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Enzyme-mediated damage repair or mitigation, while common for nucleic acids, is rare for proteins. Examples of protein damage are elimination of phosphorylated Ser/Thr to dehydroalanine/dehydrobutyrine (Dha/Dhb) in pathogenesis and aging. Bacterial LanC enzymes use Dha/Dhb to form carbon-sulfur linkages in antimicrobial peptides, but the functions of eukaryotic LanC-like (LanCL) counterparts are unknown. We show that LanCLs catalyze the addition of glutathione to Dha/Dhb in proteins, driving irreversible C-glutathionylation. Chemo-enzymatic methods were developed to site-selectively incorporate Dha/Dhb at phospho-regulated sites in kinases. In human MAPK-MEK1, such "elimination damage" generated aberrantly activated kinases, which were deactivated by LanCL-mediated C-glutathionylation. Surveys of endogenous proteins bearing damage from elimination (the eliminylome) also suggest it is a source of electrophilic reactivity. LanCLs thus remove these reactive electrophiles and their potentially dysregulatory effects from the proteome. As knockout of LanCL in mice can result in premature death, repair of this kind of protein damage appears important physiologically.
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Alanina/análogos & derivados , Aminobutiratos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Proteoma , Receptores Acoplados a Proteínas G/metabolismo , Alanina/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Feminino , Glutationa/metabolismo , Células HEK293 , Humanos , MAP Quinase Quinase 1/metabolismo , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas de Ligação a Fosfato/química , Proteínas de Ligação a Fosfato/genética , Fosforilação , Domínios Proteicos , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Sulfetos/metabolismoRESUMO
In both eukarya and bacteria, the addition of Cys to dehydroalanine (Dha) and dehydrobutyrine (Dhb) occurs in various biological processes. In bacteria, intramolecular thia-Michael addition catalyzed by lanthipeptide cyclases (LanC) proteins or protein domains gives rise to a class of natural products called lanthipeptides. In eukarya, dehydroamino acids in signaling proteins are introduced by effector proteins produced by pathogens like Salmonella to dysregulate host defense mechanisms. A eukaryotic LanC-like (LanCL) enzyme catalyzes the addition of Cys in glutathione to Dha/Dhb to protect the cellular proteome from unwanted chemical and biological activity. To date, the mechanism of the enzyme-catalyzed thia-Michael addition has remained elusive. We report here the crystal structures of the human LanCL1 enzyme complexed with different ligands, including the product of thia-Michael addition of glutathione to a Dhb-containing peptide that represents the activation loop of Erk. The structures show that a zinc ion activates the Cys thiolate for nucleophilic attack and that a conserved His is poised to protonate the enolate intermediate to achieve a net anti-addition. A second His hydrogen bonds to the carbonyl oxygen of the former Dhb and may stabilize the negative charge that builds up on this oxygen atom in the enolate intermediate. Surprisingly, the latter His is not conserved in orthologous enzymes that catalyze thia-Michael addition to Dha/Dhb. Eukaryotic LanCLs contain a His, whereas bacterial stand-alone LanCs have a Tyr residue, and LanM enzymes that have LanC-like domains have a Lys, Asn, or His residue. Mutational and binding studies support the importance of these residues for catalysis.
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Peptídeos , Proteínas , Humanos , Peptídeos/química , Glutationa , Bactérias/metabolismo , Catálise , OxigênioRESUMO
Molecular self-assembly plays a very important role in various aspects of technology as well as in biological systems. Governed by covalent, hydrogen or van der Waals interactions-self-assembly of alike molecules results in a large variety of complex patterns even in two dimensions (2D). Prediction of pattern formation for 2D molecular networks is extremely important, though very challenging, and so far, relied on computationally involved approaches such as density functional theory, classical molecular dynamics, Monte Carlo, or machine learning. Such methods, however, do not guarantee that all possible patterns will be considered and often rely on intuition. Here, we introduce a much simpler, though rigorous, hierarchical geometric model founded on the mean-field theory of 2D polygonal tessellations to predict extended network patterns based on molecular-level information. Based on graph theory, this approach yields pattern classification and pattern prediction within well-defined ranges. When applied to existing experimental data, our model provides a different view of self-assembled molecular patterns, leading to interesting predictions on admissible patterns and potential additional phases. While developed for hydrogen-bonded systems, an extension to covalently bonded graphene-derived materials or 3D structures such as fullerenes is possible, significantly opening the range of potential future applications.
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BACKGROUND: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct diabetic cardiomyopathy progression. Herein, we assessed the potential role and therapeutic value of USP28 (ubiquitin-specific protease 28) on the metabolic vulnerability of diabetic cardiomyopathy. METHODS: The type 2 diabetes mouse model was established using db/db leptin receptor-deficient mice and high-fat diet/streptozotocin-induced mice. Cardiac-specific knockout of USP28 in the db/db background mice was generated by crossbreeding db/m and Myh6-Cre+/USP28fl/fl mice. Recombinant adeno-associated virus serotype 9 carrying USP28 under cardiac troponin T promoter was injected into db/db mice. High glucose plus palmitic acid-incubated neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing, immunoprecipitation and mass spectrometry analysis, protein pull-down, chromatin immunoprecipitation sequencing, and chromatin immunoprecipitation assay. RESULTS: Microarray profiling of the UPS (ubiquitin-proteasome system) on the basis of db/db mouse hearts and diabetic patients' hearts demonstrated that the diabetic ventricle presented a significant reduction in USP28 expression. Diabetic Myh6-Cre+/USP28fl/fl mice exhibited more severe progressive cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared with their controls. On the other hand, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Adeno-associated virus serotype 9-USP28 diabetic mice also exhibited less lipid storage, reduced reactive oxygen species formation, and mitochondrial impairment in heart tissues than adeno-associated virus serotype 9-null diabetic mice. As a result, USP28 overexpression attenuated cardiac remodeling and dysfunction, lipid accumulation, and mitochondrial impairment in high-fat diet/streptozotocin-induced type 2 diabetes mice. These results were also confirmed in neonatal rat ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes. RNA sequencing, immunoprecipitation and mass spectrometry analysis, chromatin immunoprecipitation assays, chromatin immunoprecipitation sequencing, and protein pull-down assay mechanistically revealed that USP28 directly interacted with PPARα (peroxisome proliferator-activated receptor α), deubiquitinating and stabilizing PPARα (Lys152) to promote Mfn2 (mitofusin 2) transcription, thereby impeding mitochondrial morphofunctional defects. However, such cardioprotective benefits of USP28 were largely abrogated in db/db mice with PPARα deletion and conditional loss-of-function of Mfn2. CONCLUSIONS: Our findings provide a USP28-modulated mitochondria homeostasis mechanism that involves the PPARα-Mfn2 axis in diabetic hearts, suggesting that USP28 activation or adeno-associated virus therapy targeting USP28 represents a potential therapeutic strategy for diabetic cardiomyopathy.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Cardiomiopatias Diabéticas , Células-Tronco Pluripotentes Induzidas , Ubiquitina Tiolesterase , Animais , Humanos , Camundongos , Ratos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Lipídeos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , PPAR alfa/metabolismo , Estreptozocina/metabolismo , Estreptozocina/uso terapêutico , Ubiquitina Tiolesterase/análise , Ubiquitina Tiolesterase/metabolismoRESUMO
Helicobacter pylori is a human pathogen that infects almost half of the population. Antibiotic resistance in H. pylori threatens health and increases the demand for prophylactic and therapeutic vaccines. Traditional oral vaccine research faces considerable challenges because of the epithelial barrier, potential enterotoxicity of adjuvants, and the challenging conditions of the gastric environment. We developed an intranasal influenza A virus (IAV) vector vaccine based on two live attenuated influenza viruses with modified acidic polymerase protein (PA) genes encoding the A subunit of H. pylori neutrophil-activating protein (NapA), named IAV-NapA, including influenza virus A/WSN/33 (WSN)-NapA and A/Puerto Rico/8/34 (PR8)-NapA. These recombinant influenza viruses were highly attenuated and exhibited strong immunogenicity in mice. Vaccination with IAV-NapA induced antigen-specific humoral and mucosal immune responses while stimulating robust Th1 and Th17 cell immune responses in mice. Our findings suggest that prophylactic and therapeutic vaccination with influenza virus vector vaccines significantly reduces colonization of H. pylori and inflammation in the stomach of mice.IMPORTANCEHelicobacter pylori is the most common cause of chronic gastritis and leads to severe gastroduodenal pathology in some patients. Many studies have shown that Th1 and Th17 cellular and gastric mucosal immune responses are critical in reducing H. pylori load. IAV vector vaccines can stimulate these immune responses while overcoming potential adjuvant toxicity and antigen dosing issues. To date, no studies have demonstrated the role of live attenuated IAV vector vaccines in preventing and treating H. pylori infection. Our work indicates that vaccination with IAV-NapA induces antigen-specific humoral, cellular, and mucosal immunity, producing a protective and therapeutic effect against H. pylori infection in BALB/c mice. This undescribed H. pylori vaccination approach may provide valuable information for developing vaccines against H. pylori infection.
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Helicobacter pylori , Vacinas contra Influenza , Animais , Humanos , Camundongos , Adjuvantes Imunológicos , Vacinas Bacterianas/imunologia , Helicobacter pylori/fisiologia , Vírus da Influenza A/fisiologia , Vacinas contra Influenza/administração & dosagem , Camundongos Endogâmicos BALB C , Infecções por Helicobacter/prevenção & controle , Administração IntranasalRESUMO
Inherent symmetry breaking at the interface has been fundamental to a myriad of physical effects and functionalities, such as efficient spin-charge interconversion, exotic magnetic structures and an emergent bulk photovoltaic effect. It has recently been demonstrated that interface asymmetry can induce sizable piezoelectric effects in heterostructures, even those consisting of centrosymmetric semiconductors, which provides flexibility to develop and optimize electromechanical coupling phenomena. Here, by targeted engineering of the interface symmetry, we achieve piezoelectric phenomena behaving as the electrical analogue of the negative Poisson's ratio. This effect, termed the auxetic piezoelectric effect, exhibits the same sign for the longitudinal (d33) and transverse (d31, d32) piezoelectric coefficients, enabling a simultaneous contraction or expansion in all directions under an external electrical stimulus. The signs of the transverse coefficients can be further tuned via in-plane symmetry anisotropy. The effects exist in a wide range of material systems and exhibit substantial coefficients, indicating potential implications for all-semiconductor actuator, sensor and filter applications.
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Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.
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Artrite Reumatoide , Isomerases de Dissulfetos de Proteínas , Fator de Transcrição STAT1 , Isomerases de Dissulfetos de Proteínas/metabolismo , Isomerases de Dissulfetos de Proteínas/genética , Humanos , Artrite Reumatoide/metabolismo , Camundongos , Animais , Fator de Transcrição STAT1/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Transporte Ativo do Núcleo Celular , Proteínas de Transporte/metabolismo , Transdução de Sinais , Proteínas de Ligação a Hormônio da Tireoide , Fatores de Transcrição NFATC/metabolismo , Ativação Linfocitária , Hormônios Tireóideos/metabolismo , Regulação da Expressão Gênica , Células Th17/metabolismo , Células Th17/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Modelos Animais de Doenças , Piruvato QuinaseRESUMO
The parathyroid hormone type 1 receptor (PTHR1), a Class B GPCR, is activated by long polypeptides, including drugs for osteoporosis and hypoparathyroidism. The PTHR1 engages peptide agonists via a two-step mechanism. Initial contact involves the extracellular domain (ECD), which has been thought to contribute primarily to receptor-peptide binding, and then the N terminus of the peptide engages the receptor transmembrane domain (TMD), which is thought to control the message conveyed to intracellular partners. This mechanism has been suggested to apply to other Class B GPCRs as well. Here, we show that modification of a PTHR1 agonist at ECD-contact sites can alter the signaling profile, an outcome that is not accommodated by the current two-step binding model. Our data support a modified two-step binding model in which agonist orientation on the ECD surface can influence the geometry of agonist-TMD engagement. This expanded binding model offers a mechanism by which altering ECD-contact residues can affect signaling profile. Our discoveries provide a rationale for exploring agonist modifications distal from the TMD-contact region in future efforts to optimize therapeutic performance of peptide hormone analogs.
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Receptor Tipo 1 de Hormônio Paratireóideo , Transdução de Sinais , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Ligação Proteica , Domínios Proteicos , Peptídeos/metabolismoRESUMO
Two-dimensional (2D) ferroelectrics promise ultrathin flexible nanoelectronics, typically utilizing a metal-ferroelectric-metal sandwich structure. Electrodes can either contribute free carriers to screen the depolarization field, enhancing nanoscale ferroelectricity, or induce charge doping, disrupting the long-range crystalline order. We explore electrodes' dual roles in 2D ferroelectric capacitors, supported by first-principles calculations covering a range of electrode work functions. Our results reveal volcano-type relationships between ferroelectric-electrode binding affinity and work function, which are further unified by a quadratic scaling between the binding energy and the transferred interfacial charge. At the monolayer limit, charge transfer dictates the ferroelectric stability and switching properties. This general characteristic is confirmed in various 2D ferroelectrics including α-In2Se3, CuInP2S6, and SnTe. As the ferroelectric layer's thickness increases, the capacitor stability evolves from a charge-transfer-dominated state to a screening-dominated state. The delicate interplay between these two effects has important implications for 2D ferroelectric capacitor applications.
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Two-dimensional materials (2DMs) have exhibited remarkably tunable optical characteristics, which have been applied for significant applications in communications, sensing, and computing. However, the reported tunable optical properties of 2DMs are almost volatile, impeding them in the applications of multifarious emerging frameworks such as programmable operation and neuromorphic computing. In this work, nonvolatile electro-optic response is developed by the graphene-Al2O3-In2Se3 heterostructure integrating with microring resonators (MRRs). In such compact devices, the optical absorption coefficient of graphene is substantially tuned by the out-of-plane ferroelectric polarization in α-In2Se3, resulting in a nonvolatile optical transmission in MRRs. This work demonstrates that integrating graphene with ferroelectric materials paves the way to develop nonvolatile devices in photonic circuits for emerging applications such as optical neural networks.
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Dielectric capacitors are highly desired in modern electronic devices and power systems to store and recycle electric energy. However, achieving simultaneous high energy density and efficiency remains a challenge. Here, guided by theoretical and phase-field simulations, we are able to achieve a superior comprehensive property of ultrahigh efficiency of 90-94% and high energy density of 85-90 J cm-3 remarkably in strontium titanate (SrTiO3), a linear dielectric of a simple chemical composition, by manipulating local symmetry breaking through introducing Ti/O defects. Atomic-scale characterizations confirm that these Ti/O defects lead to local symmetry breaking and local lattice strains, thus leading to the formation of the isolated ultrafine polar nanoclusters with varying sizes from 2 to 8 nm. These nanoclusters account for both considerable dielectric polarization and negligible polarization hysteresis. The present study opens a new realm of designing high-performance dielectric capacitors utilizing a large family of readily available linear dielectrics with very simple chemistry.
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Parathyroid hormone 1 receptor (PTH1R) plays a key role in mediating calcium homeostasis and bone development, and aberrant PTH1R activity underlies several human diseases. Peptidic PTH1R antagonists and inverse agonists have therapeutic potential in treating these diseases, but their poor pharmacokinetics and pharmacodynamics undermine their in vivo efficacy. Herein, we report the use of a backbone-modification strategy to design a peptidic PTH1R inhibitor that displays prolonged activity as an antagonist of wild-type PTH1R and an inverse agonist of the constitutively active PTH1R-H223R mutant both in vitro and in vivo. This peptide may be of interest for the future development of therapeutic agents that ameliorate PTH1R malfunction.
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Agonismo Inverso de Drogas , Receptor Tipo 1 de Hormônio Paratireóideo , Humanos , Peptídeos , Hormônio Paratireóideo/farmacologiaRESUMO
Incipient ferroelectrics have emerged as an attractive class of functional materials owing to their potential to be engineered for exotic ferroelectric behavior, holding great promise for expanding the ferroelectric family. However, thus far, their artificially engineered ferroelectricity has fallen far short of rivaling classic ferroelectrics. In this study, we address this challenge by developing a superfine nanodomain engineering strategy. By applying this approach to representative incipient ferroelectric of SrTiO3-based films, we achieve unprecedentedly strong ferroelectricity, not only surpassing previous records for incipient ferroelectrics but also being comparable to classic ferroelectrics. The remanent polarization of the thin film reaches up to 17.0 µC cm-2 with an ultrahigh Curie temperature of 973 K. Atomic-scale investigations elucidate the origin of this robust ferroelectricity in the emergent high-density superfine nanodomains spanning merely 3-10 unit cells. Combining experimental results with theoretical assessments, we unveil the underlying mechanism, where the intentionally introduced diluted foreign Fe element creates a deeper Landau energy well and promotes a short-range ordering of polarization. Our developed strategy significantly streamlines the design of unconventional ferroelectrics, providing a versatile pathway for exploring new and superior ferroelectric materials.
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The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.
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Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteína Beclina-1/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , AVC Isquêmico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Autofagia , Linhagem Celular , Modelos Animais de Doenças , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Camundongos , Estresse Oxidativo , FosforilaçãoRESUMO
BACKGROUNDS: There is little evidence on the safety, efficacy, and survival benefit of restarting immune checkpoint inhibitors (ICI) in patients with cancer after discontinuation due to immune-related adverse events (irAEs) or progressive disease (PD). Here, we performed a meta-analysis to elucidate the possible benefits of ICI rechallenge in patients with cancer. METHODS: Systematic searches were conducted using PubMed, Embase, and Cochrane Library databases. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of irAEs were the outcomes of interest. RESULTS: Thirty-six studies involving 2026 patients were analyzed. ICI rechallenge was associated with a lower incidence of all-grade (OR, 0.05; 95%CI, 0.02-0.13, Pâ <â .05) and high-grade irAEs (OR, 0.37; 95%CI, 0.21-0.64, Pâ <â .05) when compared with initial ICI treatment. Though no significant difference was observed between rechallenge and initial treatment regarding ORR (OR, 0.69; 95%CI, 0.39-1.20, Pâ =â .29) and DCR (OR, 0.85; 95%CI, 0.51-1.40, Pâ =â 0.52), patients receiving rechallenge had improved PFS (HR, 0.56; 95%CI, 0.43-0.73, Pâ <â .05) and OS (HR, 0.55; 95%CI, 0.43-0.72, Pâ <â .05) than those who discontinued ICI therapy permanently. Subgroup analysis revealed that for patients who stopped initial ICI treatment because of irAEs, rechallenge showed similar safety and efficacy with initial treatment, while for patients who discontinued ICI treatment due to PD, rechallenge caused a significant increase in the incidence of high-grade irAEs (OR, 4.97; 95%CI, 1.98-12.5, Pâ <â .05) and a decrease in ORR (OR, 0.48; 95%CI, 0.24-0.95, Pâ <â .05). CONCLUSION: ICI rechallenge is generally an active and feasible strategy that is associated with relative safety, similar efficacy, and improved survival outcomes. Rechallenge should be considered individually with circumspection, and randomized controlled trials are required to confirm these findings.
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BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) risk prediction models established in patients with chronic hepatitis B (CHB) receiving nucleoside analogue (NA) rarely included viral factors because of mediocre predictability of traditional viral markers. Here, we investigate the role of serum hepatitis B virus (HBV) RNA, a novel biomarker, in predicting HCC risk in NA-treated patients. METHODS: A total of 1374 NA-treated patients were enrolled from two prospective CHB cohorts. Serum HBV RNA was detected at baseline, year 1, 2 and 3 of treatment. Cox proportional-hazard model was used to investigate the association of HBV RNA kinetics with HCC risk. RESULTS: After a median follow-up of 5.4 years, 76 patients developed HCC. HBV RNA declines at year 1 (adjusted hazard ratio (aHR) = 0.70, P = .009) and 2 (aHR = 0.71, P = .016) were independently associated with HCC risk. Patients with less HBV RNA decline at year 1 (=< 0.4 log10 copies/mL) or 2 (=<0.6 log10 copies/mL) had 2.22- and 2.09-folds higher HCC risk, respectively, than those with more declines. When incorporating these early on-treatment HBV RNA declines into existing HCC risk scores, including PAGE B, mPAGE B and aMAP score, they could enhance their predictive performance [i.e. C-index, 0.814 vs. 0.788 (Model (PAGE B + year-1 HBV RNA decline)vs. PAGE B score based on baseline parameters)]. CONCLUSIONS: Serum HBV RNA declines at year 1 and 2 were significantly associated with on-treatment HCC risk. Incorporating early on-treatment HBV RNA declines into HCC risk prediction models can be useful tools to guide appropriate surveillance strategies in NA-treated patients.
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Epithelial mesenchymal transition (EMT) is a critical process implicated in the pathogenesis of retinal fibrosis and the exacerbation of diabetic retinopathy (DR) within retinal pigment epithelium (RPE) cells. Apigenin (AP), a potential dietary supplement for managing diabetes and its associated complications, has demonstrated inhibitory effects on EMT in various diseases. However, the specific impact and underlying mechanisms of AP on EMT in RPE cells remain poorly understood. In this study, we have successfully validated the inhibitory effects of AP on high glucose-induced EMT in ARPE-19 cells and diabetic db/db mice. Notably, our findings have identified CBP/p300 as a potential therapeutic target for EMT in RPE cells and have further substantiated that AP effectively downregulates the expression of EMT-related genes by attenuating the activity of CBP/p300, consequently reducing histone acetylation alterations within the promoter region of these genes. Taken together, our results provide novel evidence supporting the inhibitory effect of AP on EMT in RPE cells, and highlight the potential of specifically targeting CBP/p300 as a strategy for inhibiting retinal fibrosis in the context of DR.
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Apigenina , Transição Epitelial-Mesenquimal , Glucose , Histonas , Epitélio Pigmentado da Retina , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Animais , Apigenina/farmacologia , Acetilação/efeitos dos fármacos , Humanos , Glucose/metabolismo , Glucose/toxicidade , Histonas/metabolismo , Linhagem Celular , Camundongos , Fatores de Transcrição de p300-CBP/metabolismo , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Retinopatia Diabética/tratamento farmacológico , Proteína p300 Associada a E1A/metabolismo , Masculino , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Proteína de Ligação a CREB/metabolismo , Proteína de Ligação a CREB/genéticaRESUMO
Serum hepatitis B virus (HBV) spliced RNAs (spRNAs) are ubiquitous in HBV-infected patients; however, their clinical significance remains unknown. Therefore, we aimed to explore the relationship between HBV spRNAs and liver disease progression in chronic hepatitis B (CHB) patients; in vitro cell line assessment was also performed. The serum HBV wild-type RNA (wtRNA) and spRNA levels were individually quantified in a cohort of 279 treatment-naïve, hepatitis B e antigen positive CHB patients with or without cirrhosis. The spRNA proportion was determined as (spRNA × 100%)/(spRNAs + wtRNA). 20 patients' serum samples underwent spRNA species profiling using next-generation sequencing. Serum spRNA species 1, 2, 3, 4, and 5 were the most common variants. The spRNA proportion varied from 0.00% to 19.02%, with higher levels in HBV genotype C patients than in those with genotype B (1.76% vs. 0.84%, p < 0.001). The spRNA proportion was positively associated with the alanine aminotransferase levels (r = 0.144, p = 0.053) and significantly higher in cirrhotic than in non-cirrhotic patients (1.69% vs. 1.04%, p = 0.001). Multivariate analysis revealed a 2.566-fold higher risk of cirrhosis in patients with elevated spRNA proportion (p = 0.024). In vitro experiments confirmed that spRNAs contributed to hepatic stellate cell activation, which is critical in liver fibrosis development. Therefore, increased HBV spRNA expression poses a risk for liver disease progression. Quantifying serum HBV spRNAs can aid in monitoring liver disease progression. Furthermore, the therapeutic targeting of spRNAs may improve the prognosis of patients with CHB.
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Vírus da Hepatite B , Hepatite B Crônica , Humanos , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , RNA/uso terapêutico , Cirrose Hepática/complicações , Antígenos E da Hepatite B , Progressão da Doença , DNA Viral/genéticaRESUMO
BACKGROUND: Chemotherapy and chemoradiation have become essential adjuncts to improve the survival of patients with resectable esophageal squamous cell carcinoma (ESCC) in the perioperative period. Although preoperative treatment plus surgery is commonly used, controversy remains regarding the optimal treatment strategy for patients with locally advanced ESCC. METHODS: A retrospective review of clinical stage II and III ESCC patients who underwent esophagectomy at Henan Cancer Hospital between October 2014 and October 2017 was performed. The patients were divided into a neoadjuvant chemotherapy (NAC) group and an adjuvant chemotherapy (AC) group. Propensity score matching (PSM) was used to exclude confounders. Survival was estimated using KaplanâMeier analysis and compared by the log-rank test. The Cox proportional hazards regression model was used for both the univariate and multivariate analyses. RESULTS: A total of 684 patients were enrolled, including 365 (53.4%) patients in the NAC group. After PSM, 294 pairs of patients were left. NAC prolonged the OS (not reached versus 57.3 months, P = 0.002) and DFS (57.2 vs. 36.4 months, P = 0.010) and decreased the total rate of recurrence (50.1% vs. 59.2%, P = 0.025) and local recurrence (27.9% vs. 36.7%, P = 0.022) compared with AC. The multivariable analyses showed that NAC plus surgery modality was an independent predictor for improved OS (HR: 0.582, 95% CI: 0.467-0.786, P = 0.001). CONCLUSION: NAC plus surgery prolonged OS and DFS, and significantly decreased the total rate of recurrence compared with surgery plus AC in patients with clinical stage II and III ESCC.
Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/patologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Terapia Neoadjuvante , Quimioterapia Adjuvante , Quimiorradioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Esofagectomia , Estudos Retrospectivos , Estadiamento de NeoplasiasRESUMO
ConspectusDuring the past decade or so, research groups around the globe have sought to answer the question: "How does electricity flow through single molecules?" In seeking the answer to this question, a series of joint theory and experimental studies have demonstrated that electrons passing through single-molecule junctions exhibit exquisite quantum interference (QI) effects, which have no classical analogues in conventional circuits. These signatures of QI appear even at room temperature and can be described by simple quantum circuit rules and a rather intuitive magic ratio theory. The latter describes the effect of varying the connectivity of electrodes to a molecular core and how electrical conductance can be controlled by the addition of heteroatoms to molecular cores. The former describes how individual moieties contribute to the overall conductance of a molecule and how the overall conductance can change when the connectivities between different moieties are varied. Related circuit rules have been derived and demonstrated, which describe the effects of connectivity on Seebeck coefficients of organic molecules. This simplicity arises because when a molecule is placed between two electrodes, charge transfer between the molecule and electrodes causes the molecular energy levels to adjust, such that the Fermi energy (EF) of the electrodes lies within the energy gap between the highest occupied molecular orbital and lowest unoccupied molecular orbital. Consequently, when electrons of energy EF pass through a molecule, their phase is protected and transport takes place via phase-coherent tunneling. Remarkably, these effects have been scaled up to self-assembled monolayers of molecules, thereby creating two-dimensional materials, whose room temperature transport properties are controlled by QI. This leads to new molecular design strategies for increasing the on/off conductance ratio of molecular switches and to improving the performance of organic thermoelectric materials. In particular, destructive quantum interference has been shown to improve the Seebeck coefficient of organic molecules and increase their on/off ratio under the influence of electrochemical gating. The aim of this Account is to introduce the novice reader to these signatures of QI in molecules, many of which have been identified in joint studies involving our theory group in Lancaster University and experimental group in Bern University.