 (ADGRG2(FL)-IP15-Gs). The Stachel sequences of both ADGRG2-ß and ADGRG4-ß assume a U shape and insert deeply into the seven-transmembrane bundles. Constituting the FXφφφXφ motif (in which φ represents a hydrophobic residue), five residues of ADGRG2-ß or ADGRG4-ß extend like fingers to mediate binding to the seven-transmembrane domain and activation of the receptor. The structure of the ADGRG2(FL)-IP15-Gs complex reveals the structural basis for the improved binding affinity of IP15 compared with VPM-p15 and indicates that rational design of peptidic agonists could be achieved by exploiting aGPCR-ß structures. By converting the 'finger residues' to acidic residues, we develop a method to generate peptidic antagonists towards several aGPCRs. Collectively, our study provides structural and biochemical insights into the tethered activation mechanism of aGPCRs.


Asunto(s)
Péptidos , Receptores Acoplados a Proteínas G , Microscopía por Crioelectrón , Humanos , Péptidos/metabolismo , Dominios Proteicos , Receptores Acoplados a Proteínas G/metabolismo
3.
Nature ; 589(7843): 620-626, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33408414

RESUMEN

Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available1-3. Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97)4-6, a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97-Go complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the 'toggle switch' residue W6.53, which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the Go protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the Go protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling.


Asunto(s)
Microscopía por Crioelectrón , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/química , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Glucocorticoides/química , Glucocorticoides/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/ultraestructura , Sitios de Unión , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/ultraestructura , Humanos , Ligandos , Lipoilación , Modelos Moleculares , Unión Proteica , Receptores Acoplados a Proteínas G/metabolismo
4.
Nat Chem Biol ; 20(4): 484-492, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37945893

RESUMEN

GPR101 is an orphan G protein-coupled receptor actively participating in energy homeostasis. Here we report the cryo-electron microscopy structure of GPR101 constitutively coupled to Gs heterotrimer, which reveals unique features of GPR101, including the interaction of extracellular loop 2 within the 7TM bundle, a hydrophobic chain packing-mediated activation mechanism and the structural basis of disease-related mutants. Importantly, a side pocket is identified in GPR101 that facilitates in silico screening to identify four small-molecule agonists, including AA-14. The structure of AA-14-GPR101-Gs provides direct evidence of the AA-14 binding at the side pocket. Functionally, AA-14 partially restores the functions of GH/IGF-1 axis and exhibits several rejuvenating effects in wild-type mice, which are abrogated in Gpr101-deficient mice. In summary, we provide a structural basis for the constitutive activity of GPR101. The structure-facilitated identification of GPR101 agonists and functional analysis suggest that targeting this orphan receptor has rejuvenating potential.


Asunto(s)
Receptores Acoplados a Proteínas G , Ratones , Animales , Microscopía por Crioelectrón , Receptores Acoplados a Proteínas G/metabolismo , Ligandos
5.
Proc Natl Acad Sci U S A ; 120(30): e2216329120, 2023 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-37478163

RESUMEN

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.


Asunto(s)
Dinoprostona , Transducción de Señal , Dinoprostona/metabolismo , Transducción de Señal/fisiología , Receptores de Prostaglandina/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Hormonas , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP3 de Receptores de Prostaglandina E/metabolismo
6.
Proc Natl Acad Sci U S A ; 119(15): e2117004119, 2022 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-35394864

RESUMEN

GPR126 is a member of the adhesion G protein-coupled receptors (aGPCRs) that is essential for the normal development of diverse tissues, and its mutations are implicated in various pathological processes. Here, through screening 34 steroid hormones and their derivatives for cAMP production, we found that progesterone (P4) and 17-hydroxyprogesterone (17OHP) could specifically activate GPR126 and trigger its downstream Gi signaling by binding to the ligand pocket in the seven-transmembrane domain of the C-terminal fragment of GPR126. A detailed mutagenesis screening according to a computational simulated structure model indicated that K1001ECL2 and F1012ECL2 are key residues that specifically recognize 17OHP but not progesterone. Finally, functional analysis revealed that progesterone-triggered GPR126 activation promoted cell growth in vitro and tumorigenesis in vivo, which involved Gi-SRC pathways in a triple-negative breast cancer model. Collectively, our work identified a membrane receptor for progesterone/17OHP and delineated the mechanisms by which GPR126 participated in potential tumor progression in triple-negative breast cancer, which will enrich our understanding of the functions and working mechanisms of both the aGPCR member GPR126 and the steroid hormone progesterone.


Asunto(s)
Progesterona , Receptores Acoplados a Proteínas G , Receptores de Progesterona , Neoplasias de la Mama Triple Negativas , 17-alfa-Hidroxiprogesterona/metabolismo , Línea Celular Tumoral , Humanos , Progesterona/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Transducción de Señal , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo
7.
Am J Physiol Cell Physiol ; 327(4): C1012-C1022, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39246140

RESUMEN

Reduced PALMD expression is strongly associated with the development of calcified aortic valve stenosis; however, the role of PALMD in vascular calcification remains unknown. Calcified arteries were collected from mice to detect PALMD expression. Heterozygous Palmd knockout (Palmd+/-) mice were established to explore the role of PALMD in subtotal nephrectomy-induced vascular calcification. RNA sequencing was applied to detect molecular changes in aortas from Palmd+/- mice. Primary Palmd+/- vascular smooth muscle cells (VSMCs) or PALMD-silenced VSMCs by short interfering RNA were used to analyze PALMD function in phenotypic changes and calcification. PALMD haploinsufficiency aggravated subtotal nephrectomy-induced vascular calcification. RNA sequencing analysis showed that loss of PALMD disturbed the synthesis and degradation of the extracellular matrix (ECM) in aortas, including collagens and matrix metalloproteinases (Col6a6, Mmp2, Mmp9, etc.). In vitro experiments revealed that PALMD-deficient VSMCs were more susceptible to high phosphate-induced calcification. Downregulation of SMAD6 expression and increased levels of p-SMAD2 were detected in Palmd+/- VSMCs, suggesting that transforming growth factor-ß signaling may be involved in PALMD haploinsufficiency-induced vascular calcification. Our data revealed that PALMD haploinsufficiency causes ECM dysregulation in VSMCs and aggravates vascular calcification. Our findings suggest that reduced PALMD expression is also linked to vascular calcification, and PALMD may be a potential therapeutic target for this disease. NEW & NOTEWORTHY We found that PALMD haploinsufficiency causes extracellular matrix dysregulation, reduced PALMD expression links to vascular calcification, and PALMD mutations may lead to the risk of both calcific aortic valve stenosis and vascular calcification.


Asunto(s)
Matriz Extracelular , Músculo Liso Vascular , Miocitos del Músculo Liso , Calcificación Vascular , Animales , Masculino , Ratones , Aorta/metabolismo , Aorta/patología , Estenosis de la Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/patología , Estenosis de la Válvula Aórtica/genética , Células Cultivadas , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética , Haploinsuficiencia , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/genética , Calcificación Vascular/metabolismo , Calcificación Vascular/patología , Calcificación Vascular/genética
8.
J Am Chem Soc ; 146(40): 27429-27442, 2024 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-39345027

RESUMEN

Orienting intelligence and multifunction, stretchable semiconductors are of great significance in constructing next-generation human-friendly wearable electronic devices. Nevertheless, rendering semiconducting polymers mechanical stretchability without compromising intrinsic electrical performance remains a major challenge. Combining geometry-innovated inorganic systems and structure-tailored organic semiconductors, a molecular-scale geometric design strategy is proposed to obtain high-performance intrinsically stretchable polymer semiconductors. Originating from the linear regioregular conjugated polymer and corresponding para-modified near-linear counterpart, a series of zigzag-structured semiconducting polymers are developed with diverse ortho-type and meta-type kinking units quantitatively incorporated. They showcase huge edges in realizing stretchability enhancement for conformational transition, likewise with long-range π-aggregation and short-range torsion disorder taking effect. Assisted by additional heteroatom embedment and flexible alkyl-chain attachment, mechanical stretchability and carrier mobility could afford a two-way promotion. Among zigzag-structured species, o-OC8-5% with the initial field-effect mobility up to 1.92 cm2 V-1 s-1 still delivers 1.43 and 1.37 cm2 V-1 s-1 under 100% strain with charge transport parallel and perpendicular to the stretching direction, respectively, accompanied by outstanding performance retention and cyclic stability. This molecular design strategy contributes to an in-depth exploration of prospective intrinsically stretchable semiconductors for cutting-edge electronic devices.

9.
Am J Epidemiol ; 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39191655

RESUMEN

Why lower low-density lipoprotein cholesterol (LDL-C) was associated with a decreased atherosclerotic cardiovascular disease (ASCVD) risk but an increased hemorrhagic stroke (HS) risk in hypertensive adults remains unclear. We examined whether the inverse LDL-C-HS association partly arises from its effect on ASCVD. We estimated separable effects of LDL-C on HS outside (i.e., separable direct effect) or only through its effect on ASCVD (i.e., separable indirect effect) in hypertensive adults from the Chinese Multi-provincial Cohort Study. We quantified such effects using numbers needed to treat (NNT) to prevent or cause an extra HS based on the restricted mean event-free time till a 25-year follow-up. LDL-C $<$ 70 mg/dL was not associated with an increased HS risk compared to LDL-C $\ge$ 70 mg/dL regarding total and separable direct effects. However, a small separable indirect effect (i.e., NNT to harm: 9722 participants) was noted and validated via a series of sensitivity analyses. Moreover, modified effects were observed, particularly in the 35-49-year age group, men, and those with SBP $\ge$ 140 mm Hg. These results suggest the inverse LDL-C-HS association in hypertensive adults is partly due to its effect on ASCVD. A better understanding of such associations would provide more enlightening into stroke prevention.

10.
Prostate ; 84(4): 317-328, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38145367

RESUMEN

BACKGROUND: Prostate leucine zipper (PrLZ) is a prostate-specific protein, and our previous study demonstrated that PrLZ enhances the malignant progression of prostate cancer (Pca). However, the roles of PrLZ in epithelial to mesenchymal transition (EMT) remain unknown. METHODS: Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) staining, hematoxylin-eosin (HE) staining, and western blotting were used to analyze the expression of protein and genes level in human PCa cell lines. Invasion assay was used to examine the effect of PrLZ, miR-200a, miR-200b, miR-200c, miR-141, miR-429, miR-205, and ZEB1 on PCa cell line invasion in vitro. Prostate cancer metastasis animal model was designed to assess the effect of PrLZ on PCa cell line invasion in vivo. RESULTS: We proved that high PrLZ expression initiates EMT, which was shown by the downregulation of E-cadherin and upregulation of vimentin in PC-3/PrLZ and ARCaP-E/PrLZ cells. Mechanistic analysis revealed that PrLZ regulates EMT by activating TGF-ß1/p-smad2 signaling and further inhibiting the expression of miR-200 family members, which negatively regulates ZEB1 expression and causes EMT in Pca. Moreover, using two of orthotopic mouse model and tail vein injection of human prostate cancer cells mouse model, we observed that PC-3/PrLZ cells led to the development of distant organ metastases in vivo. CONCLUSIONS: Our results show the mechanism by which PrLZ regulates EMT and metastasis and suggest that PrLZ may be a potential therapeutic target for Pca metastasis.


Asunto(s)
MicroARNs , Neoplasias de la Próstata , Masculino , Animales , Ratones , Humanos , MicroARNs/genética , Factor de Crecimiento Transformador beta1/metabolismo , Próstata/patología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Leucina Zippers , Homeobox 1 de Unión a la E-Box con Dedos de Zinc , Neoplasias de la Próstata/patología , Regulación Neoplásica de la Expresión Génica , Movimiento Celular
11.
Lancet ; 402(10395): 41-53, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37331369

RESUMEN

BACKGROUND: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. METHODS: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting. FINDINGS: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). INTERPRETATION: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. FUNDING: HUTCHMED.


Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Trifluridina/efectos adversos , Factor A de Crecimiento Endotelial Vascular , Calidad de Vida , Neoplasias del Recto/tratamiento farmacológico , Método Doble Ciego , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
12.
Planta ; 260(1): 24, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38858226

RESUMEN

MAIN CONCLUSION: The resurrection plant Boea hygrometrica selectively recruits and assembles drought-specific microbial communities across the plant-soil compartments, which may benefit plant growth and fitness under extreme drought conditions. Plant-associated microbes are essential for facilitating plant growth and fitness under drought stress. The resurrection plant Boea hygrometrica in natural habitats with seasonal rainfall can survive rapid desiccation, yet their interaction with microbiomes under drought conditions remains unexplored. This study examined the bacterial and fungal microbiome structure and drought response across plant-soil compartments of B. hygrometrica by high-throughput amplicon sequencing of 16S rRNA gene and internal transcribed spacer. Our results demonstrated that the diversity, composition, and functional profile of the microbial community varied considerably across the plant-soil compartments and were strongly affected by drought stress. Bacterial and fungal diversity was significantly reduced from soil to endosphere and belowground to aboveground compartments. The compartment-specific enrichment of the dominant bacteria phylum Cyanobacteriota and genus Methylorubrum in leaf endosphere, genera Pseudonocardia in rhizosphere soil and Actinoplanes in root endosphere, and fungal phylum Ascomycota in the aboveground compartments and genera Knufia in root endosphere and Cladosporium in leaf endosphere composed part of the core microbiota with corresponding enrichment of beneficial functions for plant growth and fitness. Moreover, the recruitment of dominant microbial genera Sphingosinicella and Plectosphaerella, Ceratobasidiaceae mycorrhizal fungi, and numerous plant growth-promoting bacteria involving nutrient supply and auxin regulation was observed in desiccated B. hygrometrica plants. Our results suggest that the stable assembled drought-specific microbial community of B. hygrometrica may contribute to plant survival under extreme environments and provide valuable microbial resources for the microbe-mediated drought tolerance enhancement in crops.


Asunto(s)
Sequías , Microbiota , Microbiología del Suelo , Microbiota/genética , Estrés Fisiológico , Bacterias/genética , Bacterias/clasificación , Raíces de Plantas/microbiología , Raíces de Plantas/genética , ARN Ribosómico 16S/genética , Hongos/fisiología , Hongos/genética , Rizosfera , Brassicaceae/microbiología , Brassicaceae/genética , Brassicaceae/fisiología , Hojas de la Planta/microbiología , Hojas de la Planta/genética
13.
Nat Chem Biol ; 18(11): 1196-1203, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35982227

RESUMEN

Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a Gs trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-Gs provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.


Asunto(s)
Receptores Acoplados a Proteínas G , Transducción de Señal , Humanos , Masculino , Microscopía por Crioelectrón , Sulfato de Deshidroepiandrosterona , Desoxicorticosterona , Ligandos , Receptores Acoplados a Proteínas G/química
14.
Langmuir ; 40(6): 3168-3180, 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38288605

RESUMEN

Hydrogen peroxide (H2O2) is an ideal green product with a broad range of applications, and visible-light-driven photocatalytic H2O2 production is deemed a sustainable and eco-friendly strategy. Herein, various ZnxCd1-xS/MXene photocatalysts with a Schottky junction were prepared for photocatalytic H2O2 production. The obtained Zn0.3Cd0.7S/MXene (ZCM-0.3) hybrid presented the highest photocatalytic H2O2 production rate in pure neutral water of 1160 µmol h-1 g-1, which was further improved to 2178.58 µmol h-1 g-1 in the presence of isopropanol as the sacrificial reagent. The experimental results demonstrated that the sufficient visible-light-harvesting ability and appropriate conduction band potential of the Zn0.3Cd0.7S solid solution, the excellent conductivity and two-electron selectivity of MXene, and the construction of Schottky junctions at the Zn0.3Cd0.7S/MXene interface resulted in the fast transfer and separation of the photogenerated charge carriers and the targeted reduction of oxygen to H2O2. The photocatalytic mechanism for H2O2 production was studied and proposed. Moreover, a simple photo-Fenton system consisting of ZnxCd1-xS/MXene and ferrous ions (Fe2+) was constructed and applied for the degradation of various emerging pollutants, which also performed effectively and exhibited universality across different pollutants. Overall, this study presents a novel and useful strategy to convert solar energy into chemical energy through efficient H2O2 production and provides an effective alternative for the degradation of emerging pollutants.

15.
Crit Rev Food Sci Nutr ; : 1-26, 2024 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-39002141

RESUMEN

Cancer-related complications pose significant challenges in the management and treatment of patients with malignancies. Several meta-analyses have indicated improving effects of probiotics on cancer complications, while some studies have reported contentious findings. The purpose of the present study was to evaluate the efficacy of probiotics in addressing cancer complications, including diarrhea, mucositis, and infections, following chemotherapy, radiotherapy, and surgery. Relevant studies were searched in the PubMed, Scopus, Embase and Web of Science databases and Google Scholar up to September 2023. All meta-analyses addressing the effects of probiotics on all cancer treatments-induced complications including infection, diarrhea and oral mucositis were included. The pooled results were calculated using a random-effects model. Analyses of subgroups, sensitivity and publication bias were also conducted. The results revealed that the probiotics supplementation was effective on reduction of total cancer complications (OR:0.53; 95% CI: 0.44, 0.62, p < 0.001; I2=79.0%, p < 0.001), total infection rate (OR:0.47; 95%CI: 0.41, 0.52, p < 0.001; I2= 48.8%, p < 0.001); diarrhea (OR:0.50; 95%CI: 0.44, 0.57, p < 0.001; I2=44.4%, p = 0.023) and severe diarrhea (OR: 0.4; 95%CI: 0.27, 0.56, p < 0.001; I2=31.3%, p = 0.178), oral mucositis (OR: 0.76; 95%CI: 0.58, 0.94, p < 0.001; I2=95.5%, p < 0.001) and severe oral mucositis (OR:0.65, 95%CI: 0.58, 0.72 p < 0.001; I2=22.1%, p = 0.274). Multi strain probiotic (OR:0.49; 95%CI: 0.32, 0.65, p < 0.001; I2=90.7%, p < 0.001) were more efficacious than single strain (OR:0.73; 95%CI: 0.66, 0.81, p < 0.001; I2=0.00%, p = 0.786). The findings of the current umbrella meta-analysis provide strong evidence that probiotic supplementation can reduce cancer complications.

16.
J Org Chem ; 89(1): 44-56, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-38088910

RESUMEN

In this paper, we present an example of a photoinduced catalyst, halogen-, and base-free TEMPO-mediated interrupted 6π-photocyclization/dehydrogenative aromatization of ortho-biaryl-appended 1,3-dicarbonyl compounds for the preparation of 10-phenanthrenols. The reaction involves rapid photocycloaddition via a 1,2-biradical of 1,3-dicarbonyl compounds, followed by subsequent dehydrogenative aromatization of 1,4-biradical intermediates using TEMPO as the commercially available oxidant rather than trapped by TEMPO to form an alkoxyamine product.

17.
J Org Chem ; 89(1): 474-483, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-38096480

RESUMEN

A radical 1,2,4-trifunctional reaction of thiosulfonate to unactivated olefin is achieved by a migration strategy under mild conditions. In this reaction, the more unstable primary free radicals are in situ generated after the migration of heteroaryl groups in the presence of DABCO. This trifunctionalization of unactivated olefins involves two C-S bond formations and one C-C bond formation.

18.
J Org Chem ; 89(12): 8804-8814, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38860924

RESUMEN

1,4-/1,3-Regioselective bifunctionalization of 1,3-enynes with selenosulfonates in water under catalyst-free conditions for the construction of sulfonyl allene and 1,3-disulfonyl-conjugated dienes respectively have been developed. The reactions feature mild reaction conditions in aqueous solution and remarkable regioselectivity controlled by substrates.

19.
Inorg Chem ; 63(2): 1337-1346, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38153815

RESUMEN

Reactions of a chiral and quasi-spherical molecule [1S,4S-2,5-2.2.1-H2dabch]I2 (1) with alkali metal halide MX (M = Na, K, Cs; X = Cl, Br) at room temperature produced a series of organic-inorganic hybrid (OIH) materials [1S,4S-2,5-2.2.1-H2dabch]NaBr3 (2), [1S,4S-2,5-2.2.1-H2dabch]CsCl3·H2O (3) and [1S,4S-2,5-2.2.1-H2dabch]KBr3·H2O (4). The single-crystal X-ray diffraction analysis revealed that the organic-inorganic framework structures comprised of the templating ligand and alkali metal halides (NaBr, CsCl, KBr) displayed dimensions spanning from one-dimensional (1D) to three-dimensional (3D). Moreover, the results of both differential scanning calorimetry (DSC) and dielectric measurements demonstrated that compounds 1-4 displayed reversible, high-temperature phase transitions and noticeable dielectric anomalies. In addition, the temperature-dependent second harmonic generation (SHG) results revealed crystals 1 and 3 can switch from the SHG-ON to the SHG-OFF state, which was proved by the variable-temperature X-ray diffraction. This research aims to streamline the exploration of multifunctional second harmonic generation (SHG) and dielectric materials that have been synthesized using chiral ligands and alkali metals. This will provide researchers with enhanced opportunities to delve further into this specific research domain.

20.
Environ Res ; 257: 119349, 2024 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-38844029

RESUMEN

Integrated aquaculture wastewater treatment systems (IAWTSs) are widely used in treating aquaculture wastewater with the aeration-microalgae unit serving as an important component. In this study, we artificially constructed an IAWTS and applied two aeration-microalgae methods: ordinary aeration or ozone nanobubbles (ONBs) with microalgae (Nannochloropsis oculata). The impact of N.oculata and ONBs on the removal performance of nutrients and the underlying micro-ecological mechanisms were investigated using 16S rRNA gene amplicon sequencing. The results demonstrated that the combined use of ONBs and N.oculata exhibited superior purification effects with 78.25%, 76.59% and 86.71% removal of CODMn, TN and TP. N.oculata played a pivotal role as the primary element in wastewater purification, while ONBs influenced nutrient dynamics by affecting both N.oculata and bacterial communities. N.oculata actively shaped bacterial communities, with a specific focus on nitrogen and phosphorus cycling in the micro-environment remodeled by ONBs. Rare bacterial communities displayed heightened activity in response to the changes in N.oculata, ONBs, and nutrient levels. These findings provide a novel approach to improve the technological processes the IAWTS, contributing to the advancement of sustainable aquaculture practices by offering valuable insights into wastewater purification efficiency and micro-ecological mechanisms.


Asunto(s)
Acuicultura , Microalgas , Microbiota , Ozono , Eliminación de Residuos Líquidos , Aguas Residuales , Acuicultura/métodos , Aguas Residuales/química , Aguas Residuales/microbiología , Microbiota/efectos de los fármacos , Eliminación de Residuos Líquidos/métodos , Fósforo/metabolismo , Nitrógeno/metabolismo
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