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The non-receptor protein tyrosine phosphatase (PTP) SHP2, encoded by PTPN11, plays an essential role in RAS-mitogen-activated protein kinase (MAPK) signaling during normal development. It has been perplexing as to why both enzymatically activating and inactivating mutations in PTPN11 result in human developmental disorders with overlapping clinical manifestations. Here, we uncover a common liquid-liquid phase separation (LLPS) behavior shared by these disease-associated SHP2 mutants. SHP2 LLPS is mediated by the conserved well-folded PTP domain through multivalent electrostatic interactions and regulated by an intrinsic autoinhibitory mechanism through conformational changes. SHP2 allosteric inhibitors can attenuate LLPS of SHP2 mutants, which boosts SHP2 PTP activity. Moreover, disease-associated SHP2 mutants can recruit and activate wild-type (WT) SHP2 in LLPS to promote MAPK activation. These results not only suggest that LLPS serves as a gain-of-function mechanism involved in the pathogenesis of SHP2-associated human diseases but also provide evidence that PTP may be regulated by LLPS that can be therapeutically targeted.
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Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Células A549 , Animales , Niño , Preescolar , Femenino , Mutación con Ganancia de Función/genética , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Ratones , Células Madre Embrionarias de Ratones , Mutación/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Transducción de Señal , Dominios Homologos src/genéticaRESUMEN
BACKGROUND: Internalizing and externalizing problems have received great attention, and children with ADHD exhibit high rates of comorbid internalizing and externalizing disorders. This study aimed to explore the relationship between sleep and internalizing problems in children with attention-deficit hyperactivity disorder (ADHD) and the probable mediating role of externalizing problems. METHODS: A total of 203 primary school children diagnosed with ADHD for the first time were recruited for this study. Children with ADHD were evaluated by Children's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ). Internalizing problems were represented by emotional symptoms and peer problems of SDQ, and externalizing problems were represented by conduct problems and hyperactivity-inattention problems of SDQ. Multi-step linear regression analysis was used to investigate the mediating effect of externalizing problems on the relationship between sleep and internalizing problems. RESULTS: Sleep in children with ADHD was associated with emotional problems in internalizing problems, and conduct problems in externalizing problems mediated the association between sleep and emotional problems. CONCLUSION: For children with ADHD, when it is difficult to identify internalizing problems, especially emotional problems, we can take sleep and externalizing problems as clues to improve our clinical ability to recognize and deal with emotional problems. IMPACT: 1. We first explored the possible mediating role of conduct problems between sleep and emotional problems in primary school children with ADHD. 2. When it is difficult to identify internalizing problems, especially emotional problems, we can take sleep and externalizing problems as clues to improve our clinical ability to recognize emotional problems for children with ADHD. 3. For children with ADHD with potential internalizing problems, especially emotional problems, interventions for their sleep and externalizing problems may be the possible methods to deal with.
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BACKGROUND: Infection with Helicobacter pylori (Hp) mostly occurs during childhood, and persistent infection may lead to severe gastric diseases and even gastric cancer. Currently, the primary method for eradicating Hp is through antibiotic treatment. However, the increasing multidrug resistance in Hp strains has diminished the effectiveness of antibiotic treatments. Vaccination could potentially serve as an effective intervention to resolve this issue. AIMS: Through extensive research and analysis of the vital protein characteristics involved in Hp infection, we aim to provide references for subsequent vaccine antigen selection. Additionally, we summarize the current research and development of Hp vaccines in order to provide assistance for future research. MATERIALS AND METHODS: Utilizing the databases PubMed and the Web of Science, a comprehensive search was conducted to compile articles pertaining to Hp antigens and vaccines. The salient aspects of these articles were then summarized to provide a detailed overview of the current research landscape in this field. RESULTS: Several potential antigens have been identified and introduced through a thorough understanding of the infection process and pathogenic mechanisms of Hp. The conserved and widely distributed candidate antigens in Hp, such as UreB, HpaA, GGT, and NAP, are discussed. Proteins such as CagA and VacA, which have significant virulence effects but relatively poor conservatism, require further evaluation. Emerging antigens like HtrA and dupA have significant research value. In addition, vaccines based on these candidate antigens have been compiled and summarized. CONCLUSIONS: Vaccines are a promising method for preventing and treating Hp. While some Hp vaccines have achieved promising results, mature products are not yet available on the market. Great efforts have been directed toward developing various types of vaccines, underscoring the need for developers to select appropriate antigens and vaccine formulations to improve success rates.
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Antígenos Bacterianos , Vacunas Bacterianas , Infecciones por Helicobacter , Helicobacter pylori , Desarrollo de Vacunas , Helicobacter pylori/inmunología , Vacunas Bacterianas/inmunología , Infecciones por Helicobacter/prevención & control , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Humanos , Antígenos Bacterianos/inmunología , AnimalesRESUMEN
Flexible metal-organic frameworks (FMOFs) exhibit reversible structural transitions ("breathing" behaviors), which can regulate the proton transport passageway effectively. This property offers remarkable advantages for improving the proton conductivity. Our objective of this work is to design a single-variable flexibility synergistic strategy for the fabrication of FMOFs with high conductivity. Herein, four two-dimensional FMOFs, {[Co(4-bpdb)(R-ip)]·xsolvents}n (x = rich, 1-4), have been successfully designed and assembled (4-bpdb = 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene and R-ip = MeO/EtO/n-PrO/n-BuO-isophthalate). Upon the release and/or absorption of different solvent molecules, they display reversible breathing behaviors, thereby resulting in the formation of the partial and complete solvent-free compounds {[Co(4-bpdb)(R-ip)]·ysolvents}n (y = free or poor, 1A-4A). This breathing behavior involves the synergistic self-adaption of the dynamic torsion of alkoxy groups and reversible structural transformation, leading to remarkable changes in cell parameters and void space, as evidenced by single-crystal X-ray diffraction, powder X-ray diffraction, and N2 and CO2 adsorption analyses. At 363 K and 98% relative humidity, 2A exhibits the best proton conductivity among the FMOFs. Its conductivity reaches 4.08 × 10-2 S cm-1 and is one of the highest conductivities shown by reported unmodified MOF-based proton conductors.
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Metal-organic frameworks (MOFs) have shown promising potential as proton-conducting materials due to their tunable structures and high porosity. In this study, two novel MOFs had been successfully synthesized, one containing sulfate groups (MOF-1; [Zn4(TIPE)2(SO4)4(H2O)]·5H2O) and the other containing sulfonate groups (MOF-2; [Zn2(TIPE)(5-sip)(NO3)0.66]·0.34NO3·17.5H2O) (TIPE = 1,1,2,2-tetrakis(4-(1H-imidazole-1-yl)phenyl)ethene, H35-sip = 5-sulfoisophthalicacid), and the effect of the two groups on the proton conductivity of Zn-based MOFs had been investigated and compared for the first time. The proton conductivity of these MOFs was systematically measured at different temperatures and humidity conditions. Remarkably, the results revealed significant differences in proton conductivity between the two sets of MOFs. At 90 °C and 98% RH, MOF-1 and MOF-2 achieved optimal proton conductivity of 4.48 × 10-3 and 5.69 × 10-2 S·cm-1, respectively. This was due to the structural differences arising from the presence of different functional groups, which subsequently affected the porosity and hydrophilicity, thereby influencing the proton conductivity. Overall, this comparative study revealed the influence of sulfate and sulfonate groups on the proton conductivity of Zn-based MOFs. This research provided a feasible idea for the development of advanced MOF materials with enhanced proton conductivity and opened up new possibilities for their application in proton devices.
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Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer. Two new prenylated indole 2,5-diketopiperazine alkaloids, brevianamides E1 (1) and E2 (2), were isolated from a Penicillium fungus. Both compounds showed moderate cytotoxic activity against select MCC cell lines (i.e., MCC13, MKL-1, UISO, and WaGa) in the low micromolar range. The relative and absolute configurations of 1 and 2 were determined by combined approaches, including NOESY spectroscopy, DFT ECD and DP4 plus calculations, and Marfey's reaction. Literature research and the comparison of NMR and ECD data led to the structure revision of three previously reported natural analogues, notoamides K and P and asperversiamide L. The structurally unstable 1 and 2 underwent steady interconversion under neutral aqueous conditions. Investigation of the degradation of 2 in acidic methanol solutions led to the identification of a new methoxylated derivative (6) and two new ring-opened products (7 and 8) with the rearranged, elongated, 4-methylpent-3-ene side chain. The facile transformation of 2 to 7 and 8 was promoted by the intrinsic impurity (i.e., formaldehyde) of HPLC-grade methanol through the aza-Cope rearrangement.
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Dicetopiperazinas , Penicillium , Penicillium/química , Dicetopiperazinas/farmacología , Dicetopiperazinas/química , Estructura Molecular , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
A high throughput screen performed to identify catalytic inhibitors of the oncogenic fusion form of cAMP-dependent protein kinase A catalytic subunit alpha (J-PKAcα) found an individual fraction from an organic extract of the marine soft coral Acrozoanthus australiae as active. Bioassay-guided isolation led to the identification of a 2-amino adenine alkaloid acroamine A (1), the first secondary metabolite discovered from this genus and previously reported as a synthetic product. As a naturally occurring protein kinase inhibitor, to unambiguously assign its chemical structure using modern spectroscopic and spectrometric techniques, five N-methylated derivatives acroamines A1-A5 (2-6) were semisynthesized. Three additional brominated congeners A6-A8 (7-9) were also semisynthesized to investigate the structure-activity relationship of the nine compounds as J-PKAcα inhibitors. Compounds 1-9 were tested for J-PKAcα and wild-type PKA inhibitory activities, which were observed exclusively in acroamine A (1) and its brominated analogs (7-9) achieving moderate potency (IC50 2-50 µM) while none of the N-methylated analogs exhibited kinase inhibition.
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Alcaloides , Antozoos , Proteínas Quinasas Dependientes de AMP Cíclico , Animales , Antozoos/química , Estructura Molecular , Alcaloides/farmacología , Alcaloides/química , Alcaloides/aislamiento & purificación , Relación Estructura-Actividad , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Adenina/farmacología , Adenina/análogos & derivados , Adenina/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Dominio CatalíticoRESUMEN
BACKGROUND AND AIM: The triglyceride and glucose (TyG) index, as a surrogate marker of insulin resistance, was related to increased mortality. Our study aimed to investigate the specific relationship between the TyG index and all-cause mortality among obese population. METHODS AND RESULTS: 6731 participants with obesity were enrolled from the National Health and Nutrition Examination Survey (NHANES). The TyG index was calculated as log [fasting triglycerides (mg/dL) x fasting glucose (mg/dL)/2]. The baseline levels of TyG associated with the risk of all-cause and cardiovascular mortality were evaluated by Cox proportional hazards models. After a follow-up of 16.7 years, 693 all-cause death and 133 cardiovascular deaths occurred. Dose-response curve showed that the association of the risk of all-cause mortality was non-linear (p = 0.019) and the corresponding TyG index ranged 8.78 to 9.64 for the lowest risk. Compared with the reference quartile of 8.79-9.22, the multivariate-adjusted hazards ratios were 1.32 ((95% confidence interval 1.03-1.70; p = 0.030) in the lowest quartile for all-cause mortality, and 0.55 (0.32-0.93; p = 0.025) in the second quartile for cardiovascular mortality. CONCLUSIONS: TyG index was associated with the risk of all-cause mortality in obese participants and the level associated with the lowest risk was 8.78-9.64.
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Enfermedades Cardiovasculares , Glucosa , Humanos , Encuestas Nutricionales , Obesidad/diagnóstico , Triglicéridos , Enfermedades Cardiovasculares/diagnóstico , Glucemia , Biomarcadores , Factores de RiesgoRESUMEN
KEY MESSAGE: SmZHDs was highly expressed in anthocyanin-rich parts of eggplant. SmZHD12 can activate the expression of SmCHS, SmANS, SmDFR and SmF3H. Overexpression of SmZHD12 promotes anthocyanin biosynthesis in Arabidopsis. The Zinc finger-homeodomain (ZHD) proteins family genes are known to play a significant role in plant development and physiological processes. However, the evolutionary history and function of the ZHD gene family in eggplant remain largely unexplored. This study categorizes a total of 15 SmZHD genes into SmMIF and SmZHD subfamilies based on conserved domains. The phylogeny, gene structure, conserved motifs, promoter elements, and chromosomal locations of the SmZHD genes were comprehensively analyzed. Tissue expression profiles indicate that the majority of SmZHD genes are expressed in anthocyanin-rich areas. qRT-PCR assays revealed distinct expression patterns of SmZHD genes in response to various treatments, indicating their potential involvement in multiple signaling pathways. Analysis of transcriptomic data from light-treated eggplant peel identified SmZHD12 as the most light-responsive gene among the 15 SmZHD genes. Consequently, this study provides further evidence that SmZHD12 facilitates anthocyanin accumulation in Arabidopsis leaves by upregulating the expression of anthocyanin biosynthesis structural genes, as confirmed by dual-luciferase assays and Arabidopsis genetic transformation. Our study will lay a solid foundation for the in-depth study of the involvement of SmZHD genes in the regulation of anthocyanin biosynthesis.
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Arabidopsis , Solanum melongena , Solanum melongena/genética , Antocianinas , Arabidopsis/genética , Evolución Biológica , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: This study examined the moderating role of outdoor time on the relationship between overweight and myopia. METHODS: The data for this study was obtained from a prospective study in Shanghai, where non-myopic children wore wristwear and were followed up for 1 year. Eye examinations were performed at each visit. The modification effect was assessed on the additive scale using multivariable logistic regression, and relative excess risk due to interaction was used to calculate the modification effect. RESULTS: A total of 4683 non-myopic children were included with 32.20% being overweight at baseline. Following a 1-year period, 17.42% of children had myopia. When compared to those who spent <90 minutes outdoors, children who spent >120 had a relative risk of myopia onset that was reduced to 0.61. As time spent outdoors decreased, more risks of myopia onset were identified among overweight children than among normal children, the modification effect on the additive scale was -0.007, with ~70% of this effect attributed to the modifying influence of outdoor time. CONCLUSIONS: Increasing outdoor time can reduce myopia more among overweight children than normal. Future interventions should focus on outdoor activities among overweight children to reduce myopia risks.
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Miopía , Obesidad Infantil , Niño , Humanos , Preescolar , Estudios de Seguimiento , Estudios Prospectivos , Sobrepeso/complicaciones , Sobrepeso/epidemiología , Obesidad Infantil/epidemiología , Obesidad Infantil/etiología , Actividades Recreativas , China/epidemiología , Miopía/epidemiología , Miopía/etiología , Encuestas y CuestionariosRESUMEN
BACKGROUND: Seeking COVID-19 information promotes individuals to adopt preventive behaviors, including wearing a mask, social distancing, staying away from risky places, and washing hands. This study aims to investigate which information and sources individuals relied on in seeking COVID-19 information and further examine their roles in individuals' adoption of preventive behaviors. METHODS: Through a statistical analysis of 1027 valid responses from citizens in different Chinese cities in 2022 to the self-designed items in an online survey, this study identified individuals' preferred information sources and content on COVID-19. Regarding the information sources and content, the study used multiple regression analysis to examine their associations with individuals' preventive behaviors, and further applied fuzzy-set qualitative comparative analysis (fsQCA) to explore their configurations that increase the likelihood of individuals adopting preventive behaviors. RESULTS: Individuals preferred information about the newest prevention and control policies, precautions and treatment, and symptoms from the sources of workplace and community, social media, and social live streaming services. Additionally, individuals' preventive behaviors were positively related to the workplace and community (ß = 0.202, p <.001), social live streaming services (ß = 0.089, p <.01), government department websites (ß = 0.079, p <.05), television (ß = 0.073, p <.05), and online news media (ß = 0.069, p <.05), but were negatively associated with newspapers (ß=-0.087, p <.05). Regarding information content, precautions and treatments (ß = 0.211, p <.001), the newest prevention and control policies (ß = 0.173, p <.001), symptoms (ß = 0.152, p <.001), and official rumor-dispelling information (ß = 0.082, p <.05) had a positive relationship with individuals' preventive behaviors. In addition, fsQCA results presented eight configurations that promote individuals to adopt preventive behaviors. The total coverage and solution consistency values were 0.869 and 0.987, respectively. Furthermore, COVID-19 information content, the sources of social media and interpersonal sources, and official news media played an essential role in increasing the likelihood of individuals adopting preventive behaviors. CONCLUSIONS: Our findings demonstrated that individuals seek various COVID-19 information from multiple sources. The direct and degree of association of information sources and content with individuals' preventive behaviors vary from source to source and from content to content. Information sources and content could combinatorially promote individuals to adopt preventive behaviors through several configurations.
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COVID-19 , Humanos , COVID-19/prevención & control , SARS-CoV-2 , Conducta en la Búsqueda de Información , Encuestas y Cuestionarios , Medios de Comunicación de MasasRESUMEN
PURPOSE: To investigate the relationship between multi-dimensional aspects of screen exposure and autistic symptoms, as well as neuropsychological development in children with ASD. METHODS: We compared the ScreenQ and Griffiths Development Scales-Chinese Language Edition (GDS-C) of 636 ASD children (40.79 ± 11.45 months) and 43 typically developing (TD) children (42.44 ± 9.61 months). Then, we analyzed the correlations between ScreenQ and Childhood Autism Rating Scale (CARS), and GDS-C. We further used linear regression model to analyze the risk factors associated with high CARS total scores and low development quotients (DQs) in children with ASD. RESULTS: The CARS of children with ASD was positively correlated with the ScreenQ total scores and "access, frequency, co-viewing" items of ScreenQ. The personal social skills DQ was negatively correlated with the "access, frequency, content, co-viewing and total scores" of ScreenQ. The hearing-speech DQ was negatively correlated with the "frequency, content, co-viewing and total scores" of ScreenQ. The eye-hand coordination DQ was negatively correlated with the "frequency and total scores" of ScreenQ. The performance DQ was negatively correlated with the "frequency" item of ScreenQ. CONCLUSION: ScreenQ can be used in the study of screen exposure in children with ASD. The higher the ScreenQ scores, the more severe the autistic symptoms tend to be, and the more delayed the development of children with ASD in the domains of personal-social, hearing-speech and eye-hand coordination. In addition, "frequency" has the greatest impact on the domains of personal social skills, hearing-speech, eye-hand coordination and performance of children with ASD.
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Trastorno del Espectro Autista , Humanos , Trastorno del Espectro Autista/diagnóstico , Masculino , Femenino , Preescolar , Pruebas Neuropsicológicas , Tiempo de Pantalla , Estudios de Casos y Controles , Niño , Desarrollo Infantil , Habilidades SocialesRESUMEN
EcGUS has drawn considerable attention for its role as a target in alleviating serious GIAEs. In this study, a series of 72 (thio)urea derivatives were designed, synthesised, and biologically assayed. The bioassay results revealed that E-9 (IC50 = 2.68 µM) exhibited a promising inhibitory effect on EcGUS, surpassing EcGUS inhibitor D-saccharic acid-1,4-lactone (DSL, IC50 = 45.8 µM). Additionally, the inhibitory kinetic study indicated that E-9 (Ki = 1.64 µM) acted as an uncompetitive inhibitor against EcGUS. The structure-activity relationship revealed that introducing an electron-withdrawing group into the benzene ring at the para-position is beneficial for enhancing inhibitory activity against EcGUS. Furthermore, molecular docking analysis indicated that E-9 has a strong affinity to EcGUS by forming interactions with residues Asp 163, Tyr 472, and Glu 504. Overall, these results suggested that E-9 could be a potent EcGUS inhibitor, providing valuable insights and guidelines for the development of future inhibitors targeting EcGUS.
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Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos , Escherichia coli , Glucuronidasa , Relación Estructura-Actividad , Estructura Molecular , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Glucuronidasa/antagonistas & inhibidores , Glucuronidasa/metabolismo , Simulación del Acoplamiento Molecular , Tiourea/farmacología , Tiourea/química , Tiourea/síntesis química , GlicoproteínasRESUMEN
Recent research [Wang et al., Nature 581, 184-189 (2020)] indicates nitric acid (NA) can participate in sulfuric acid (SA)-ammonia (NH3) nucleation in the clean and cold upper free troposphere, whereas NA exhibits no obvious effects at the boundary layer with relatively high temperatures. Herein, considering that an SA-dimethylamine (DMA) nucleation mechanism was detected in megacities [Yao et al., Science 361, 278-281 (2018)], the roles of NA in SA-DMA nucleation are investigated. Different from SA-NH3 nucleation, we found that NA can enhance SA-DMA-based particle formation rates in the polluted atmospheric boundary layer, such as Beijing in winter, with the enhancement up to 80-fold. Moreover, we found that NA can promote the number concentrations of nucleation clusters (up to 27-fold) and contribute 76% of cluster formation pathways at 280 K. The enhancements on particle formation by NA are critical for particulate pollution in the polluted boundary layer with relatively high NA and DMA concentrations.
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Amoníaco/química , Dimetilaminas/química , Contaminantes Ambientales/química , Contaminación Ambiental/análisis , Ácido Nítrico/química , Ácidos Sulfúricos/química , Atmósfera , Modelos Químicos , TermodinámicaRESUMEN
Neural networks are popular data-driven modeling tools that come with high data collection costs. This paper proposes a residual-based multipeaks adaptive sampling (RMAS) algorithm, which can reduce the demand for a large number of samples in the identification of stochastic dynamical systems. Compared to classical residual-based sampling algorithms, the RMAS algorithm achieves higher system identification accuracy without relying on any hyperparameters. Subsequently, combining the RMAS algorithm and neural network, a few-shot identification (FSI) method for stochastic dynamical systems is proposed, which is applied to the identification of a vegetation biomass change model and the Rayleigh-Van der Pol impact vibration model. We show that the RMAS algorithm modifies residual-based sampling algorithms and, in particular, reduces the system identification error by 76% with the same sample sizes. Moreover, the surrogate model accurately predicts the first escape probability density function and the P bifurcation behavior in the systems, with the error of less than 1.59×10-2. Finally, the robustness of the FSI method is validated.
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Two uncommon epoxyquinols, pyrrolocytosporin A (1) and cytosporin E2 (2), along with the known cytosporin Y1 (3), were isolated from the solid defined medium of the Arctic-derived fungus Eutypella sp. D-1. Their structures were established through comprehensive analyses of spectroscopic and electronic circular dichroism data. Structurally, compound 1 represented the first nitrogen-containing epoxyquinol characterized by a pyrrole fused cytosporin framework, while compound 2 contained an uncommon cyclic carbonate functionality. The antibacterial, immunosuppressive, anti-inflammatory, and cytotoxic activities of all compounds were evaluated. Among the three metabolites, only compound 1 exhibited inhibitory effects on nitric oxide production induced by lipopolysaccharide with an IC50 value of 6.55â µM. Additionally, only compound 2 displayed inhibitory activity against ConA-induced T-cell proliferation with an IC50 value of 9.85â µM.
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Proliferación Celular , Lipopolisacáridos , Óxido Nítrico , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Óxido Nítrico/metabolismo , Proliferación Celular/efectos de los fármacos , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Humanos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Animales , Ratones , Linfocitos T/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Pirroles/química , Pirroles/farmacología , Pirroles/aislamiento & purificación , Estructura Molecular , Conformación Molecular , Células RAW 264.7 , Relación Dosis-Respuesta a DrogaRESUMEN
Wound infection is one of the most important factors affecting wound healing, so its effective control is critical to promote the process of wound healing. However, with the increasing prevalence of multi-drug-resistant (MDR) bacterial strains, the prevention and treatment of wound infections are now more challenging, imposing heavy medical and financial burdens on patients. Furthermore, the diminishing effectiveness of conventional antimicrobials and the declining research on new antibiotics necessitate the urgent exploration of alternative treatments for wound infections. Recently, phage therapy has been revitalized as a promising strategy to address the challenges posed by bacterial infections in the era of antibiotic resistance. The use of phage therapy in treating infectious diseases has demonstrated positive results. This review provides an overview of the mechanisms, characteristics, and delivery methods of phage therapy for combating pathogenic bacteria. Then, we focus on the clinical application of various phage therapies in managing refractory wound infections, such as diabetic foot infections, as well as traumatic, surgical, and burn wound infections. Additionally, an analysis of the potential obstacles and challenges of phage therapy in clinical practice is presented, along with corresponding strategies for addressing these issues. This review serves to enhance our understanding of phage therapy and provides innovative avenues for addressing refractory infections in wound healing.
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Terapia de Fagos , Infección de Heridas , Terapia de Fagos/métodos , Humanos , Infección de Heridas/terapia , Infección de Heridas/microbiología , Cicatrización de Heridas , Infecciones Bacterianas/terapia , Infecciones Bacterianas/microbiología , Bacteriófagos/fisiología , Animales , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana MúltipleRESUMEN
Strigolactones (SLs) are plant hormones that regulate several key agronomic traits, including shoot branching, leaf senescence, and stress tolerance. The artificial regulation of SL biosynthesis and signaling has been considered as a potent strategy in regulating plant architecture and combatting the infection of parasitic weeds to help improve crop yield. DL1b is a previously reported SL receptor inhibitor molecule that significantly promotes shoot branching. Here, we synthesized 18 novel compounds based on the structure of DL1b. We performed rice tillering activity assay and selected a novel small molecule, C6, as a candidate SL receptor inhibitor. In vitro bioassays demonstrated that C6 possesses various regulatory functions as an SL inhibitor, including inhibiting germination of the root parasitic seeds Phelipanche aegyptiaca, delaying leaf senescence and promoting hypocotyl elongation of Arabidopsis. ITC analysis and molecular docking experiments further confirmed that C6 can interact with SL receptor proteins, thereby interfering with the binding of SL to its receptor. Therefore, C6 is considered a novel SL receptor inhibitor with potential applications in plant architecture control and prevention of root parasitic weed infestation.
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Arabidopsis , Ésteres , Compuestos Heterocíclicos con 3 Anillos , Lactonas , Naftalenos , Simulación del Acoplamiento Molecular , Ácidos CarboxílicosRESUMEN
Leptospirosis is a recurring but neglected zoonotic disease caused by pathogenic Leptospira. The explicit underlying mechanism of necroptosis and its role in Leptospira infection have not yet been elucidated. Here we reported that leptospiral pathogen-associated molecular patterns, lipopolysaccharide, and glycolipoprotein activate the necroptotic RIPK1-RIPK3-MLKL cascade through the TLR4 signaling pathway in mouse macrophages. Using the murine acute leptospirosis model, we reveal that abolition of necroptosis exhibited significantly improved outcomes in acute phases, with enhanced eradication of Leptospira from liver, mild clinical symptoms, and decreased cytokine production. RIPK3 was also found to exert a necroptosis-independent function in CXCL1 production and neutrophil recruitment, with the consequence of improved Leptospira control. These findings improve our understanding of the mechanism of Leptospira-macrophage interactions, indicating potential therapeutic values by targeting necroptosis signaling pathways.
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Leptospira , Leptospirosis , Ratones , Animales , Lipopolisacáridos , Necroptosis , Leptospirosis/patología , Leptospira/metabolismo , Macrófagos/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con ReceptoresRESUMEN
BACKGROUND: Trehalose-6-phosphate phosphatase (TPP) is an essential enzyme catalyzing trehalose synthesis, an important regulatory factor for plant development and stress response in higher plants. However, the TPP gene family in soybean has not been reported. RESULTS: A comprehensive analysis of the TPP gene family identified 18 GmTPPs classified into eight groups based on the phylogenetic relationships and the conservation of protein in six monocot and eudicot plants. The closely linked subfamilies had similar motifs and intron/exon numbers. Segmental duplication was the main driving force of soybean GmTPPs expansion. In addition, analysis of the cis-regulatory elements and promoter regions of GmTPPs revealed that GmTPPs regulated the response to several abiotic stresses. Moreover, RNA-seq and qRT-PCR analysis of the tissue-specific GmTPPs under different abiotic stresses revealed that most GmTPPs were associated with response to different stresses, including cold, drought, saline-alkali, and exogenous trehalose. Notably, exogenous trehalose treatment up-regulated the expression of most TPP genes under saline-alkali conditions while increasing the carbohydrate and trehalose levels and reducing reactive oxygen species (ROS) accumulation in soybean sprouts, especially in the saline-alkali tolerant genotype. Furthermore, the interaction network and miRNA target prediction revealed that GmTPPs interacted with abiotic stress response-related transcription factors. CONCLUSIONS: The findings in this study lay a foundation for further functional studies on TPP-based breeding to improve soybean development and stress tolerance.