RESUMO
Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/química , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Domínios Proteicos/efeitos dos fármacos , Piridinas/farmacologia , Pirróis/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/química , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Elementos Facilitadores Genéticos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Piridinas/efeitos adversos , Piridinas/toxicidade , Pirróis/efeitos adversos , Pirróis/toxicidade , Ratos , Receptores Androgênicos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Previous studies have shown the essential roles of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in neuronal development, function and neurologic diseases. However, the function of Ogt and O-GlcNAcylation in the adult cerebellum has not been well elucidated. Here, we have found that cerebellum has the highest level of O-GlcNAcylation relative to cortex and hippocampus of adult male mice. Specific deletion of Ogt in granule neuron precursors (GNPs) induces abnormal morphology and decreased size of the cerebellum in adult male Ogt deficient [conditional knock-out (cKO)] mice. Adult male cKO mice show the reduced density and aberrant distribution of cerebellar granule cells (CGCs), the disrupted arrangement of Bergman glia (BG) and Purkinje cells. In addition, adult male cKO mice exhibit aberrant synaptic connection, impaired motor coordination, and learning and memory abilities. Mechanistically, we have identified G-protein subunit α12 (Gα12) is modified by Ogt-mediated O-GlcNAcylation. O-GlcNAcylation of Gα12 facilitates its binding to Rho guanine nucleotide exchange factor 12 (Arhgef12) and consequently activates RhoA/ROCK signaling. RhoA/ROCK pathway activator LPA can rescue the developmental deficits of Ogt deficient CGCs. Therefore, our study has revealed the critical function and related mechanisms of Ogt and O-GlcNAcylation in the cerebellum of adult male mice.SIGNIFICANCE STATEMENT Cerebellar function are regulated by diverse mechanisms. To unveil novel mechanisms is critical for understanding the cerebellar function and the clinical therapy of cerebellum-related diseases. In the present study, we have shown that O-GlcNAc transferase gene (Ogt) deletion induces abnormal cerebellar morphology, synaptic connection, and behavioral deficits of adult male mice. Mechanistically, Ogt catalyzes O-GlcNAcylation of Gα12, which promotes the binding to Arhgef12, and regulates RhoA/ROCK signaling pathway. Our study has uncovered the important roles of Ogt and O-GlcNAcylation in regulating cerebellar function and cerebellum-related behavior. Our results suggest that Ogt and O-GlcNAcylation could be potential targets for some cerebellum-related diseases.
Assuntos
Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP , Transdução de Sinais , Camundongos , Masculino , Animais , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , N-Acetilglucosaminiltransferases/genética , Camundongos KnockoutRESUMO
AIMS/HYPOTHESIS: Continuous glucose monitoring (CGM) provides comprehensive information on the exposure to dysglycaemia. This study aimed to investigate the threshold of hyperglycaemia related to mortality risk in critically ill patients using CGM technology. METHODS: A total of 293 adult critically ill patients admitted to intensive care units of five medical centres were prospectively included between May 2020 and November 2021. Participants wore intermittently scanned CGM for a median of 12.0 days. The relationships between different predefined time above ranges (TARs), with the thresholds of hyperglycaemia ranging from 7.8 to 13.9 mmol/l (140-250 mg/dl), and in-hospital mortality risk were assessed by multivariate Cox proportional regression analysis. Time in ranges (TIRs) of 3.9 mmol/l (70 mg/dl) to the predefined hyperglycaemic thresholds were also assessed. RESULTS: Overall, 66 (22.5%) in-hospital deaths were identified. Only TARs with a threshold of 10.5 mmol/l (190 mg/dl) or above were significantly associated with the risk of in-hospital mortality, after adjustment for covariates. Furthermore, as the thresholds for TAR increased from 10.5 mmol/l to 13.9 mmol/l (190 mg/dl to 250 mg/dl), the hazards of in-hospital mortality increased incrementally with every 10% increase in TARs. Similar results were observed concerning the associations between TIRs with various upper thresholds and in-hospital mortality risk. For per absolute 10% decrease in TIR 3.9-10.5 mmol/l (70-190 mg/dl), the risk of in-hospital mortality was increased by 12.1% (HR 1.121 [95% CI 1.003, 1.253]). CONCLUSIONS/INTERPRETATION: A glucose level exceeding 10.5 mmol/l (190 mg/dl) was significantly associated with higher risk of in-hospital mortality in critically ill patients.
Assuntos
Glicemia , Estado Terminal , Mortalidade Hospitalar , Hiperglicemia , Humanos , Estado Terminal/mortalidade , Hiperglicemia/mortalidade , Hiperglicemia/sangue , Masculino , Estudos Prospectivos , Feminino , Glicemia/análise , Glicemia/metabolismo , Pessoa de Meia-Idade , Idoso , Unidades de Terapia Intensiva , Monitorização Fisiológica/métodos , Monitoramento Contínuo da GlicoseRESUMO
BACKGROUND: In aquaculture, sturgeons are generally maintained in the confined spaces, which not only hinders sturgeon movement, but also threatens their flesh quality that seriously concerned by aquaculture industry. As a typical antioxidant, resveratrol can improve the flesh quality of livestock and poultry. However, the mechanism of resveratrol's effect on the muscle of Siberian sturgeon is still unclear. RESULTS: In this study, the dietary resveratrol increased the myofiber diameter, the content of the amino acids, antioxidant capacity markers (CAT, LDH and SOD) levels and the expression levels of mTORC1 and MYH9 in muscle of Siberian sturgeon. Further transcriptome analysis displayed that ROS production-related pathways ("Oxidative phosphorylation" and "Chemical carcinogenes-reactive oxygen species") were enriched in KEGG analysis, and the expression levels of genes related to the production of ROS (COX4, COX6A, ATPeF1A, etc.) in mitochondria were significantly down-regulated, while the expression levels of genes related to scavenging ROS (SOD1) were up-regulated. CONCLUSIONS: In summary, this study reveals that resveratrol may promote the flesh quality of Siberian sturgeon probably by enhancing myofiber growth, nutritional value and the antioxidant capacity of muscle, which has certain reference significance for the development of a new type of feed for Siberian sturgeon.
Assuntos
Antioxidantes , Peixes , Resveratrol , Animais , Resveratrol/farmacologia , Peixes/metabolismo , Peixes/crescimento & desenvolvimento , Peixes/genética , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Nutrientes/metabolismo , Ração Animal/análise , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/citologia , Cadeias Pesadas de Miosina/metabolismo , Cadeias Pesadas de Miosina/genética , Dieta/veterinária , Perfilação da Expressão GênicaRESUMO
The recent revolution in the superconductivity field stems from hydride superconductors. Multicomponent hydrides provide a crucial platform for tracking high-temperature superconductors. Besides high superconducting transition temperature (Tc), achieving both giant upper critical magnetic field [µ0Hc2(0)] and high critical current density [Jc(0)] is also key to the latent potential of the application for hydride superconductors. In this work, we have successfully synthesized quaternary La-Y-Ce hydrides with excellent properties under moderate pressure by using the concept of "entropy engineering." The obtained temperature dependence of the resistance provides evidence for the superconductivity of Fm3m-(La,Y,Ce)H10, with the maximum Tc â¼ 190 K (at 112 GPa). Notably, Fm3m-(La,Y,Ce)H10 boasts exceptional properties: µ0Hc2(0) reaching 292 T and Jc(0) surpassing 4.61 × 107 A/cm2. Compared with the binary LaH10/YH10, we find that the Fm3m structure in (La,Y,Ce)H10 can be stable at relatively low pressures (112 GPa). These results indicate that multicomponent hydrides can significantly enhance the superconducting properties and regulate stabilizing pressure through the application of "entropy engineering." This work stimulates the experimental exploration of multihydride superconductors and also provides a reference for the search of room-temperature superconductors in more diversified hydride materials in the future.
RESUMO
With increasing resistance of SARS-CoV-2 variants to antibodies, there is interest in developing entry inhibitors that target essential receptor-binding regions of the viral Spike protein and thereby present a high bar for viral resistance. Such inhibitors could be derivatives of the viral receptor, ACE2, or peptides engineered to interact specifically with the Spike receptor-binding pocket. We compared the efficacy of a series of both types of entry inhibitors, constructed as fusions to an antibody Fc domain. Such a design can increase protein stability and act to both neutralize free virus and recruit effector functions to clear infected cells. We tested the reagents against prototype variants of SARS-CoV-2, using both Spike pseudotyped vesicular stomatitis virus vectors and replication-competent viruses. These analyses revealed that an optimized ACE2 derivative could neutralize all variants we tested with high efficacy. In contrast, the Spike-binding peptides had varying activities against different variants, with resistance observed in the Spike proteins from Beta, Gamma, and Omicron (BA.1 and BA.5). The resistance mapped to mutations at Spike residues K417 and N501 and could be overcome for one of the peptides by linking two copies in tandem, effectively creating a tetrameric reagent in the Fc fusion. Finally, both the optimized ACE2 and tetrameric peptide inhibitors provided some protection to human ACE2 transgenic mice challenged with the SARS-CoV-2 Delta variant, which typically causes death in this model within 7-9 days. IMPORTANCE The increasing resistance of SARS-CoV-2 variants to therapeutic antibodies has highlighted the need for new treatment options, especially in individuals who do not respond to vaccination. Receptor decoys that block viral entry are an attractive approach because of the presumed high bar to developing viral resistance. Here, we compare two entry inhibitors based on derivatives of the ACE2 receptor, or engineered peptides that bind to the receptor-binding pocket of the SARS-CoV-2 Spike protein. In each case, the inhibitors were fused to immunoglobulin Fc domains, which can further enhance therapeutic properties, and compared for activity against different SARS-CoV-2 variants. Potent inhibition against multiple SARS-CoV-2 variants was demonstrated in vitro, and even relatively low single doses of optimized reagents provided some protection in a mouse model, confirming their potential as an alternative to antibody therapies.
Assuntos
COVID-19 , Inibidores da Fusão de HIV , Animais , Camundongos , Humanos , SARS-CoV-2/genética , Enzima de Conversão de Angiotensina 2/genética , Glicoproteína da Espícula de Coronavírus/genética , Camundongos Transgênicos , Peptídeos/farmacologiaRESUMO
In recent years, the interaction of intracellular organelles such as mitochondria and lysosomal functions has attracted increasing attention. Recent evidence suggests that mitochondrion-lysosomal contact plays a key role in regulating lysosomal biogenesis and maintaining cellular homeostasis. Myocardial ischemia and reperfusion will lead to corresponding changes in the autophagy flux in cardiomyocytes, and lysosomes are a key link in the process of autophagy, and the fusion of lysosomes and autophagosomes is an essential link in the occurrence of autophagy. Therefore, the function and homeostasis of lysosomes also undergo different changes during myocardial ischemia and reperfusion. Lysosomal-related biological factors and membrane proteins also play different roles. This article will review the mechanism of lysosomes in myocardial ischemia-reperfusion injury and the research progress of lysosomal-related proteins.
RESUMO
Photocatalytic ammonia synthesis (PAS) represents an emerging environmentally friendly approach to ammonia production. In this work, we employed Fe doping to modify the cocatalyst 1T MoS2, enhancing the active N2 sites on Fe-1T MoS2 by inducing defects on the surface of 1T MoS2. Afterward, Fe-1T MoS2 was loaded onto a hollow coral-like graphitic carbon nitride (CCN)/FeOCl composite. Under simulated sunlight, the efficiency of 5% Fe-1T MoS2@CCN/FeOCl (Fe-MCN/FeOCl) reached 367.62 µmol g-1 h-1, surpassing 1T MoS2@CCN(MCN) by 3.2 times, CCN by 16.9 times, and g-C3N4 by 32.5 times, where 5% means the doping amount of Fe in 1T MoS2. The good performance of Fe MCN/FeOCl should be attributed to the Fe doping in Fe-MCN/FeOCl which not only increases the separation efficiency of active sites and charge carriers, but also reduces the sample impedance significantly through the heterojunction formed between CCN and FeOCl. This work also presents a method for creating more efficient and stable photocatalysts for ammonia synthesis.
RESUMO
We have established an efficient ruthenium(II) and iodine anion cocatalyzed dihalogenation and cascade cyclization of internal alkyne-tethered cyclohexadienones, which stereoselectively afforded numerous dihalogenation products with a bioactive hydrobenzofuran skeleton in high yields under mild conditions. In this transformation, the reaction pathway was determined by the concentration of electrophilic iodine reagent, which also provided a strategy for control of the reaction selectivity. Furthermore, this method features the use of 1,2-dihaloroethane as the halogen source via iodine anion catalyst.
RESUMO
As an ancient species with both conservation and commercial value, Sturgeon's inflammatory regulation mechanism is a research point. Nucleotide-binding and oligomerization domain-containing proteins 1 and 2 (NOD1/2) are classical intracellular pattern recognition receptors (PRRs) in immunity of anti-bacterial infection. However, the characterization and function of NOD1/2 in Sturgeon are still unclear. In this study, we analyzed the synteny relationship of NOD1/2 genes between Acipenser ruthenus and representative fishes at the genome-level. Results showed that the ArNOD2 collinear genes pair was present in all representative fishes. The duplicated ArNOD1/2 genes were under purifying selection during evolution as indicated by their Ka/Ks values. To explore the function of NOD1/2, we further investigated their expression patterns and the effects of pathogenic infection, PAMPs treatment, and siRNA interference in Acipenser baerii, the sibling species of A. ruthenus. Results showed that both AbNOD1/2 were expressed at early developmental stages and in different tissues. Pathogenic infection in vivo and PAMPs treatment in vitro demonstrated that AbNOD1/2 could respond to pathogen stimulation. siRNA interference with AbNOD1/2 inhibited expression levels of RIPK2 and inflammatory cytokines compared to the control group after iE-DAP or MDP treatment. This study hinted that the AbNOD1/2 could stimulate the inflammatory cytokines response during evolutionary processes.
Assuntos
Infecções Bacterianas , Moléculas com Motivos Associados a Patógenos , Animais , Peixes/genética , Citocinas , RNA Interferente Pequeno , Proteína Adaptadora de Sinalização NOD1/genética , Proteína Adaptadora de Sinalização NOD2/genéticaRESUMO
Because of the low host specificity, Ichthyophthirius multifiliis (Ich) can widely cause white spot disease in aquatic animals, which is extremely difficult to treat. Prior research has demonstrated a considerable impact of concentrated mannan-oligosaccharide (cMOS) on the prevention of white spot disease in goldfish, but the specific mechanism is still unknown. In this study, transcriptome sequencing, histological analysis, immunofluorescence analysis, phagocytosis activity assay and qRT-PCR assay were used to systematically reveal the potential mechanism of cMOS in supporting the resistance of goldfish (Carrasius auratus) to Ich invasion. According to the transcriptome analysis, the gill tissue of goldfish receiving the cMOS diet showed greater expression of mannose-receptor (MRC) related genes, higher phagocytosis activity, up-regulated expression of phagocytosis-related genes and inflammatory-related genes compared with the control, indicating that cMOS can have an effect on phagocytosis and non-specific immunity of goldfish. After the Ich challenge, transcriptome analysis revealed that cMOS fed goldfish displayed a higher level of phagocytic response, whereas non-cMOS fed goldfish displayed a greater inflammatory reaction. Besides, after Ich infection, cMOS-fed goldfish displayed greater phagocytosis activity, a stronger MRC positive signal, higher expression of genes associated with phagocytosis (ABCB2, C3, MRC), and lower expression of genes associated with inflammation (IL-1ß, IL-17, IL-8, TNF-α, NFKB). In conclusion, our experimental results suggest that cMOS may support phagocytosis by binding to MRC on the macrophage cell membrane and change the non-specific immunity of goldfish by stimulating cytokine expression. The results of this study provide new insights for the mechanism of cMOS on parasitic infection, and also suggest phagocytosis-related pathways may be potential targets for prevention of Ich infection.
Assuntos
Doenças dos Peixes , Carpa Dourada , Animais , Mananas/farmacologia , Citocinas/genética , Macrófagos/metabolismo , FagocitoseRESUMO
Plant polysaccharides as immunomodulators are considered one of the effective measures to reduce antibiotic therapy in aquaculture. The immunomodulatory function of Salvia miltiorrhiza polysaccharides (SMP) has been demonstrated and begun to be applied in vertebrates, but its potential effect on crustaceans is unclear. In this study, crayfish (Procambarus clarkii) was fed with 0 %, 0.3 %, 0.7 %, 1.1 %, and 1.5 % SMP for 4 weeks to investigate the effects of SMP on hemocytes phagocytosis, hepatopancreatic function, and intestinal barrier function. The results revealed that hemocyte phagocytic activity was increased in all SMP groups. During the process of hemocytes phagocytic recognition and formation of phagosomes and phagolysosomes, the mRNA expression levels of mas, hem, rab3, ctsb, and lamp-1 were up-regulated mainly in the 0.3 % SMP group. During the clearance phase of phagocytosis, respiratory burst activity, ROS level, T-SOD, CAT, GST, and LZM activities were mainly increased in the 1.5 % SMP group. Hepatopancreas AKP and GOT activity were no significant change in all SMP groups. ACP activity was significantly enhanced in the 1.1 % SMP group. The GPT activity of 0.3-0.7 % SMP group was significantly decreased. The 0.7 % SMP group had the highest intestinal fold height. The highest index values of OTUs, Ace, Chao, and Shannon were in the 0.3 % SMP group. The dietary addition of 0.3 % SMP led to a tendency of increased relative abundance of Firmicutes and Bacteroidota at the phylum level, while the relative abundance of Proteobacteria at the phylum level decreased. In conclusion, dietary SMP could promote crayfish health by enhancing phagocytosis, protecting hepatopancreas and enhancing intestinal barrier function. This study contributes to the theoretical foundation for exploring the potential application of plant polysaccharides in crustaceans.
Assuntos
Astacoidea , Salvia miltiorrhiza , Animais , Astacoidea/genética , Hemócitos , Hepatopâncreas , Função da Barreira Intestinal , Fagocitose , Polissacarídeos/farmacologiaRESUMO
Infection with Vibrio mimicus in the Siluriformes has demonstrated a rapid and high infectivity and mortality rate, distinct from other hosts. Our earlier investigations identified necrosis, an inflammatory storm, and tissue remodeling as crucial pathological responses in yellow catfish (Pelteobagrus fulvidraco) infected with V. mimicus. The objective of this study was to further elucidate the impact linking these pathological responses within the host during V. mimicus infection. Employing metabolomics and transcriptomics, we uncovered infection-induced dense vacuolization of perimysium; Several genes related to nucleosidase and peptidase activities were significantly upregulated in the skin and muscles of infected fish. Concurrently, the translation processes of host cells were impaired. Further investigation revealed that V. mimicus completes its infection process by enhancing its metabolism, including the utilization of oligopeptides and nucleotides. The high susceptibility of yellow catfish to V. mimicus infection was associated with the composition of its body surface, which provided a microenvironment rich in various nucleotides such as dIMP, dAMP, deoxyguanosine, and ADP, in addition to several amino acids and peptides. Some of these metabolites significantly boost V. mimicus growth and motility, thus influencing its biological functions. Furthermore, we uncovered an elevated expression of gangliosides on the surface of yellow catfish, aiding V. mimicus adhesion and increasing its infection risk. Notably, we observed that the skin and muscles of yellow catfish were deficient in over 25 polyunsaturated fatty acids, such as Eicosapentaenoic acid, 12-oxo-ETE, and 13-Oxo-ODE. These substances play a role in anti-inflammatory mechanisms, possibly contributing to the immune dysregulation observed in yellow catfish. In summary, our study reveals a host immune deviation phenomenon that promotes bacterial colonization by increasing nutrient supply. It underscores the crucial factors rendering yellow catfish highly susceptible to V. mimicus, indicating that host nutritional sources not only enable the establishment and maintenance of infection within the host but also aid bacterial survival under immune pressure, ultimately completing its lifecycle.
Assuntos
Peixes-Gato , Doenças dos Peixes , Vibrioses , Vibrio mimicus , Animais , Peixes-Gato/imunologia , Peixes-Gato/genética , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Vibrioses/veterinária , Vibrioses/imunologia , Vibrio mimicus/imunologia , Suscetibilidade a Doenças/veterinária , Suscetibilidade a Doenças/imunologia , Epiderme/imunologia , Epiderme/microbiologia , NutrientesRESUMO
The immune system of bony fish closely resembles that of mammals, comprising both specific (adaptive) and non-specific (innate) components. Notably, the mucosa-associated lymphoid tissue (MALT) serves as the first line of defense within the non-specific immune system, playing a critical role in protecting these aquatic organisms against invading pathogens. MALT encompasses a network of immune cells strategically distributed throughout the gills and intestines, forming an integral part of the mucosal barrier that interfaces directly with the surrounding aquatic environment. Spring Viremia of Carp Virusï¼SVCVï¼, a highly pathogenic agent causing substantial harm to common carp populations, has been designated as a Class 2 animal disease by the Ministry of Agriculture and Rural Affairs of China. Utilizing a comprehensive array of research techniques, including Hematoxylin and Eosin (HE)ãAlcian Blue Periodic Acid-Schiff (AB-PAS)ãtranscriptome analysis for global gene expression profiling and Reverse Transcription-Polymerase Chain Reaction (RT-qPCR), this study uncovered several key findings: SVCV is capable of compromising the mucosal architecture in the gill and intestinal tissues of carp, and stimulate the proliferation of mucous cells both in gill and intestinal tissues. Critically, the study revealed that SVCV's invasion elicits a robust response from the carp's mucosal immune system, demonstrating the organism's capacity to resist SVCV invasion despite the challenges posed by the pathogen.
Assuntos
Carpas , Doenças dos Peixes , Perfilação da Expressão Gênica , Brânquias , Intestinos , Infecções por Rhabdoviridae , Rhabdoviridae , Animais , Brânquias/imunologia , Brânquias/virologia , Rhabdoviridae/fisiologia , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Carpas/imunologia , Carpas/genética , Perfilação da Expressão Gênica/veterinária , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/veterinária , Infecções por Rhabdoviridae/virologia , Intestinos/imunologia , Intestinos/virologia , Imunidade Inata/genética , Transcriptoma/imunologia , Imunidade nas MucosasRESUMO
Colorectal cancer was one of the major malignant tumors threatening human health and ß-Gal was recognized as a principal biomarker for primary colorectal cancer. Thus, designing specific and efficient quantitative detection methods for measuring ß-Gal enzyme activity was of great clinical test significance. Herein, an ultrasensitive detection method based on Turn-on fluorescence probe (CS-ßGal) was reported for visualizing the detection of exogenous and endogenous ß-galactosidase enzyme activity. The test method possessed a series of excellent performances, such as a significant fluorescence enhancement (about 11.3-fold), high selectivity as well as superior sensitivity. Furthermore, under the optimal experimental conditions, a relatively low limit of detection down to 0.024 U/mL was achieved for fluorescence titration experiment. It was thanks to the better biocompatibility and low cytotoxicity, CS-ßGal had been triumphantly employed to visual detect endogenous and exogenous ß-Gal concentration variations in living cells with noteworthy anti-interference performance. More biologically significant was the fact that the application of CS-ßGal in BALB/c nude mice was also achieved successfully for monitoring endogenous ß-Gal enzyme activity.
RESUMO
The experimentally discovered FeH5 exhibits a structure built of atomic hydrogen that only has bonding between hydrogen and iron atoms [C. M. Pepin, G. Geneste, A. Dewaele, M. Mezouar and P. Loubeyre, Science, 2017, 357, 382]. However, its superconductivity has remained unsolved since its discovery. In this work, we have synthesized I4/mmm-FeH5 at 139 GPa combined with laser-heating conditions. The electrical resistance measurements at ultrahigh pressures indicate that no evidence of superconducting transition of FeH5 is observed in the temperature range of 1.5 K to 270 K. These results indicate that I4/mmm-FeH5 does not exhibit superconductivity within the experimental temperature range, and the introduction of iron atoms is not beneficial to the formation of the superconducting phase.
RESUMO
The compound Honokiol, derived from the bark of Magnolia officinalis, possesses the ability to induce apoptosis and inhibit cellular damage caused by reactive oxygen species. The objective of this study was to investigate the toxicological and histopathological effects of Honokiol on zebrafish (Danio rerio) through conducting a semistatic acute toxicity test involving immersion in an Honokiol-containing solution. The results showed that the toxic effects of Honokiol on zebrafish were primarily manifested in the liver and gills. When exposed to 0.6 mg/L of Honokiol, it could lead to liver hemorrhage as well as swelling and necrosis of gill tissues, and high concentrations of Honokiol could trigger inflammatory responses. Additionally, research found that Honokiol could induce apoptosis in liver and gill tissues through the P53 pathway and possessed the ability to enhance antioxidation. The present findings significantly contribute to a more profound understanding of the toxic impact of Honokiol and its underlying mechanism, thereby providing a valuable reference for the future safe utilization of Honokiol and related pharmaceutical advancements.
Assuntos
Apoptose , Compostos de Bifenilo , Lignanas , Fígado , Peixe-Zebra , Lignanas/farmacologia , Lignanas/toxicidade , Animais , Compostos de Bifenilo/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Apoptose/efeitos dos fármacos , Brânquias/efeitos dos fármacos , Brânquias/patologia , Proteína Supressora de Tumor p53/metabolismo , Magnolia/química , Compostos Alílicos , FenóisRESUMO
BACKGROUND: Lowe syndrome is characterized by the presence of congenital cataracts, psychomotor retardation, and dysfunctional proximal renal tubules. This study presents a case of an atypical phenotype, investigates the genetic characteristics of eight children diagnosed with Lowe syndrome in southern China, and performs functional analysis of the novel variants. METHODS: Whole-exome sequencing was conducted on eight individuals diagnosed with Lowe syndrome from three medical institutions in southern China. Retrospective collection and analysis of clinical and genetic data were performed, and functional analysis was conducted on the five novel variants. RESULTS: In our cohort, the clinical symptoms of the eight Lowe syndrome individuals varied. One patient was diagnosed with Lowe syndrome but did not present with congenital cataracts. Common features among all patients included cognitive impairment, short stature, and low molecular weight proteinuria. Eight variations in the OCRL gene were identified, encompassing three previously reported and five novel variations. Among the novel variations, three nonsense mutations were determined to be pathogenic, and two patients harboring novel missense variations of uncertain significance exhibited severe typical phenotypes. Furthermore, all novel variants were associated with altered protein expression levels and impacted primary cilia formation. CONCLUSION: This study describes the first case of an atypical Lowe syndrome patient without congenital cataracts in China and performs a functional analysis of novel variants in the OCRL gene, thereby expanding the understanding of the clinical manifestations and genetic diversity associated with Lowe syndrome.
Assuntos
Síndrome Oculocerebrorrenal , Fenótipo , Monoéster Fosfórico Hidrolases , Humanos , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/diagnóstico , Masculino , Feminino , Criança , Monoéster Fosfórico Hidrolases/genética , China , Pré-Escolar , Estudos Retrospectivos , Sequenciamento do Exoma , Lactente , Adolescente , Mutação , Povo Asiático/genética , Códon sem Sentido , População do Leste AsiáticoRESUMO
BACKGROUND: Older adults with postprandial hypotension (PPH) increase susceptibility to falls, syncope, stroke, acute cardiovascular diseases and even death. However, the prevalence of this condition varies significantly across studies. We aimed to determine the prevalence of PPH in older adults. METHODS: Web of Science, PubMed, Cochrane Library, Embase and CINAHL were searched from their inception until February 2023. Search terms included 'postprandial period', 'hypotension' and 'postprandial hypotension'. Eligible studies were assessed using the Joanna Briggs Institute tool. Meta-analyses were performed among similar selected studies. RESULTS: Thirteen eligible studies were included, and data from 3,021 participants were pooled. The meta-analysis revealed a PPH prevalence of 40.5% [95% confidence interval (CI): 0.290-0.519] in older adults, and this was prevalent in the community (32.8%, 95% CI: 0.078-0.647, n = 1,594), long-term healthcare facility (39.4%, 95% CI: 0.254-0.610, n = 1,062) and geriatrics department of hospitals (49.3%, 95% CI: 0.357-0.630, n = 365). The pooled results showed significant heterogeneity (I2 > 90%), partially related to the different ages, sex, pre-prandial systolic blood pressure levels of participants, or the different criteria and methodology used to diagnose PPH. CONCLUSIONS: PPH is a prevalent condition in older adults. Further research is needed to confirm this result, and priority should be given to establishing international consensus on PPH diagnostic criteria and designing its diagnostic procedure.
Assuntos
Hipotensão , Período Pós-Prandial , Humanos , Hipotensão/epidemiologia , Hipotensão/diagnóstico , Hipotensão/fisiopatologia , Prevalência , Idoso , Masculino , Feminino , Fatores Etários , Idoso de 80 Anos ou mais , Fatores de RiscoRESUMO
The intestinal microbiota interacts with the host and plays an important role in the immune response, digestive physiology, and regulation of body functions. In addition, it is also well documented that the intestinal microbiota of aquatic animals are closely related to their growth rate. However, whether it resulted in different sizes of crayfish in the rice-crayfish coculture model remained vague. Here, we analyzed the intestinal microbiota characteristics of crayfish of three sizes in the same typical rice-crayfish coculture field by high-throughput sequencing technology combined with quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme activity, investigating the relationship between intestinal microbiota in crayfish and water and sediments. The results showed that the dominant intestinal microbiota of crayfish was significantly different between the large size group (BS), normal size group (NS), and small size group (SS), where Bacteroides and Candidatus_Bacilloplasma contributed to the growth of crayfish by facilitating food digestion through cellulolysis, which might be one of the potential factors affecting the difference in sizes. Follow-up experiments confirmed that the activity of lipase (LPS) and protease was higher in BS, and the relative expression of development-related genes, including alpha-amylase (α-AMY), myocyte-specific enhancer factor 2a (MEF2a), glutathione reductase (GR), chitinase (CHI), and ecdysone receptor (EcR), in BS was significantly higher than that in SS. These findings revealed the intestinal microbiota characteristics of crayfish of different sizes and their potential impact on growth, which is valuable for managing and manipulating the intestinal microbiota in crayfish to achieve high productivity in practice. KEY POINTS: ⢠Significant differences in the dominant microflora of BS, NS, and SS in crayfish. ⢠Cellulolysis might be a potential factor affecting different sizes in crayfish. ⢠Adding Bacteroides and Candidatus_Bacilloplasma helped the growth of crayfish.