ABSTRACT
Inspired by efficient natural biomolecule assembly with precise control on key parameters such as distance, number, orientation, and pattern, the constructions and applications of artificial precise molecule assembly are highly important in many research areas including chemistry, biology, and medicine. DNA origami, a sophisticated DNA nanotechnology with rational design, can offer a predictable, programmable, and addressable nanoscale scaffold for the precise assembly of various kinds of molecules. Herein, we summarize recent progress, particularly in the last three years, in DNA-origami-based precise molecule assembly and their emerging biological applications. We first introduce DNA origami and the progress on DNA-origami-based precise molecule assembly, including assembly of various kinds of molecules (e.g., nucleic acids, proteins, organic molecules, nanoparticles), and precise control of important parameters (e.g., distance, number, orientation, pattern). Their biological applications in sensing, imaging, therapy, bionics, biophysics, and chemical biology are then summarized, and current challenges and opportunities are finally discussed.
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BACKGROUND: Hypoxic-ischemic injury of neurons is a pathological process observed in several neurological conditions, including ischemic stroke and neonatal hypoxic-ischemic brain injury (HIBI). An optimal treatment strategy for these conditions remains elusive. The present study delved deeper into the molecular alterations occurring during the injury process in order to identify potential therapeutic targets. METHODS: Oxygen-glucose deprivation/reperfusion (OGD/R) serves as an established in vitro model for the simulation of HIBI. This study utilized RNA sequencing to analyze rat primary hippocampal neurons that were subjected to either 0.5 or 2 h of OGD, followed by 0, 9, or 18 h of reperfusion. Differential expression analysis was conducted to identify genes dysregulated during OGD/R. Time-series analysis was used to identify genes exhibiting similar expression patterns over time. Additionally, functional enrichment analysis was conducted to explore their biological functions, and protein-protein interaction (PPI) network analyses were performed to identify hub genes. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for validation of hub-gene expression. RESULTS: The study included a total of 24 samples. Analysis revealed distinct transcriptomic alterations after OGD/R processes, with significant dysregulation of genes such as Txnip, Btg2, Egr1 and Egr2. In the OGD process, 76 genes, in two identified clusters, showed a consistent increase in expression; functional analysis showed involvement of inflammatory responses and signaling pathways like tumor necrosis factor (TNF), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and interleukin 17 (IL-17). PPI network analysis suggested that Ccl2, Jun, Cxcl1, Ptprc, and Atf3 were potential hub genes. In the reperfusion process, 274 genes, in three clusters, showed initial upregulation followed by downregulation; functional analysis suggested association with apoptotic processes and neuronal death regulation. PPI network analysis identified Esr1, Igf-1, Edn1, Hmox1, Serpine1, and Spp1 as key hub genes. qRT-PCR validated these trends. CONCLUSIONS: The present study provides a comprehensive transcriptomic profile of an in vitro OGD/R process. Key hub genes and pathways were identified, offering potential targets for neuroprotection after hypoxic ischemia.
Subject(s)
Hypoxia-Ischemia, Brain , Neurons , Transcriptome , Animals , Hypoxia-Ischemia, Brain/metabolism , Hypoxia-Ischemia, Brain/genetics , Rats , Neurons/metabolism , Hippocampus/metabolism , Rats, Sprague-Dawley , Glucose/metabolism , Cells, Cultured , Disease Models, Animal , Protein Interaction MapsABSTRACT
Efficient transformation of platform chemicals into key intermediates has been increasingly important for the pharmaceutical industry. The development of the catalytic reduction of abundant carboxylic acids with molecular hydrogen has been of both practical and theoretical value. We herein report the homogeneous hydrogenation of dicarboxylic acids with the strategy of desymmetrization. Using a rhodium/bisphosphine catalyst, one carboxyl group of meso-diacids was selectively reduced to yield chiral lactones with satisfactory enantioselectivity. This method provides a straightforward approach to produce chiral lactone intermediates for the manufacture of biotin, telaprevir, and other antivirus drugs. Both experimental and computational investigations were carried out, revealing a novel neighboring group coordination mechanism in the catalytic cycle.
ABSTRACT
The flash organometallic catalysis is a new concept that refers to the study of fast and controlled organometallic catalytic reactions by using microfluidic devices. Flash reactions' kinetics (ms-s scale) is often ignored due to the lack of proper research tool in organometallic chemistry. The development of microfluidic systems offers the opportunity to discover under-studied mechanisms and new reactions. In this concept, the basic theory of kinetic measurement in a microreactor is briefly reviewed and then two examples on studying flash organometallic catalytic transformation are introduced. One example is the discovery of a highly active palladium catalytic species for Suzuki Coupling and the other example is the study of a neglected isomerization catalytic cycle with a time scale of seconds before isomerization-hydroformylation by customized microfluidic devices. The last part is summary and prospect of this new area. Customizing a microfluidic device with good engineering design for a target reaction supports flash reactions' kinetic experimentation and could become a general strategy in chemistry lab.
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Rapid, sensitive and selective biosensing is highly important for analyzing biological targets and dynamic physiological processes in cells and living organisms. As an emerging tool, clustered regularly interspaced short palindromic repeats (CRISPR) system is featured with excellent complementary-dependent cleavage and efficient trans-cleavage ability. These merits enable CRISPR system to improve the specificity, sensitivity, and speed for molecular detection. Herein, the structures and functions of several CRISPR proteins for biosensing are summarized in depth. Moreover, the strategies of target recognition, signal conversion, and signal amplification for CRISPR-based biosensing were highlighted from the perspective of biosensor design principles. The state-of-art applications and recent advances of CRISPR system are then outlined, with emphasis on their fluorescent, electrochemical, colorimetric, and applications in POCT technology. Finally, the current challenges and future prospects of this frontier research area are discussed.
Subject(s)
Biosensing Techniques , Colorimetry , Coloring Agents , CRISPR-Cas Systems/geneticsABSTRACT
A new class of cobalt catalytic system for asymmetric hydrogenation of ketones was herein reported, involving the development of novel ferrocene-based secondary phosphine oxide ligands. An unusual P-O bidentate coordination pattern with cobalt was confirmed by an X-ray diffraction study. The bichelating tetrahedral cobalt(II) complexes afforded high reactivities (up to 99% yield) and good to excellent enantioselectivities (up to 92% ee) in the AH of various ortho-substituted diaryl ketones. In addition, the diferrocenyl cobalt complex was characterized with intriguing UV-vis absorption and electrochemical properties.
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In this work, a novel "turn-on" fluorescence sensor for the detection of H2O2 and glucose was developed based on green fluorescent carbon dots (CDs). The CDs was newly prepared by a facile one-pot hydrothermal method with Eosin Y and branched polyethylenimine as precursors. Interestingly, in the presence of H2O2 and HRP, the fluorescence of the CDs enhanced significantly with a red-shift emission due to their "aggregation". Meanwhile, the oxidation of glucose catalyzed by glucose oxidase could generate H2O2. Thus, a simple sensing system based on the CDs as fluorescent probes was constructed for H2O2 and glucose determination, avoiding the fluorescence quenching and subsequent recovery process in conventional turn-on strategy. The method showed good selectivity and sensitivity for glucose sensing with the detection limit of 0.12 µM. The method was further applied to glucose detection in real samples. The obtained results demonstrated the simplicity, selectivity and practicality of the method. This work expands the carbon nanomaterials with fluorescence emission enhancement properties. It provides a new and direct "turn-on" strategy for H2O2 and glucose detection, which could be a simple and effective tool for screening biological substances involved in H2O2-generation reaction.
Subject(s)
Glucose , Quantum Dots , Carbon , Hydrogen Peroxide , Glucose Oxidase , Fluorescent Dyes , Limit of DetectionABSTRACT
We herein reported the design and synthesis of a ferrocene-based tetradentate ligand that is featured with modular synthesis and rigid skeleton. Its iron(II) complex facilitates asymmetric direct hydrogenation of ketones without the participation of extra strong-field ligand such as CO and isocyanide. Hydride donor lithium aluminum hydride (LAH) converted non-reactive Fe(II) species to reactive Fe(II) hydride species. With this catalyst, various chiral alcohols including the intermediate for montelukast could be prepared with satisfactory yields and enantioinduction.
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By combining the concept of flash chemistry and radial synthesis, a novel microreactor (Flashstop reactor) was designed to study isomerization process of hydroformylation by a Rh/tetraphosphite catalyst in a time scale of seconds. It was found that in the initial 313â seconds, 60-99 % of 1-octene was isomerized to 2- and 3-octenes before the formation of aldehydes. Within this period, two different types of isomerization reactions were observed. It was proposed that a monohydride complex without CO ligand accounts for the ultrafast isomerization in the initial 30â seconds. The isomerization rate with such monohydride species was calculated much faster than that with the well-known H(CO)Rh(P-P) species. Both experimental and DFT computational studies were carried out to support this assumption. Fast transformations early on in catalytic cycles have been rarely studied due to the lack of proper tools. We believe that the Flashstop reactor is a powerful tool for analysis of kinetics in gas-liquid biphasic reactions within a time scale of seconds to minutes.
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BACKGROUNDS: Many studies suggest that both psychotherapy and drug therapy are effective in the treatment of bipolar disorders (BDs). However, the pathophysiology of both types of intervention has not been established definitively. METHODS: An activation likelihood estimation meta-analysis was performed to identify the distinct brain activity alterations between psychotherapy and drug therapy for the treatment of BDs. Articles were identified by searching databases including PubMed, Embase, Cochrane Library, and Web of Science databases. Eligible studies on BDs were published up until 10 June 2021. RESULTS: 21 studies were included and we conducted a meta-analysis for different therapies and imaging tasks. After receiving psychotherapy, BD patients showed increased activation in the inferior frontal gyrus (IFG) and superior temporal gyrus. While after taking drug therapy, BD patients displayed increased activation in the anterior cingulate cortex, medial frontal gyrus, IFG, and decreased activation in the posterior cingulate cortex. The regions of brain activity changes caused by psychotherapy were mostly focused on the frontal areas, while drug therapy mainly impacted on the limbic areas. Different type of tasks also affected brain regions which were activated. CONCLUSIONS: Our comprehensive meta-analysis indicates that these two treatments might have effect on BD in their own therapeutic modes. Psychotherapy might have a top-down effect, while drug therapy might have a bottom-up effect. This study may contribute to differential diagnosis of BDs and would be helpful to finding more accurate neuroimaging biomarkers for BD treatment.
Subject(s)
Bipolar Disorder , Humans , Bipolar Disorder/diagnostic imaging , Bipolar Disorder/drug therapy , Likelihood Functions , Magnetic Resonance Imaging/methods , Brain , PsychotherapyABSTRACT
Arene hydrogenation is the most straightforward method to prepare carbo- and heterocycles. However, the high resonance energy prevents aromatic substrates from hydrogenation. Herein the homogeneous, nucleophilic hydrogenation of less electron-rich arenes and heteroarenes is reported. The Co(P4 N2 )H species that has been demonstrated to be a strong hydride donor could deliver a hydride ion to the cyano (hetero)arene substrates. Deuterium labeling experiments supported a Michael-type reaction pathway. Theoretical analyses have been conducted to investigate the hydricity of the catalytically active CoH species and the electrophilicity of the arene substrates. An outlook for the synthesis of more challenging substituted benzenes was proposed based on the inâ silico modification of the CoH species.
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BACKGROUND: Hypoxia-ischemic brain damage (HIBD) is a primary cause of morbidity and disability in survivors of preterm infants. We previously discovered that miR-200b-3p plays an important role in HIBD via targeting Slit2. This study was designed to identify novel targets of miR-200b-3p and investigate the relationship between miR-200b-3p and its downstream effectors. METHODS AND RESULTS: Cultured primary rat hippocampal neurons were used in the model of oxygen-glucose deprivation (OGD) and RT-qPCR was utilized to detect the alterations of miR-200b-3p in these cells following the OGD. Our study found that the expression of miR-200b-3p was up-regulated in neurons post OGD. Bioinformatics analysis identified that ß transducin repeat-containing protein (ß-TrCP) is a target gene of miR-200b-3p, and our luciferase reporter gene assay confirmed that miR-200b-3p can interact with ß-TrCP mRNA. Hypoxia-ischemic brain damage was induced in three-day-old SD rats and inhibition of miR-200b-3p by injection of antagomir into bilateral lateral ventricles enhanced ß-TrCP expression at both the mRNA and protein levels in rats' brains. TUNEL staining and CCK-8 assays found that the survival of hippocampal neurons in the miR-200b-3p antagomir group was improved significantly (pï¼0.05), whereas apoptosis of neurons in the miR-200b-3p antagomir group was significantly decreased (pï¼0.05), as compared with the OGD group. However, silencing of ß-TrCP by ß-TrCP siRNA impaired the neuroprotective effect of miR-200b-3p antagomir. H&E staining showed that miR-200b-3p attenuated the pathological changes in the hippocampal region of rats with HIBD. CONCLUSION: Our study has demonstrated that ß-TrCP is a target gene of miR-200b-3p and that inhibition of miR-200b-3p by antagomir attenuates hypoxia-ischemic brain damage via ß-TrCP.
Subject(s)
Hypoxia-Ischemia, Brain , MicroRNAs , Infant, Newborn , Humans , Rats , Animals , Oxygen/metabolism , MicroRNAs/metabolism , beta-Transducin Repeat-Containing Proteins/pharmacology , Antagomirs/pharmacology , Rats, Sprague-Dawley , Glucose/pharmacology , Infant, Premature , Hypoxia-Ischemia, Brain/pathology , Apoptosis , RNA, MessengerABSTRACT
Assays utilizing in situ fluorogenic reactions provide a simple and convenient alternative approach for the detection of biological molecules and activities. In this work, a novel ratiometric fluorescent probe based on in situ fluorogenic reaction is explored and developed for alkaline phosphatase (ALP) activity sensing. An intriguing fluorogenic reaction between 2,3-diaminonaphthalene (2,3-DAN) and ascorbic acid (AA) in alkaline aqueous solutions could generate the fluorescent quinoxaline derivative. The resultant quinoxaline emits intense yellow fluorescence, differing from the blue fluorescence of 2,3-DAN. Thus, a ratiometric fluorescent probe based on this fluorogenic reaction is constructed for ALP activity sensing, combining with ALP-triggered hydrolysis of AA2P into AA. Meanwhile, the addition of copper(II) acetate into the reaction system largely improves reaction rate and efficiency. This sensing strategy shows high sensitivity for ALP activity with detection limit of 0.08 U/L, and excellent selectivity towards ALP out of various interferences. This method is extended to human salivary ALP detection. The present method provides a simple and reliable alternative for the detection of ALP activity and has the potential for clinical applications. It also shows a feasible way to construct ratiometric fluorescent methods.
Subject(s)
Alkaline Phosphatase , Fluorescent Dyes , Ascorbic Acid , Humans , Quinoxalines , Spectrometry, Fluorescence/methodsABSTRACT
The construction of chiral quaternary carbon stereocenters has been a long-standing challenge in organic chemistry. Particularly, α-quaternary amino acids that are of high importance in biochemistry still lack a straightforward synthetic method. We here reported a hydroformylation approach to access chiral quaternary stereogenic centers, which has been a long-standing challenge in transition metal catalysis. α,ß-Unsaturated carboxylic acid derivatives undergo hydroformylation with a rhodium catalyst to generate an α-quaternary stereocenter under mild conditions. By using this method, a variety of chiral α-quaternary amino acids could be synthesized with satisfactory enantioselectivity. In-depth investigation revealed that the regioselectivity is dramatically influenced by the electronic properties of the substituents attached to the target C[double bond, length as m-dash]C bond. By applying NMR and DFT analyses, the chiral environment of a rhodium/Yanphos complex was depicted, based on which a substrate-catalyst interaction model was proposed.
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Objective: Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of epilepsy and chronic neurologic morbidity in premature infants. This study aimed to investigate the characteristics of acute seizures and the pattern of background activity on amplitude-integrated electroencephalography (aEEG) in neonatal rats with HIE. Methods: Hypoxia-ischemia (HI) was induced in postnatal day (P) 3 neonatal rats (n = 12) by ligation of the left carotid artery and exposure to airtight hypoxia for 2 h. Data regarding seizure type, frequency, and duration and those related to neurobehavioral development were collected, and the integrated power of background EEG was analyzed to evaluate the effect of HI. Results: All neonatal rats in the HI group experienced frequent seizures during hypoxia, and 83.3% of rats (10/12) experienced seizures immediately after hypoxia. Seizure frequency and duration gradually decreased with increasing age. The mortality rate of the HI group was 8.33% (1/12); 120 h after HI induction, only 27.3% (3/11) of pups had low-frequency and short-duration electrographic seizures, respectively. HI rats, which presented seizure activities 96 h after HI insult, exhibited an increase in righting reflex time and a decrease in forelimb grip reflex time. Background EEG was significantly inhibited during HI induction and immediately after hypoxia and gradually recovered 72 h after hypoxia. Conclusion: Seizures caused by HI brain damage in premature infants can be simulated in the P3 neonatal rat model.
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Objective: Sleep is necessary for brain maturation in infants. Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of chronic neurological disease in infants. Although the developmental changes of electroencephalogram (EEG) in human newborns have been described, little is known about the EEG normal maturation characteristics in rodents and the changes in sleep-awake states caused by hypoxia-ischemia (HI). This study aimed to investigate the pathological response of sleep-wake states in neonatal rats with HIE. Methods: We constructed HIE and sham models on postnatal day (P) 3 rats and continuously monitored them using electroencephalography and electromyography for up to P12. The distribution of sleep-wake states was analyzed to estimate the effects of HIE. Results: Compared with the sham group, the HI group showed lower rapid eye movement (REM) sleep percentage, but wake percentage and frequency was higher during P4-P12. The frequency of REM and non-rapid eye movement (NREM) sleep increased and the duration of REM and NREM sleep decreased after HI induction. However, it gradually returned to the normal level with an increase in daytime. Conclusion: HI damage alters the sleep-wake patterns during early neural development. The findings provide a comprehensive assessment of serial sleep-wake state recordings in neonatal rats from P4-P12.
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We herein report a convenient method to convert olefins to organic iodides and amines using an Ir/ZhaoPhos catalyst, molecular hydrogen, and an electrophilic iodine(I) reagent. High yields and regioselectivities were obtained under mild conditions. In addition, basic workup with potassium carbonate leads to C-N products. Control experiments and DFT calculations tentatively excluded the pathway involving the in situ formation of HI. Instead, a catalytic cycle involving the hydrogenation of the haliranium ion intermediate was proposed.
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Asymmetric hydrogenation (AH) of double bonds has been one of the most effective methods for the preparation of chiral molecules and for the synthesis of important chiral building blocks. In the past 60 years, noble metals with bidentate ligands have shown marvelous reactivity and enantioselectivity in asymmetric hydrogenation of a series of prochiral substrates. In recent years, developing chiral tridentate ligands has played an increasingly important role in AH. With modular frameworks and a variety of functionalities on the side arms, chiral tridentate ligand complexes enable both reactivities and stereoselectivities. Although great achievements have been made for noble metal catalysts with chiral tridentate ligands since the 1990s, the design of chiral tridentate ligands for earth abundant metal catalysts has still been in high demand. This review summarizes the development of chiral tridentate ligands for homogeneous asymmetric hydrogenation. The philosophy of ligand design and the reaction mechanisms are highlighted and discussed as well.
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This review provides a comprehensive view of the application of first-row transition metals in asymmetric hydrogenation and asymmetric transfer hydrogenation. The catalytic behavior of 3d metals is significantly different from that of 4d and 5d metals. The replacement of noble metals with first-row transition metals has encountered challenges such as different reaction mechanisms and unexpected deactivation of the catalyst. The potential involvement of a single-electron process has been the most notorious feature of first-row metals. This review aims to give readers a picture of how first-row transition metals catalyze hydrogenation reactions and the corresponding enantioinduction models. Although this article is partitioned according to the substrate type, it is mechanism-oriented and is focused on catalytic systems. A certain catalytic system could be applied in the hydrogenation of different types of double bonds. Similarities within first-row metals and differences from their 4d and 5d congeners were emphasized.