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1.
Biomedicines ; 10(4)2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35453497

RESUMO

Over the past decade, lignin-based porous biomaterials have been found to have strong potential applications in the areas of drug delivery, tissue engineering, wound dressing, pharmaceutical excipients, biosensors, and medical devices. Lignin-based porous biomaterials have the addition of lignin obtained from lignocellulosic biomass. Lignin as an aromatic compound is likely to modify the materials' mechanical properties, thermal properties, antioxidant, antibacterial property, biodegradability, and biocompatibility. The size, shape, and distribution of pores can determine the materials' porous structure, porosity, surface areas, permeability, porosity, water solubility, and adsorption ability. These features could be suitable for medical applications, especially controlled drug delivery systems, wound dressing, and tissue engineering. In this review, we provide an overview of the current status and future potential of lignin-based porous materials for medical and pharmaceutical uses, focusing on material types, key properties, approaches and techniques of modification and fabrication, and promising medical applications.

2.
Cardiovasc Diagn Ther ; 12(2): 241-252, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35433344

RESUMO

Background: Mitral regurgitation (MR) is common in patients with ischemic or idiopathic cardiomyopathies and may be associated with a poor prognosis; however, the impact of different degrees of MR on cardiovascular magnetic resonance images, left ventricular features, and clinical outcomes of left ventricular noncompaction are unknown. We aimed to investigate and compare cardiovascular magnetic resonance characteristics and clinical consequences in patients with left ventricular non-compaction (LVNC) with and without MR. Methods: A cohort of 75 patients with left ventricular noncompaction were retrospectively studied from three institutions; all had undergone cardiovascular magnetic resonance examination with subsequent clinical follow-up. MR was evaluated by echocardiography. Left ventricular myocardial strains including global radial, circumferential, and longitudinal peak strains and left ventricular geometric and functional parameters, including left ventricular ejection fraction, end-diastolic volume, end-systolic volume, left ventricular mass, left ventricular sphericity index, longitudinal shorten, and late gadolinium enhancement (LGE) were measured and compared among groups. The primary endpoint was a composite of heart transplantation, implantable cardioverter-defibrillator insertion, and cardiac death. Results: Compared with the no MR group, the MR groups showed significant deterioration in left ventricular myocardial strains (all P<0.05), and impaired left ventricular geometry and function, including lower left ventricular ejection fraction and greater left ventricular end-systolic volume and left ventricular mass (P<0.05). In the subgroup of moderate-severe MR, patients showed more impaired cardiovascular magnetic resonance features, including left ventricular sphericity index, left ventricular end-diastolic volume, and longitudinal shorten (P<0.05). In this subgroup, Kaplan-Meier analysis showed a significant difference in clinical outcomes (log-rank χ2=4.516, P=0.034; log-rank χ2=4.419, P=0.036, respectively). Additionally, multivariate analyses showed a 6.5-fold higher [hazard ratio, 6.5 (95% CI, 1.015-41.881)] risk of cardiac death with LGE in the moderate-severe MR cohort. Conclusions: In patients with left ventricular noncompaction, MR induced more maladaptive left ventricular remodeling. The incidence of adverse outcomes may be related to the degree of MR. In moderate-severe MR patients, coexisting of LGE may have an additive deleterious effect on clinical outcomes.

3.
World J Clin Cases ; 10(9): 2751-2763, 2022 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-35434091

RESUMO

BACKGROUND: The exact definition of Acute kidney injury (AKI) for patients with traumatic brain injury (TBI) is unknown. AIM: To compare the power of the "Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease" (RIFLE), Acute Kidney Injury Network (AKIN), Creatinine kinetics (CK), and Kidney Disease Improving Global Outcomes (KDIGO) to determine AKI incidence/stage and their association with the in-hospital mortality rate of patients with TBI. METHODS: This retrospective study collected the data of patients admitted to the intensive care unit for neurotrauma from 2001 to 2012, and 1648 patients were included. The subjects in this study were assessed for the presence and stage of AKI using RIFLE, AKIN, CK, and KDIGO. In addition, the propensity score matching method was used. RESULTS: Among the 1648 patients, 291 (17.7%) had AKI, according to KDIGO. The highest incidence of AKI was found by KDIGO (17.7%), followed by AKIN (17.1%), RIFLE (12.7%), and CK (11.5%) (P = 0.97). Concordance between KDIGO and RIFLE/AKIN/CK was 99.3%/99.1%/99.3% for stage 0, 36.0%/91.5%/44.5% for stage 1, 35.9%/90.6%/11.3% for stage 2, and 47.4%/89.5%/36.8% for stage 3. The in-hospital mortality rates increased with the AKI stage in all four definitions. The severity of AKI by all definitions and stages was not associated with in-hospital mortality in the multivariable analyses (all P > 0.05). CONCLUSION: Differences are seen in AKI diagnosis and in-hospital mortality among the four AKI definitions or stages. This study revealed that KDIGO is the best method to define AKI in patients with TBI.

4.
Chembiochem ; 23(9): e202200012, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35235240

RESUMO

Small-molecule splicing modulators exemplified by an FDA-approved drug, risdiplam, are a new pharmacological modality for regulating the expression and stability of splice isoforms. We report a CRISPR-mediated enzyme fragment complementation (EFC) assay to quantify the splice isoform stability. The EFC assay harnessed a 42 amino acid split of a ß-galactosidase (designate α-tag), which could be fused at the termini of the target genes using CRISPR/cas9. The α-tagged splice isoform would be quantified by measuring the enzymatic activity upon complementation with the rest of ß-galactosidase. This EFC assay retained all the sequences of introns and exons of the target gene in the native genomic environment that recapitulates the cell biology of the diseases of interest. For a proof-of-concept, we developed a CRISPR-mediated EFC assay targeting the exon 7 of the survival of motor neuron 2 (SMN2) gene. The EFC assay is compatible with 384-well plates and robustly quantified the splicing modulation activity of small molecules. In this study, we also discovered that a coumarin derivative, compound 4, potently modulated SMN2 exon 7 splicing at as low as 1.1 nM.


Assuntos
Ensaios Enzimáticos , Éxons/genética , Mutação , Isoformas de Proteínas , beta-Galactosidase
5.
Exp Gerontol ; 161: 111733, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35143872

RESUMO

Poor muscle function is increasingly obvious with aging and needs effective and safe medicine for treatment. Trimetazidine (TMZ) has potential benefits for the condition but has not yet been fully recognized. In the randomized-control pilot study part, fifty-three old patients were assigned to the TMZ group or control group. For the TMZ group, a dose of 35 mg of oral TMZ was administered with a meal twice a day for 3 months. Only conventional treatments were administrated in the control group. Muscle strength, gait speed, muscle endurance, and balance maintenance were measured during the visits. In the experiments part, thirty mice were screened and randomly assigned to three groups: model group received a D-gal (500 mg/kg) intraperitoneal injection every two days for six weeks, the control group received saline at the same condition, and the intervention group received 5 mg/kg TMZ solution every two days by gavage for two weeks. Swimming tests and forelimb grip strength measurements were also performed. Furthermore, significantly clustered profiles from differentially expressed genes were found by RNA-seq and verified by qRT-PCR and WB. Myofiber analyses were done by H&E staining. Here, we found the improvement of skeletal performance in aged individuals and aged mouse. The dominant handgrip strength (HS) was increased by 24.4% and dominant pinch strength (PS) by 12.4% in participants with TMZ modified-release tablets consumption. Exhaustive time was increased by 23.6% and upper limb grip strength by 44.1% in aged mouse with TMZ-treated. Besides, we also identified some newly discovered molecules associated with TMZ on muscle function improvement during aging. To aged C2C12 cells and aged mouse muscle, TMZ-treated was related to a statistically significant decrease in the expressions of NOS3 and MMP-9, but a statistically significant increase in the expressions of OMD and MyoG. In summary, TMZ modified-release tablets can improve the muscle strength of elderly patients. Besides, the improvement of skeletal muscle function affected by TMZ was associated with reducing NOS3 expression in senescent myoblasts.


Assuntos
Trimetazidina , Idoso , Envelhecimento , Animais , Força da Mão , Humanos , Camundongos , Músculo Esquelético , Mioblastos , Projetos Piloto , Trimetazidina/farmacologia , Vasodilatadores/farmacologia
6.
Front Chem ; 10: 842171, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35186888

RESUMO

[This corrects the article DOI: 10.3389/fchem.2021.802766.].

7.
Ecotoxicol Environ Saf ; 232: 113234, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35085889

RESUMO

Accumulation and biotransformation of pesticides in fish tissues are essential to assess their toxicity and associated human exposure risk. The mechanisms on time-dependent and tissue-specific accumulation and transformation of fipronil in adult fish are limited. An experiment consisting of 25-d uptake of fipronil at two levels (10 and 50 µg/L) and 25-d depuration in adult crucian carp (Carassius auratus) was conducted. Fipronil concentration at 25-d exposure was tissue-specific with the order of liver > kidney > blood > muscle. The uptake rate constant of fipronil in the liver (low exposure group: 2.38 ± 0.27 L/kg/d; high exposure group: 1.10 ± 0.11 L/kg/d) was significantly higher than that in other tissues (p < 0.05), and the lowest in muscle (low exposure group: 0.10 ± 0.01 L/kg/d; high exposure group: 0.16 ± 0.11 L/kg/d). The bioconcentration factors of fipronil in different tissues were 1.04-12.7 L/kg wet weight and 177-4268 L/kg lipid. The tissue-blood distribution coefficients of the liver and kidney were lower than 1 based on lipid normalized concentration but higher than 1 based on wet weight concentration, suggesting fipronil was dispersed into other tissues mainly via blood in the lipid-combination pattern. Fipronil sulfone had 1.2-32 times higher concentration and longer depuration time than fipronil, implying fipronil sulfone was more retender in fish bodies. The estimated daily intake of fipronil via fish muscle consumption at 25-d exposure was 8.5-101 and 27-320 ng/kg bw/d for adults and children, respectively. Overall, the human health risk of fipronil and its metabolites with consumption of the polluted fish cannot be negligible.


Assuntos
Carpas , Poluentes Químicos da Água , Animais , Biotransformação , Carpas/metabolismo , Carpa Dourada/metabolismo , Humanos , Pirazóis , Distribuição Tecidual , Poluentes Químicos da Água/metabolismo
8.
Plants (Basel) ; 11(2)2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-35050037

RESUMO

Western Siberia is one of the major spring wheat regions of Russia, cultivating over 7 Mha. The objective of the study was to evaluate the variation of macro- and microelements, and of trace metals in four distinct groups of genetic resources: primary synthetics from CIMMYT (37 entries), primary synthetics from Japan (8), US hard red spring wheat cultivars (14), and material from the Kazakhstan-Siberian Network on Spring Wheat Improvement (KASIB) (74). The experiment was conducted at Omsk State Agrarian University, using a random complete block design with four replicates in 2017 and 2018. Concentrations of 15 elements were included in the analysis: macroelements, Ca, K, Mg, P, and S; microelements, Fe, Cu, Mn, and Zn; toxic trace elements, Cd, Co, Ni; and trace elements, Mo, Rb, and Sr. Protein content was found to be positively correlated with the concentrations of 11 of the elements in one or both years. Multiple regression was used to adjust the concentration of each element, based on significant correlations with agronomic traits and macroelements. All 15 elements were evaluated for their suitability for genetic enhancement, considering phenotypic variation, their share of the genetic component in this variation, as well as the dependence of the element concentration on other traits. Three trace elements (Sr, Mo, and Co) were identified as traits that were relatively easy to enhance through breeding. These were followed by Ca, Cd, Rb, and K. The important biofortification elements Mn and Zn were among the traits that were difficult to enhance genetically. The CIMMYT and Japanese synthetics had significantly higher concentrations of K and Sr, compared to the local check. The Japanese synthetics also had the highest concentrations of Ca, S, Cd, and Mo. The US cultivars had concentrations of Ca as high as the Japanese synthetics, and the highest concentrations of Mg and Fe. KASIB's germplasm had near-average values for most elements. Superior germplasm, with high macro- and microelement concentrations and low trace-element concentrations, was found in all groups of material included.

9.
J Virol ; 96(2): e0132621, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34669461

RESUMO

Parvovirus B19 (B19V) infection can cause hematological disorders and fetal hydrops during pregnancy. Currently, no antivirals or vaccines are available for the treatment or prevention of B19V infection. To identify novel small-molecule antivirals against B19V replication, we developed a high-throughput screening (HTS) assay, which is based on an in vitro nicking assay using recombinant N-terminal amino acids 1 to 176 of the viral large nonstructural protein (NS1N) and a fluorescently labeled DNA probe (OriQ) that spans the nicking site of the viral DNA replication origin. We collectively screened 17,040 compounds and identified 2,178 (12.78%) hits that possess >10% inhibition of the NS1 nicking activity, among which 84 hits were confirmed to inhibit nicking in a dose-dependent manner. Using ex vivo-expanded primary human erythroid progenitor cells (EPCs) infected by B19V, we validated 24 compounds that demonstrated >50% in vivo inhibition of B19V infection at 10 µM, which can be categorized into 7 structure scaffolds. Based on the therapeutic index (half-maximal cytotoxic concentration [CC50]/half-maximal effective concentration [EC50] ratio) in EPCs, the top 4 compounds were chosen to examine their inhibitions of B19V infection in EPCs at two times of the 90% maximal effective concentration (EC90). A purine derivative (P7) demonstrated an antiviral effect (EC50 = 1.46 µM) without prominent cytotoxicity (CC50 = 71.8 µM) in EPCs and exhibited 92% inhibition of B19V infection in EPCs at 3.32 µM, which can be used as the lead compound in future studies for the treatment of B19V infection-caused hematological disorders. IMPORTANCE B19V encodes a large nonstructural protein, NS1. Its N-terminal domain (NS1N) consisting of amino acids 1 to 176 binds to viral DNA and serves as an endonuclease to nick the viral DNA replication origins, which is a pivotal step in rolling-hairpin-dependent B19V DNA replication. For high-throughput screening (HTS) of anti-B19V antivirals, we miniaturized a fluorescence-based in vitro nicking assay, which employs a fluorophore-labeled probe spanning the terminal resolution site (trs) and the NS1N protein, into a 384-well-plate format. The HTS assay showed high reliability and capability in screening 17,040 compounds. Based on the therapeutic index (half-maximal cytotoxic concentration [CC50]/half-maximal effective concentration [EC50] ratio) in EPCs, a purine derivative demonstrated an antiviral effect of 92% inhibition of B19V infection in EPCs at 3.32 µM (two times the EC90). Our study demonstrated a robust HTS assay for screening antivirals against B19V infection.


Assuntos
Antivirais/farmacologia , Células Precursoras Eritroides/virologia , Ensaios de Triagem em Larga Escala/métodos , Parvovirus B19 Humano/efeitos dos fármacos , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , DNA Viral/metabolismo , Células Precursoras Eritroides/efeitos dos fármacos , Corantes Fluorescentes , Humanos , Parvovirus B19 Humano/fisiologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Origem de Replicação , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
10.
Ann Bot ; 129(1): 101-112, 2022 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-34668958

RESUMO

BACKGROUND AND AIMS: Initiation of cluster roots in white lupin (Lupinus albus) under phosphorus (P) deficiency requires auxin signalling, whereas flavonoids inhibit auxin transport. However, little information is available about the interactions between P deficiency and flavonoids in terms of cluster-root formation in white lupin. METHODS: Hydroponic and aeroponic systems were used to investigate the role of flavonoids in cluster-root formation, with or without 75 µm P supply. KEY RESULTS: Phosphorus-deficiency-induced flavonoid accumulation in cluster roots depended on developmental stage, based on in situ determination of fluorescence of flavonoids and flavonoid concentration. LaCHS8, which codes for a chalcone synthase isoform, was highly expressed in cluster roots, and silencing LaCHS8 reduced flavonoid production and rootlet density. Exogenous flavonoids suppressed cluster-root formation. Tissue-specific distribution of flavonoids in roots was altered by P deficiency, suggesting that P deficiency induced flavonoid accumulation, thus fine-tuning the effect of flavonoids on cluster-root formation. Furthermore, naringenin inhibited expression of an auxin-responsive DR5:GUS marker, suggesting an interaction of flavonoids and auxin in regulating cluster-root formation. CONCLUSIONS: Phosphorus deficiency triggered cluster-root formation through the regulation of flavonoid distribution, which fine-tuned an auxin response in the early stages of cluster-root development. These findings provide valuable insights into the mechanisms of cluster-root formation under P deficiency.


Assuntos
Lupinus , Flavonoides/metabolismo , Flavonoides/farmacologia , Ácidos Indolacéticos/metabolismo , Lupinus/genética , Lupinus/metabolismo , Fósforo/metabolismo , Raízes de Plantas
11.
Plant Biotechnol J ; 20(1): 59-74, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465003

RESUMO

Aroma is a key grain quality trait that directly influences the market price of rice globally. Loss of function of betaine aldehyde dehydrogenase 2 (OsBADH2) affects the biosynthesis of 2-acetyl-1-pyrroline (2-AP), which is responsible for aroma in fragrant rice. The current study was aimed at creating new alleles of BADH2 using CRISPR/Cas9 gene editing technology under the genetic background of the japonica Ningjing 1 (NJ1) and indica Huang Huazhan (HHZ) varieties. Sensory evaluation and analysis using headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) showed that the grains of the four homozygous T1 lines with new alleles of BADH2 (nj1-cr BADH2 -1, nj1-cr BADH2 -2, hhz-cr BADH2 -1 and hhz-cr BADH2 -2) produced moderate fragrance and had significantly increased 2-AP content compared with wild-types. Moreover, there were no significant differences in the amylose content and gelatinization temperature among the four lines with new alleles of BADH2 to the wild-types. Thereafter, we crossed the HHZ background new alleles of BADH2 with CMS line Taonong 1A (TN1A) to produce a three-line hybrid variety B-Tao-You-Xiangzhan (BTYXZ) with increased grain aroma. The 2-AP content in grains of the improved BTYXZ-1 and BTYXZ-2 reached at 26.16 and 18.74 µg/kg, and the gel consistency of BTYXZ-1 and BTYXZ-2 increased significantly by 9.1% and 6.5%, respectively, compared with the wild-type Tao-You-Xiangzhan (TYXZ). However, the γ-aminobutyric acid (GABA) content in the improved three-line hybrid rice BTYXZ-1 (5.6 mg/100 g) and BTYXZ-2 (10.7 mg/100 g) was significantly lower than that of the TYXZ. These results demonstrated that CRISPR/Cas9 gene editing technology could be successfully utilized in improving aroma in non-fragrant japonica and indica varieties. In addition, the newly developed BADH2 alleles provided important genetic resources for grain aroma improvement in three-line hybrid rice.


Assuntos
Oryza , Alelos , Betaína-Aldeído Desidrogenase/genética , Grão Comestível/genética , Odorantes , Oryza/genética , Fenótipo
12.
Chem Commun (Camb) ; 58(4): 513-516, 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-34897338

RESUMO

We report an efficient and straightforward method to synthesize enantio-enriched N-unprotected α-amino acetals via ruthenium-catalyzed direct asymmetric reductive amination. The α-amino acetal products are versatile and valuable platform molecules that can be converted to the corresponding α-amino acids, amino alcohols, and other derivatives by convenient transformations.

13.
Cognition ; 218: 104922, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34634533

RESUMO

A compelling account of the reading process holds that words must be encoded serially, and so recognized strictly one at a time in the order they are encountered. However, this view has been challenged recently, based on evidence showing that readers sometimes fail to notice when adjacent words appear in ungrammatical order. This is argued to show that words are actually encoded in parallel, so that multiple words are processed simultaneously and therefore might be recognized out of order. We tested this account in an experiment in Chinese with 112 skilled readers, employing methods used previously to demonstrate flexible word order processing, and display techniques that allowed or disallowed the parallel encoding of words. The results provided evidence for flexible word order processing even when words must be encoded serially. Accordingly, while word order can be processed flexibly during reading, this need not entail that words are encoded in parallel.


Assuntos
Idioma , Leitura , China , Humanos
14.
Front Vet Sci ; 9: 872828, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35498735

RESUMO

The pharmacokinetics, tissue distribution, and elimination of enrofloxacin (ENR) and its metabolite ciprofloxacin (CIP) were investigated to the crucian carp (Carassius auratus gibelio) after single (20 mg/kg b. w.) and multiple oral administration (20 mg/kg b.w. one time daily for 5 days) at 28°C. The concentrations of ENR and CIP in the plasma and tested tissues (muscle/skin, liver, and kidney) were detected simultaneously by high-performance liquid chromatography (HPLC), and the pharmacokinetic data were analyzed with a non-compartmental model using WinNonLin 6.1 PK software (Pharsight Corporation, Mountain View, CA, USA). The pharmacokinetic characteristics of ENR in crucian carp exhibited slow absorption, wide tissue distribution, and long elimination half-life. In the single-dose group, the peak concentrations (Cmax) of ENR in the plasma, muscle/skin, liver, and kidney were 8.93 µg/mL, 13.9 µg/g, 31.2 µg/g, and 27.3 µg/g, respectively, observed at 3 h, 6 h, 1 h, and 3 h after dosing. The elimination half-lives (T1/2λz ) of ENR in plasma, muscle/skin, liver, and kidney were calculated to be 67.4, 82.8, 94.4, and 114 h, respectively. In the multiple-dose group, the Cmax of ENR in the plasma, muscle/skin, liver, and kidney were 18.4 µg/mL, 26.8 µg/g, 82.8 µg/g, and 74.5 µg/g, respectively, achieved at 3 h, 6 h, 1 h, and 1 h after the last dose. The T1/2λz of ENR in the plasma, muscle/skin, liver, and kidney were calculated to be 76.4 h, 91.5 h, 114 h, and 148 h, respectively. During the multiple-dose administration, significant accumulations of ENR and CIP were observed in the plasma and tissues of crucian carp, possibly due to their long elimination half-lives. In both dose groups, the AUC0-∞ for both ENR and CIP followed the order of liver > kidney > muscle/skin > plasma. The finding suggested that the liver may play an important role in the metabolism of ENR. According to the calculated PK/PD indices of Cmax/minimum inhibitory concentrations (MIC) and AUC24h/MIC, the multiple-dose regimen would be highly effective against pathogenic bacteria with a MIC value of ≤ 1.84 µg/ml. Depletion studies indicated that a withdrawal period of at least 29 or 32 days was necessary to guarantee food security after single or multiple oral gavage administration at 28°C.

15.
Nucleic Acids Res ; 49(14): 7870-7883, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34283224

RESUMO

Risdiplam is the first approved small-molecule splicing modulator for the treatment of spinal muscular atrophy (SMA). Previous studies demonstrated that risdiplam analogues have two separate binding sites in exon 7 of the SMN2 pre-mRNA: (i) the 5'-splice site and (ii) an upstream purine (GA)-rich binding site. Importantly, the sequence of this GA-rich binding site significantly enhanced the potency of risdiplam analogues. In this report, we unambiguously determined that a known risdiplam analogue, SMN-C2, binds to single-stranded GA-rich RNA in a sequence-specific manner. The minimum required binding sequence for SMN-C2 was identified as GAAGGAAGG. We performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method, which captured spontaneous binding of a risdiplam analogue to the target nucleic acids. We uncovered, for the first time, a ligand-binding pocket formed by two sequential GAAG loop-like structures. The simulation findings were highly consistent with experimental data obtained from saturation transfer difference (STD) NMR and structure-affinity-relationship studies of the risdiplam analogues. Together, these studies illuminate us to understand the molecular basis of single-stranded purine-rich RNA recognition by small-molecule splicing modulators with an unprecedented binding mode.


Assuntos
Compostos Azo/metabolismo , Atrofia Muscular Espinal/genética , Pirimidinas/metabolismo , Precursores de RNA/genética , Splicing de RNA , Compostos Azo/química , Compostos Azo/uso terapêutico , Sequência de Bases , Sítios de Ligação/genética , DNA de Cadeia Simples/química , DNA de Cadeia Simples/genética , DNA de Cadeia Simples/metabolismo , Éxons/genética , Cinética , Espectroscopia de Ressonância Magnética/métodos , Simulação de Dinâmica Molecular , Estrutura Molecular , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/metabolismo , Mutação , Fármacos Neuromusculares/química , Fármacos Neuromusculares/metabolismo , Fármacos Neuromusculares/uso terapêutico , Conformação de Ácido Nucleico , Pirimidinas/química , Pirimidinas/uso terapêutico , Precursores de RNA/química , Precursores de RNA/metabolismo , Proteína 2 de Sobrevivência do Neurônio Motor/genética
16.
Org Lett ; 23(15): 5658-5663, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34255532

RESUMO

We report an asymmetric 1,2-reduction of cyclic α,ß-unsaturated ketones to access various enantiomerically enriched cyclic allylic alcohols under mild conditions, catalyzed by in situ generated copper hydride ligated with (R)-DTBM-C3*-TunePhos. α-Brominated cycloalkenones were reduced with excellent enantioselectivities of up to 98% ee, while substrates that were without α-substituents were reduced chemoselectively, with moderate enantioselectivities.

17.
J Clin Pharm Ther ; 46(5): 1373-1381, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34101878

RESUMO

WHAT IS KNOWN AND OBJECTIVE: We have previously shown that the saponins of Sanguisorba parviflora (Maxim.) Takeda (Sp. T) relieved cyclophosphamide-induced myelosuppression in leukopenic mice. Haematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) participated in the survival of neutrophils through the regulation of mitochondrial function. The aim of the present study was to comprehensively identify the role of HAX-1 in the mechanism of leukopenia alleviation by Sp. T. METHODS: HAX-1 gene and protein expression levels in peripheral blood neutrophils were examined using real-time quantitative reverse transcription-polymerase chain reaction, western blot and immunohistochemical assays. Neutrophil apoptosis was measured using flow cytometry. Mitochondrial function was determined via assessments of the reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) integrity levels. RESULTS AND DISCUSSION: The HAX-1 gene expression level in the peripheral blood neutrophils was significantly lower in patients with leukopenia than in healthy donors. The saponins of Sp. T induced HAX-1 expression and promoted myeloid progenitor cell (mEB8-ER cell) viability. HAX-1 overexpression reduced the production of ROS and maintained ΔΨm integrity. Cyclophosphamide-induced mitochondrial dysfunction and apoptosis could be abrogated by treatment with Sp. T or metformin. WHAT IS NEW AND CONCLUSION: Our data suggest a mechanism through which Sp. T protects against chemotherapy-induced leukopenia by regulating HAX-1 gene expression in a mitochondrial-dependent manner.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Ciclofosfamida/efeitos adversos , Leucopenia/induzido quimicamente , Leucopenia/tratamento farmacológico , Sanguisorba/química , Saponinas/farmacologia , Adulto , Apoptose/efeitos dos fármacos , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Células Progenitoras Mieloides/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
18.
J Clin Pharm Ther ; 46(5): 1334-1342, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34075619

RESUMO

WHAT IS KNOWN AND THE OBJECTIVE: Our previous studies have shown that saponins of Sanguisorba parviflora (Maxim) Takeda (Sp. T) relieved cyclophosphamide-induced myelosuppression in mice with leukopenia. The hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) participated in the survival of neutrophils through the regulation of mitochondrial function. This study aimed to comprehensively identify the role of HAX-1 in Sp. T to alleviate leukopenia. METHODS: HAX-1 expression was examined in the peripheral blood neutrophils using real-time polymerase chain reaction (PCR), Western blot analysis and immunohistochemical staining. Neutrophil apoptosis was measured by flow cytometry. Mitochondrial function was evaluated via reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) integrity. RESULTS AND DISCUSSION: Our study indicated that the expression of the HAX-1 gene was significantly decreased in the peripheral blood neutrophils of leukopenia patients compared with healthy donors. The saponins of Sp. T induced HAX-1 expression and promoted myeloid progenitor cell (mEB8-ER cell) viability, while overexpression of HAX-1 reduced the production of reactive oxygen species (ROS) and maintained the integrity of the mitochondrial membrane potential. Cyclophosphamide-induced mitochondrial dysfunction and apoptosis could be abrogated by treatment with Sp. T or the addition of metformin. WHAT IS NEW AND OUR CONCLUSION: Our data support a mechanism where Sp. T protects against chemotherapy-induced leukopenia by regulating HAX-1 gene expression in a mitochondrial-dependent manner.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Ciclofosfamida/efeitos adversos , Leucopenia/induzido quimicamente , Leucopenia/tratamento farmacológico , Sanguisorba/química , Saponinas/farmacologia , Adulto , Apoptose/efeitos dos fármacos , Feminino , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
19.
Molecules ; 26(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919699

RESUMO

RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered "undruggable" genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers.


Assuntos
Desenvolvimento de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Splicing de RNA/genética , Animais , Sequência de Bases , Doença/genética , Humanos , Bibliotecas de Moléculas Pequenas/farmacologia , Spliceossomos/metabolismo
20.
Acta Psychol (Amst) ; 215: 103272, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33640595

RESUMO

Recent research using a speeded grammaticality decision revealed novel transposed-word effects when reading alphabetic languages such as French (Mirault, Snell, & Grainger, 2018), and nonalphabetic languages such as Chinese (Liu, Li, Paterson, & Wang, 2020). Transposed-word effects are considered to reflect flexibility in word order processing, but the factors that might modulate such effects remain unknown. The present study investigated this issue by using a within-subjects design in Chinese reading. In experiment 1, the participants were asked to read sentences at their normal and speeded reading speed and to make grammaticality decisions as accurately as possible. No significant interaction between transposed-word effects and reading speed was found, suggesting that transposed-word effects are not modulated by reading speed and that they are similar regardless of whether the participants read slowly or quickly. In experiment 2, we manipulated the context before the transposed words and used a speeded grammaticality decision task. We observed significant interactive effects between transposed-word effects and context, and analyses revealed that transposed-word effects decreased when the first and second words were transposed in a sentence. We conclude that context rather than reading speed modulates transposed-word effects in Chinese reading and discuss these findings with regard to the noisy bottom-up allocation of word identities and top-down sentence-level constraints.


Assuntos
Idioma , Leitura , China , Humanos
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