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BACKGROUND: Quantitative measurement of pupil change has not been assessed against the Richmond Agitation and Sedation Scale (RASS) and spectral edge frequency (SEF) during sedation. The aim of this study was to evaluate pupillometry against these measures in sedated critically ill adult patients. METHODS: In ventilated and sedated patients, pupillary variables were measured by automated pupillometry at each RASS level from -5 to 0 after discontinuation of hypnotics, while processed electroencephalogram variables were displayed continuously and SEF was recorded at each RASS level. Correlations were made between percentage pupillary light reflex (%PLR) and RASS, and between %PLR and SEF. The ability of %PLR to differentiate light sedation (RASS ≥-2), moderate (RASS =-3), and deep sedation (RASS ≤-4) was assessed by areas under receiver operating characteristic (ROC) curves. RESULTS: A total of 163 paired measurements were recorded in 38 patients. With decreasing sedation depth, median %PLR increased progressively from 20% (interquartile range 17-25%) to 36% (interquartile range 33-40%) (P<0.001). Strong correlations were found between %PLR and RASS (Rho=0.635) and between %PLR and SEF (R=0.641). Area under the curve (AUC) of 0.87 with a %PLR threshold of 28% differentiated moderate/light sedation from deep sedation with sensitivity of 83% and specificity of 83%. An AUC of 0.82 with a threshold of 31% distinguished light sedation from moderate/deep sedation with a sensitivity of 81% and a specificity of 75%. CONCLUSIONS: Quantitative assessment of %PLR correlates with other indicators of sedation depth in critically ill patients.
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Enfermedad Crítica , Hipnóticos y Sedantes , Adulto , Humanos , Estudios Prospectivos , Sedación Consciente , ElectroencefalografíaRESUMEN
Aminoacyl-tRNA synthetases are enzymes that ensure accurate protein synthesis. Variants of the dual-functional cytoplasmic human glutamyl-prolyl-tRNA synthetase, EPRS1, have been associated with leukodystrophy, diabetes and bone disease. Here, we report compound heterozygous variants in EPRS1 in a 4-year-old female patient presenting with psychomotor developmental delay, seizures and deafness. Functional studies of these two missense mutations support major defects in enzymatic function in vitro and contributed to confirmation of the diagnosis.
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Aminoacil-ARNt Sintetasas , Sordera , Epilepsia , Femenino , Humanos , Preescolar , Aminoacilación , Aminoacil-ARNt Sintetasas/genética , Mutación , Epilepsia/diagnóstico , Epilepsia/genética , Convulsiones/genética , Sordera/genéticaRESUMEN
Aminoacyl-tRNA synthetases (ARSs) catalyze the charging of specific amino acids onto cognate tRNAs, an essential process for protein synthesis. Mutations in ARSs are frequently associated with a variety of human diseases. The human EPRS1 gene encodes a bifunctional glutamyl-prolyl-tRNA synthetase (EPRS) with two catalytic cores and appended domains that contribute to nontranslational functions. In this study, we report compound heterozygous mutations in EPRS1, which lead to amino acid substitutions P14R and E205G in two patients with diabetes and bone diseases. While neither mutation affects tRNA binding or association of EPRS with the multisynthetase complex, E205G in the glutamyl-tRNA synthetase (ERS) region of EPRS is defective in amino acid activation and tRNAGlu charging. The P14R mutation induces a conformational change and altered tRNA charging kinetics in vitro. We propose that the altered catalytic activity and conformational changes in the EPRS variants sensitize patient cells to stress, triggering an increased integrated stress response (ISR) that diminishes cell viability. Indeed, patient-derived cells expressing the compound heterozygous EPRS show heightened induction of the ISR, suggestive of disruptions in protein homeostasis. These results have important implications for understanding ARS-associated human disease mechanisms and development of new therapeutics.
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Enfermedades Óseas , Diabetes Mellitus , Enfermedades Genéticas Congénitas , Glutamato-ARNt Ligasa , Mutación Missense , Estrés Fisiológico/genética , Sustitución de Aminoácidos , Enfermedades Óseas/enzimología , Enfermedades Óseas/genética , Diabetes Mellitus/enzimología , Diabetes Mellitus/genética , Enfermedades Genéticas Congénitas/enzimología , Enfermedades Genéticas Congénitas/genética , Glutamato-ARNt Ligasa/química , Glutamato-ARNt Ligasa/genética , Glutamato-ARNt Ligasa/metabolismo , Células HEK293 , Humanos , MasculinoRESUMEN
Neothalfine is a natural bisbenzylisoquinoline alkaloid with the abundant resource in medicinal plants and has not been reported its anti-tumor efficacy. In the present study, the anti-tumor efficacy was investigated and it showed broad-spectrum activity against several cancer cell lines, especially metastatic colorectal cancer (HCT116, SW620, T84) with the IC50 values of 7.2, 5.9, 8.2 nM, respectively, roughly equal to well-known anti-tumor agent docetaxel (4.0, 4.7, 2.7 nM) and nearly 1000 folds than CPT-11 (4.4, 5.1, 6.9 µM). Furthermore, neothalfine inhibited colorectal cell proliferation by resulting in cell cycle arrest at the G2/M phase and induced apoptosis through the dysfunction of mitochondria to trigger intrinsic apoptotic pathway by untargeted metabolomic method, mitochondrial membrane potential, and caspase-3/7 activity assay. Moreover, neothalfine damaged colorectal cancer clonal spheres expansion significantly at the concentration of 3.5 nM with nearly 1000 folds efficacy than CPT-11 (3.0 µM). The results supported that neothalfine might be an anti-tumor lead for further investigation.
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Antineoplásicos/farmacología , Productos Biológicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Antineoplásicos/química , Productos Biológicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/secundario , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The lifecycle of retroviruses and retrotransposons includes a reverse transcription step, wherein dsDNA is synthesized from genomic RNA for subsequent insertion into the host genome. Retroviruses and retrotransposons commonly appropriate major components of the host cell translational machinery, including cellular tRNAs, which are exploited as reverse transcription primers. Nonpriming functions of tRNAs have also been proposed, such as in HIV-1 virion assembly, and tRNA-derived fragments may also be involved in retrovirus and retrotransposon replication. Moreover, host cellular proteins regulate retroviral replication by binding to tRNAs and thereby affecting various steps in the viral lifecycle. For example, in some cases, tRNA primer selection is facilitated by cognate aminoacyl-tRNA synthetases (ARSs), which bind tRNAs and ligate them to their corresponding amino acids, but also have many known nontranslational functions. Multi-omic studies have revealed that ARSs interact with both viral proteins and RNAs and potentially regulate retroviral replication. Here, we review the currently known roles of tRNAs and their derivatives in retroviral and retrotransposon replication and shed light on the roles of tRNA-binding proteins such as ARSs in this process.
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Aminoacil-ARNt Sintetasas , Infecciones por VIH , VIH-1/fisiología , ARN de Transferencia , Ensamble de Virus/fisiología , Aminoacil-ARNt Sintetasas/genética , Aminoacil-ARNt Sintetasas/metabolismo , Animales , Infecciones por VIH/genética , Infecciones por VIH/metabolismo , Humanos , ARN de Transferencia/genética , ARN de Transferencia/metabolismoRESUMEN
BACKGROUND: Previous phylogenetic analyses of species within the genus Golovinomyces (Ascomycota, Erysiphales), based on ITS and 28S rDNA sequence data, revealed a co-evolutionary relationship between powdery mildew species and hosts of certain tribes of the plant family Asteraceae. Golovinomyces growing on host plants belonging to the Heliantheae formed a single lineage, comprised of a morphologically differentiated complex of species, which included G. ambrosiae, G. circumfusus, and G. spadiceus. However, the lineage also encompassed sequences retrieved from Golovinomyces specimens on other Asteraceae tribes as well as other plant families, suggesting the involvement of a plurivorous species. A multilocus phylogenetic examination of this complex, using ITS, 28S, IGS (intergenic spacer), TUB2 (beta-tubulin), and CHS1 (chitin synthase I) sequence data was carried out to clarify the discrepancies between ITS and 28S rDNA sequence data and morphological differences. Furthermore, the circumscription of species and their host ranges were emended. RESULTS: The phylogenetic and morphological analyses conducted in this study revealed three distinct species named, viz., (1) G. ambrosiae emend. (including G. spadiceus), a plurivorous species that occurs on a multitude of hosts including, Ambrosia spp., multiple species of the Heliantheae and plant species of other tribes of Asteraceae including the Asian species of Eupatorium; (2) G. latisporus comb. nov. (≡ Oidium latisporum), the closely related, but morphologically distinct species confined to hosts of the Heliantheae genera Helianthus, Zinnia, and most likely Rudbeckia; and (3) G. circumfusus confined to Eupatorium cannabinum in Europe. CONCLUSIONS: The present results provide strong evidence that the combination of multi-locus phylogeny and morphological analysis is an effective way to identify species in the genus Golovinomyces.
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ADN de Hongos/genética , Erysiphe/clasificación , Tipificación de Secuencias Multilocus/métodos , Código de Barras del ADN Taxonómico , Erysiphe/genética , Evolución Molecular , Técnicas de Tipificación Micológica , Filogenia , Análisis de Secuencia de ADNRESUMEN
UNLABELLED: The principles underlying membrane binding and assembly of retroviral Gag proteins into a lattice are understood. However, little is known about how these processes are related. Using purified Rous sarcoma virus Gag and Gag truncations, we studied the interrelation of Gag-Gag interaction and Gag-membrane interaction. Both by liposome binding and by surface plasmon resonance on a supported bilayer, Gag bound to membranes much more tightly than did matrix (MA), the isolated membrane binding domain. In principle, this difference could be explained either by protein-protein interactions leading to cooperativity in membrane binding or by the simultaneous interaction of the N-terminal MA and the C-terminal nucleocapsid (NC) of Gag with the bilayer, since both are highly basic. However, we found that NC was not required for strong membrane binding. Instead, the spacer peptide assembly domain (SPA), a putative 24-residue helical sequence comprising the 12-residue SP segment of Gag and overlapping the capsid (CA) C terminus and the NC N terminus, was required. SPA is known to be critical for proper assembly of the immature Gag lattice. A single amino acid mutation in SPA that abrogates assembly in vitro dramatically reduced binding of Gag to liposomes. In vivo, plasma membrane localization was dependent on SPA. Disulfide cross-linking based on ectopic Cys residues showed that the contacts between Gag proteins on the membrane are similar to the known contacts in virus-like particles. Taken together, we interpret these results to mean that Gag membrane interaction is cooperative in that it depends on the ability of Gag to multimerize. IMPORTANCE: The retroviral structural protein Gag has three major domains. The N-terminal MA domain interacts directly with the plasma membrane (PM) of cells. The central CA domain, together with immediately adjoining sequences, facilitates the assembly of thousands of Gag molecules into a lattice. The C-terminal NC domain interacts with the genome, resulting in packaging of viral RNA. For assembly in vitro with purified Gag, in the absence of membranes, binding of NC to nucleic acid somehow facilitates further Gag-Gag interactions that lead to formation of the Gag lattice. The contributions of MA-mediated membrane binding to virus particle assembly are not well understood. Here, we report that in the absence of nucleic acid, membranes provide a platform that facilitates Gag-Gag interactions. This study demonstrates that the binding of Gag, but not of MA, to membranes is cooperative and identifies SPA as a major factor that controls this cooperativity.
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Productos del Gen gag/metabolismo , Membrana Dobles de Lípidos/metabolismo , Multimerización de Proteína , Virus del Sarcoma de Rous/fisiología , Análisis Mutacional de ADN , Productos del Gen gag/genética , Unión Proteica , Estructura Terciaria de Proteína , Virus del Sarcoma de Rous/genéticaRESUMEN
The sesquiterpenoid curdione is one of the main bioactive components in the essential oil of Rhizoma Curcumae (Curcuma wenyujin, Curcuma phaeocaulis, and Curcuma kwangsiensis), which has been clinically used for the treatment of cancer in mainland China. Recently it was reported that natural curdione could be hydroxylated by Aspergillus niger and transferred to its corresponding curcumalactones under acidic conditions. Based on this study, the development of a sesquiterpenoid library through the "mirror-image" manipulation of bioactive (non)natural curdione scaffolds by chemical and biological approaches is presented herein. A. niger induced the hydroxylation of two pairs of curdione enantiomers, yielding the corresponding mirror-image hydroxylated curdiones. Simultaneously, the acid-mediated intramolecular "ene" rearrangements of these curdiones and hydroxylated curdione enantiomers yielded the corresponding mirror-image curcumalactones and hydroxylated curcumalactones. Among the 16 pairs of enantiomers obtained in this study, 23 compounds are new sesquiterpenoids. These curdione and curcumalactone derivatives are of particular interest, as they have the potential to be used as lead compounds and scaffolds in drug discovery.
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Curcuma/química , Aceites Volátiles/química , Sesquiterpenos de Germacrano/química , Aspergillus niger/metabolismo , China , Técnicas Químicas Combinatorias , Descubrimiento de Drogas , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Rizoma/química , Sesquiterpenos , EstereoisomerismoRESUMEN
This study investigated the effects of octenyl succinic anhydride (OSA)-starch-fatty acid (FA) interactions on the structural, digestibility and release characteristics of high amylose corn starch (HAS). FTIR and XRD analysis showed that the hydrophobic interaction between HAS and FA promoted the covalent binding between OSA and HAS. With the increasing of the FA chain length, the complex index, degree of substitution, R1047/1022 and relative crystallinity of OSA-HAS-FA increased first and then decreased, whereas the first-order rate coefficient and percentage of digested in infinite time showed an opposite trend. Structural changes and the molecular interactions of OSA-HAS-FA with 12carbon FA resulted in highest resistant starch content (45.43%) and encapsulation efficiency of curcumin (Cur) (47.98%). In vitro release test revealed that Cur could be gradually released from OSA-HAS-FA in simulated gastric, intestinal and colonic fluids. Results provided novel insights into HAS-FA complex grafted with OSA as carrier for colon-specific of functional materials.
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Amilosa , Digestión , Ácidos Grasos , Almidón , Zea mays , Amilosa/química , Amilosa/metabolismo , Almidón/química , Almidón/metabolismo , Almidón/análogos & derivados , Ácidos Grasos/química , Ácidos Grasos/metabolismo , Zea mays/química , Zea mays/metabolismo , Anhídridos Succínicos/química , HumanosRESUMEN
This study aimed at gaining insight into the mechanism of interactions between pectin (PE), starch and unsaturated fatty acids (UFAs) in relation to structure, in vitro digestibility and release properties of starch. Due to the barrier and encapsulation effects of PE, the complexing behavior of potato starch (PtS) with linoleic acid (LOA) was enhanced, which increased the complexing index, the compactness of network structure, short-range ordered structure and relative crystallinity of PtS-LOA-PE films. These structural changes resulted in the increases of slowly digestible starch and resistant starch and in the decreases of first-order rate coefficient in PtS-LOA-PE films. Besides, the in vitro release results also showed that the release properties of PtS-LOA could be controlled by the PE addition with the decreases in LOA release rate and increase in LOA bioavailability under simulated gastrointestinal conditions. Notably, at different PtS-LOA:PE ratios, the PtS-LOA-PE film with the PtS-LOA:PE ratio of 5:1 showed the better complexing degree, structural order, anti-digestibility and colon-targeted release properties than other PtS-LOA-PE films. These results indicated that PE influenced the release properties of the PtS-LOA-PE films, which was closely related to their complexing degree, structural order, and digestibility. This study provided new insights into the design of resistant films for delivery of UFAs to colon.
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Digestión , Ácido Linoleico , Pectinas , Almidón , Pectinas/química , Almidón/química , Ácido Linoleico/química , Solanum tuberosum/química , Liberación de FármacosRESUMEN
mRNA therapeutics offer a potentially universal strategy for the efficient development and delivery of therapeutic proteins. Current mRNA vaccines include chemically modified nucleotides to reduce cellular immunogenicity. Here, we develop an efficient, high-throughput method to measure human translation initiation on therapeutically modified as well as endogenous RNAs. Using systems-level biochemistry, we quantify ribosome recruitment to tens of thousands of human 5' untranslated regions and identify sequences that mediate 250-fold effects. We observe widespread effects of coding sequences on translation initiation and identify small regulatory elements of 3-6 nucleotides that are sufficient to potently affect translational output. Incorporation of N1-methylpseudouridine (m1Ψ) selectively enhances translation by specific 5' UTRs that we demonstrate surpass those of current mRNA vaccines. Our approach is broadly applicable to dissect mechanisms of human translation initiation and engineer more potent therapeutic mRNAs. Highlights: Measurement of >30,000 human 5' UTRs reveals a 250-fold range of translation outputSystematic mutagenesis demonstrates the causality of short (3-6nt) regulatory elementsN1-methylpseudouridine alters translation initiation in a sequence-specific mannerOptimal modified 5' UTRs outperform those in the current class of mRNA vaccines.
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Host factor tRNAs facilitate the replication of retroviruses such as human immunodeficiency virus type 1 (HIV-1). HIV-1 uses human tRNALys3 as the primer for reverse transcription, and the assembly of HIV-1 structural protein Gag at the plasma membrane (PM) is regulated by matrix (MA) domain-tRNA interactions. A large, dynamic multi-aminoacyl-tRNA synthetase complex (MSC) exists in the cytosol and consists of eight aminoacyl-tRNA synthetases (ARSs) and three other cellular proteins. Proteomic studies to identify HIV-host interactions have identified the MSC as part of the HIV-1 Gag and MA interactomes. Here, we confirmed that the MA domain of HIV-1 Gag forms a stable complex with the MSC, mapped the primary interaction site to the linker domain of bi-functional human glutamyl-prolyl-tRNA synthetase (EPRS), and showed that the MA-EPRS interaction was RNA dependent. MA mutations that significantly reduced the EPRS interaction reduced viral infectivity and mapped to MA residues that also interact with phosphatidylinositol-(4,5)-bisphosphate. Overexpression of EPRS or EPRS fragments did not affect susceptibility to HIV-1 infection, and knockdown of EPRS reduced both a control reporter gene and HIV-1 protein translation. EPRS knockdown resulted in decreased progeny virion production, but the decrease could not be attributed to selective effects on virus gene expression, and the specific infectivity of the virions remained unchanged. While the precise function of the Gag-EPRS interaction remains uncertain, we discuss possible effects of the interaction on either virus or host activities.
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Aminoacil-ARNt Sintetasas , VIH-1 , Humanos , Aminoacil-ARNt Sintetasas/genética , Citoplasma , Citosol , VIH-1/genética , Proteómica , Subunidades de Proteína/metabolismoRESUMEN
All betacoronaviruses (ß-CoVs) encode non-structural protein 1 (Nsp1), an essential pathogenicity factor that potently restricts host gene expression. Among the ß-CoV family, MERS-CoV is the most distantly related member to SARS-CoV-2, and the mechanism for host translation inhibition by MERS-CoV Nsp1 remains controversial. Herein, we show that MERS-CoV Nsp1 directly interacts with the 40S ribosomal subunit. Using cryogenic electron microscopy (cryo-EM), we report a 2.6-Å structure of the MERS-CoV Nsp1 bound to the human 40S ribosomal subunit. The extensive interactions between C-terminal domain of MERS-CoV Nsp1 and the mRNA entry channel of the 40S ribosomal subunit are critical for its translation inhibition function. This mechanism of MERS-CoV Nsp1 is strikingly similar to SARS-CoV and SARS-CoV-2 Nsp1, despite modest sequence conservation. Our results reveal that the mechanism of host translation inhibition is conserved across ß-CoVs and highlight a potential therapeutic target for the development of antivirals that broadly restrict ß-CoVs.
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Coronavirus del Síndrome Respiratorio de Oriente Medio , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , SARS-CoV-2/genética , ARN Mensajero/metabolismo , Proteínas no Estructurales Virales/metabolismoRESUMEN
This study aimed to improve the complexing degree, digestibility and controlled release properties of the potato starch (PS)-linoleic acid (LA) complexes by encapsulating PS-LA complexes to sodium alginate (AG) beads. The results revealed that AG had a positive effect on the complexing index, R1047/1022 values, relative crystallinity, enthalpy and morphological structure of PS-LA-AG films, especially for PS-LA-AG film with the PS-LA: AG of 5:1. The in vitro digestion and hydrolysis kinetic analysis indicated that AG addition reduced the digestibility of PS-LA-AG films to a higher slowly digestible starch content and resistant starch content and a lower equilibrium hydrolysis percentage and kinetic constant. Furthermore, in vivo release study of PS-LA-AG films indicated a restrained release in simulated gastrointestinal conditions. Consequently, the results indicated that AG addition significantly improved the inclusion efficiency for the complex formation between PS and LA, which was beneficial for the design of resistant films to entrap and control release of unsaturated fatty.
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Ácido Linoleico , Almidón , Cinética , Alginatos , Suplementos DietéticosRESUMEN
Objectives: Approximately 20~30% of all traffic accidents are caused by fatigue driving. However, limited practicability remains a barrier for the real application of available techniques to detect driving fatigue. Use of pupillary light reflex (PLR) may be potentially effective for driving fatigue detection. Methods: A 90 min monotonous simulated driving task was utilized to induce driving fatigue. During the task, PLR measurements were performed at baseline and at an interval of 30 min. Subjective rating scales, heart rate variability (HRV) were monitored simultaneously. Results: Thirty-two healthy volunteers in China participated in our study. Based on the results of subjective evaluation and behavioral performances, driving fatigue was verified to be successfully induced by a simulated driving task. Significant variations of PLR and HRV parameters were observed, which also showed significant relevance with the change in Karolinska Sleepiness Scale at several timepoints (|r| = 0.55 ~ 0.72, P < 0.001). Furthermore, PLR variations had excellent ability to detect driving fatigue with high sensitivity and specificity, of which maximum constriction velocity variations achieved a sensitivity of 85.00% and specificity of 72.34% for driving fatigue detection, vs. 82.50 and 78.72% with a combination of HRV variations, a nonsignificant difference (AUC = 0.835, 0.872, P > 0.05). Conclusions: Pupillary light reflex variation may be a potential indicator in the detection of driving fatigue, achieving a comparative performance compared with the combination with heart rate variability. Further work may be involved in developing a commercialized driving fatigue detection system based on pupillary parameters.
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Pupila , Reflejo Pupilar , China , Frecuencia Cardíaca/fisiología , Humanos , Pupila/fisiología , Reflejo Pupilar/fisiologíaRESUMEN
The phylogeny and taxonomy of Podosphaera filipendulae (including P. filipendulensis, syn. nov.) have been examined. Asian, European and North American collections were examined and the nucleotides sequences of their partial rDNA region were determined. In particular, the relationship between P. filipendulae and P. spiraeae was analysed. The results confirmed P. filipendulae and P. spiraeae as two separate, morphologically similar species. The phylogenetic analysis revealed a similar phylogeny to that of the host genera. Although ITS sequences retrieved from Asian, European and North American specimens of P. filipendulae on various Filipendula spp. are identical to sequences from P. macularis on hop, there is consistently one base substitution at the 5'-end of 28S rRNA gene between the species. This result provides evidence that the hop powdery mildew and P. filipendulae are biologically and morphologically clearly distinguished, and should be maintained as two separate species.
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New nanoparticles (Y6 NPs) based on the A-DA'D-A fused-ring conjugated small molecule Y6 have been prepared for the combined photothermal and photodynamic therapy of cancer. Y6 NPs show excellent light absorption from 300 to 900 nm, a good photothermal conversion efficiency of 57% and reactive oxygen species generation capability. The high photothermal conversion ability and superior photodynamic activity of Y6 NPs endow them with great potential for cancer therapy.
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Nanopartículas , Fotoquimioterapia , Células HeLa , Humanos , Fármacos Fotosensibilizantes , PorfirinasRESUMEN
Gas therapy as a burgeoning and promising research field has attracted considerable attention in biomedicine due to its high therapeutic efficacy, biocompatibility, and biosafety. However, the lack of tumor site accumulation and controlled release of therapeutic gas molecules limited the therapeutic efficacy. Therefore, the development of gas-releasing nanoplatforms to realize tumor targeting and controllable release is highly desired. The structural diversity and tailorability and ultrahigh surface area make metal-organic frameworks (MOFs) find potential applications in the delivery and release of gas or gas releasing molecules (GRMs). In this Frontier article, we provide an overview of the recent developments achieved in gas-involving cancer therapy using MOFs or MOF-based materials. The main emphasis is focused on the design of multifunctional MOF-based nanoplatforms for the delivery and release of therapeutic gas molecules, and emphasizing their synergistic mechanism against tumor. Moreover, the challenges, future trends, and prospects of gas-related cancer therapy are also discussed.
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Antineoplásicos/uso terapéutico , Desarrollo de Medicamentos , Estructuras Metalorgánicas/uso terapéutico , Nanopartículas/química , Nanopartículas/uso terapéutico , Neoplasias/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Monóxido de Carbono/química , Monóxido de Carbono/uso terapéutico , Humanos , Hidrógeno/química , Hidrógeno/uso terapéutico , Estructuras Metalorgánicas/síntesis química , Estructuras Metalorgánicas/química , Óxido Nítrico/química , Óxido Nítrico/uso terapéutico , Oxígeno/química , Oxígeno/uso terapéuticoRESUMEN
Chaenomeles speciosa (Sweet) Nakai is a dual-purpose Chinese herbal medicine and functional food favored by minorities in Southwest China, and its fruits are used for the treatment of dyspepsia, dysentery, enteritis, and rheumatism inflammation. Some diseases may be related to microbial infection; however, it is not known how the fruits possess antimicrobial activity. We evaluated the antimicrobial bioctivity of different evaluation extracts of C. speciosa fruits by in vitro and in vivo with colony-forming unit assays, and the strongest bioactive-guided fraction was selected for column chromatography (CC), UHPLC-QTOF-MS/MS, and NMR spectroscopy to confirm the chemical constituents. The most possible antimicrobial mechanism of C. speciosa fruits was explored by metabolomics approach, fluorescence microscopy imaging, and scanning electron microscopy (SEM). Thirty compounds, which were major characteristic ions of the bioactive fraction, were determined precisely. The bioactive fraction could inhibit 18 pathogenic microorganisms, significantly reduced, especially drug-resistant bacteria, compared to ampicillin sodium salt, fluconazole, and berberine chloride form; and the minimum inhibitory concentration (MIC) or minimum fungicidal concentration (MFC) values were in the range of 0.1-1 mg/mL. The compounds 2'-methoxyaucuparin (1) and oleanolic acid (20) not only have antibacterial activity but also may have synergistic effects. Further, the bioactive fraction might inhibit the biofilm formation, enhance immunity, and restore bacterial infection damage in vitro and in vivo to kill microorganisms. The data indicated that C. speciosa fruits' major bioactive fraction enriched with triterpenes, flavonoids, and phenolics could be developed as a functional supplement for individuals to prevent and treat microbial infection.
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Rosaceae , Espectrometría de Masas en Tándem , China , Cromatografía Liquida , Humanos , Pruebas de Sensibilidad Microbiana , Extractos Vegetales/farmacologíaRESUMEN
ETHNOPHARMACOLOGY RELEVANCE: The root bark of Morus alba Linn. (M. alba), a traditional folk medicine, has been documented in the Chinese Pharmacopoeia, which has been widely used for asthma, fever, pneumonia, edema, vomit, colitis, bronchitis and keratitis diseases. Some of the diseases may be related to respiratory, digestive, urinary tract infections. Although Diels-Alder adducts (DAAs), flavonoids, 2-arylbenzofurans and stilbene compounds have been isolated from the root bark of M. alba, few compounds are reported for their antimicrobial efficacy in vivo and the mechanism. AIM OF THE STUDY: The aim of the study was to isolate and identify compounds of the root bark of M. alba in view of their anti-MRSA bioactivity, evaluate the anti-MRSA bioactivity of compounds and 60% ethanol elution (MA-6) in vitro and in vivo, and explore preliminary antibacterial mechanism in order to provide natural resources against MRSA infection. MATERIALS AND METHODS: Systematic phytochemical investigations were carried out according to the thin layer chromatography (TLC) of the active fraction MA-6 to find more anti-MRSA ingredients. The compounds of the root bark of M. alba were separated by column chromatography and identified by LC-MS/MS and NMR spectroscopy. The anti-MRSA efficacy of the active ingredients were evaluated by broth microdilution method and a murine infection model. The mode of action of compounds was explored by time-kill curve and post-contact effect. The preliminary mechanism of compounds against MRSA was explored by drug efflux pumps and bacterial biofilms. RESULTS: Chemical isolation resulted in twenty-nine known compounds, most with one or more geranyl and prenyl units exhibited superior anti-MRSA bioactivity, with MIC values of 2-16 µg/mL. In addition, the mode of action indicated that compounds presented persistent antimicrobial effect, which also produced concentration-dependent and time-dependent killing activity or property. Preliminary mechanism showed that the compound kuwanon O (29) damaged the bacterial cell membranes, leading to the accumulation of antibiotics inside bacterial cells, moreover, MA-6 and kuwanon O (29) inhibited the efflux of drugs by combining with methicillin or ethidium bromide (EtBr), resulting in the MICs of EtBr and methicillin were obviously decreased three-fold. The anti-MRSA efficacy in vivo indicated that the active fraction MA-6 could reduce bacteria in spleen, liver, kidney and mortality of acutely infectious mice, which was better than the positive drug berberine chloride. CONCLUSION: Experimental investigation showed that the MA-6 and compound 29 have promising bioactivity against MRSA in vitro and in vivo, which might be used as a potential source of new antibacterial medicine or a potential efflux pump inhibitor against MRSA infection.