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1.
Cell ; 186(17): 3726-3743.e24, 2023 08 17.
Article in English | MEDLINE | ID: mdl-37442136

ABSTRACT

Elucidating the cellular organization of the cerebral cortex is critical for understanding brain structure and function. Using large-scale single-nucleus RNA sequencing and spatial transcriptomic analysis of 143 macaque cortical regions, we obtained a comprehensive atlas of 264 transcriptome-defined cortical cell types and mapped their spatial distribution across the entire cortex. We characterized the cortical layer and region preferences of glutamatergic, GABAergic, and non-neuronal cell types, as well as regional differences in cell-type composition and neighborhood complexity. Notably, we discovered a relationship between the regional distribution of various cell types and the region's hierarchical level in the visual and somatosensory systems. Cross-species comparison of transcriptomic data from human, macaque, and mouse cortices further revealed primate-specific cell types that are enriched in layer 4, with their marker genes expressed in a region-dependent manner. Our data provide a cellular and molecular basis for understanding the evolution, development, aging, and pathogenesis of the primate brain.


Subject(s)
Cerebral Cortex , Macaca , Single-Cell Analysis , Transcriptome , Animals , Humans , Mice , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Macaca/metabolism , Transcriptome/genetics
2.
Cell ; 185(10): 1777-1792.e21, 2022 05 12.
Article in English | MEDLINE | ID: mdl-35512705

ABSTRACT

Spatially resolved transcriptomic technologies are promising tools to study complex biological processes such as mammalian embryogenesis. However, the imbalance between resolution, gene capture, and field of view of current methodologies precludes their systematic application to analyze relatively large and three-dimensional mid- and late-gestation embryos. Here, we combined DNA nanoball (DNB)-patterned arrays and in situ RNA capture to create spatial enhanced resolution omics-sequencing (Stereo-seq). We applied Stereo-seq to generate the mouse organogenesis spatiotemporal transcriptomic atlas (MOSTA), which maps with single-cell resolution and high sensitivity the kinetics and directionality of transcriptional variation during mouse organogenesis. We used this information to gain insight into the molecular basis of spatial cell heterogeneity and cell fate specification in developing tissues such as the dorsal midbrain. Our panoramic atlas will facilitate in-depth investigation of longstanding questions concerning normal and abnormal mammalian development.


Subject(s)
Organogenesis , Transcriptome , Animals , DNA/genetics , Embryo, Mammalian , Female , Gene Expression Profiling/methods , Mammals/genetics , Mice , Organogenesis/genetics , Pregnancy , Sequence Analysis, RNA/methods , Single-Cell Analysis/methods , Transcriptome/genetics
3.
Nature ; 601(7892): 274-279, 2022 01.
Article in English | MEDLINE | ID: mdl-34880492

ABSTRACT

Glucose is a primary energy source in living cells. The discovery in 1960s that a sodium gradient powers the active uptake of glucose in the intestine1 heralded the concept of a secondary active transporter that can catalyse the movement of a substrate against an electrochemical gradient by harnessing energy from another coupled substrate. Subsequently, coupled Na+/glucose transport was found to be mediated by sodium-glucose cotransporters2,3 (SGLTs). SGLTs are responsible for active glucose and galactose absorption in the intestine and for glucose reabsorption in the kidney4, and are targeted by multiple drugs to treat diabetes5. Several members within the SGLT family transport key metabolites other than glucose2. Here we report cryo-electron microscopy structures of the prototypic human SGLT1 and a related monocarboxylate transporter SMCT1 from the same family. The structures, together with molecular dynamics simulations and functional studies, define the architecture of SGLTs, uncover the mechanism of substrate binding and selectivity, and shed light on water permeability of SGLT1. These results provide insights into the multifaceted functions of SGLTs.


Subject(s)
Cryoelectron Microscopy , Glucose , Glucose/metabolism , Humans , Monocarboxylic Acid Transporters/chemistry , Monocarboxylic Acid Transporters/metabolism , Monocarboxylic Acid Transporters/ultrastructure , Sodium/metabolism , Sodium-Glucose Transporter 1/chemistry , Sodium-Glucose Transporter 1/metabolism , Sodium-Glucose Transporter 1/ultrastructure , Substrate Specificity
4.
Nature ; 604(7907): 723-731, 2022 04.
Article in English | MEDLINE | ID: mdl-35418686

ABSTRACT

Studying tissue composition and function in non-human primates (NHPs) is crucial to understand the nature of our own species. Here we present a large-scale cell transcriptomic atlas that encompasses over 1 million cells from 45 tissues of the adult NHP Macaca fascicularis. This dataset provides a vast annotated resource to study a species phylogenetically close to humans. To demonstrate the utility of the atlas, we have reconstructed the cell-cell interaction networks that drive Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases, and intersected our data with human genetic disease orthologues to establish potential clinical associations. Our M. fascicularis cell atlas constitutes an essential reference for future studies in humans and NHPs.


Subject(s)
Macaca fascicularis , Transcriptome , Animals , Cell Communication , Macaca fascicularis/genetics , Receptors, Virus/genetics , Transcriptome/genetics , Wnt Signaling Pathway
5.
Plant Cell ; 2024 Jun 29.
Article in English | MEDLINE | ID: mdl-38943676

ABSTRACT

The cell wall shapes plant cell morphogenesis and affects the plasticity of organ growth. However, the way in which cell wall establishment is regulated by ethylene remains largely elusive. Here, by analyzing cell wall patterns, cell wall composition and gene expression in rice (Oryza sativa, L.) roots, we found that ethylene induces cell wall thickening and the expression of cell wall synthesis-related genes, including CELLULOSE SYNTHASE-LIKE C1, 2, 7, 9, 10 (OsCSLC1, 2, 7, 9, 10) and CELLULOSE SYNTHASE A3, 4, 7, 9 (OsCESA3, 4, 7, 9). Overexpression and mutant analyses revealed that OsCSLC2 and its homologs function in ethylene-mediated induction of xyloglucan biosynthesis mainly in the cell wall of root epidermal cells. Moreover, OsCESA-catalyzed cellulose deposition in the cell wall was enhanced by ethylene. OsCSLC-mediated xyloglucan biosynthesis likely plays an important role in restricting cell wall extension and cell elongation during the ethylene response in rice roots. Genetically, OsCSLC2 acts downstream of ETHYLENE-INSENSITIVE3-LIKE1 (OsEIL1)-mediated ethylene signaling, and OsCSLC1, 2, 7, 9 are directly activated by OsEIL1. Furthermore, the auxin signaling pathway is synergistically involved in these regulatory processes. These findings link plant hormone signaling with cell wall establishment, broadening our understanding of root growth plasticity in rice and other crops.

6.
Brief Bioinform ; 25(4)2024 May 23.
Article in English | MEDLINE | ID: mdl-38796691

ABSTRACT

Limited gene capture efficiency and spot size of spatial transcriptome (ST) data pose significant challenges in cell-type characterization. The heterogeneity and complexity of cell composition in the mammalian brain make it more challenging to accurately annotate ST data from brain. Many algorithms attempt to characterize subtypes of neuron by integrating ST data with single-nucleus RNA sequencing (snRNA-seq) or single-cell RNA sequencing. However, assessing the accuracy of these algorithms on Stereo-seq ST data remains unresolved. Here, we benchmarked 9 mapping algorithms using 10 ST datasets from four mouse brain regions in two different resolutions and 24 pseudo-ST datasets from snRNA-seq. Both actual ST data and pseudo-ST data were mapped using snRNA-seq datasets from the corresponding brain regions as reference data. After comparing the performance across different areas and resolutions of the mouse brain, we have reached the conclusion that both robust cell-type decomposition and SpatialDWLS demonstrated superior robustness and accuracy in cell-type annotation. Testing with publicly available snRNA-seq data from another sequencing platform in the cortex region further validated our conclusions. Altogether, we developed a workflow for assessing suitability of mapping algorithm that fits for ST datasets, which can improve the efficiency and accuracy of spatial data annotation.


Subject(s)
Algorithms , Benchmarking , Brain , Single-Cell Analysis , Animals , Mice , Brain/metabolism , Single-Cell Analysis/methods , RNA-Seq/methods , Transcriptome , Sequence Analysis, RNA/methods , Neurons/metabolism , Gene Expression Profiling/methods
7.
Proc Natl Acad Sci U S A ; 120(27): e2302367120, 2023 07 04.
Article in English | MEDLINE | ID: mdl-37364107

ABSTRACT

Antimicrobial susceptibility testing plays a pivotal role in the discovery of new antibiotics. However, the development of simple, sensitive, and rapid assessment approaches remains challenging. Herein, we report an activated alkyne-based cascade signal amplification strategy for ultrafast and high-throughput antibiotic screening. First of all, a novel water-soluble aggregation-induced emission (AIE) luminogen is synthesized, which contains an activated alkyne group to enable fluorescence turn-on and metal-free click bioconjugation under physiological conditions. Taking advantage of the in-house established method for bacterial lysis, a number of clickable biological substances (i.e., bacterial solutes and debris) are released from the bacterial bodies, which remarkably increases the quantity of analytes. By means of the activated alkyne-mediated turn-on click bioconjugation, the system fluorescence signal is significantly amplified due to the increased labeling sites as well as the AIE effect. Such a cascade signal amplification strategy efficiently improves the detection sensitivity and thus enables ultrafast antimicrobial susceptibility assessment. By integration with a microplate reader, this approach is further applied to high-throughput antibiotic screening.


Subject(s)
Alkynes , Anti-Bacterial Agents , Anti-Bacterial Agents/pharmacology , Fluorescence , Click Chemistry/methods , Azides
8.
Eur J Immunol ; 54(5): e2350730, 2024 May.
Article in English | MEDLINE | ID: mdl-38430202

ABSTRACT

Sepsis, a multiorgan dysfunction with high incidence and mortality, is caused by an imbalanced host-to-infection immune response. Organ-support therapy improves the early survival rate of sepsis patients. In the long term, those who survive the "cytokine storm" and its secondary damage usually show higher susceptibility to secondary infections and sepsis-induced immunosuppression, in which regulatory T cells (Tregs) are evidenced to play an essential role. However, the potential role and mechanism of Tregs in sepsis-induced immunosuppression remains elusive. In this review, we elucidate the role of different functional subpopulations of Tregs during sepsis and then review the mechanism of sepsis-induced immunosuppression from the aspects of regulatory characteristics, epigenetic modification, and immunometabolism of Tregs. Thoroughly understanding how Tregs impact the immune system during sepsis may shed light on preclinical research and help improve the translational value of sepsis immunotherapy.


Subject(s)
Immune Tolerance , Sepsis , T-Lymphocytes, Regulatory , Humans , Sepsis/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Immune Tolerance/immunology , Epigenesis, Genetic/immunology , Immunosuppression Therapy , Immunotherapy/methods
9.
Nano Lett ; 24(14): 4165-4171, 2024 Apr 10.
Article in English | MEDLINE | ID: mdl-38534019

ABSTRACT

An electrical-controllable antiferromagnet tunnel junction is a key goal in spintronics, holding immense promise for ultradense and ultrastable antiferromagnetic memory with high processing speed for modern information technology. Here, we have advanced toward this goal by achieving an electrical-controllable antiferromagnet-based tunnel junction of Pt/Co/Pt/Co/IrMn/MgO/Pt. The exchange coupling between antiferromagnetic IrMn and Co/Pt perpendicular magnetic multilayers results in the formation of an interfacial exchange bias and exchange spring in IrMn. Encoding information states "0" and "1" is realized through the exchange spring in IrMn, which can be electrically written by spin-orbit torque switching with high cyclability and electrically read by antiferromagnetic tunneling anisotropic magnetoresistance. Combining spin-orbit torque switching of both exchange spring and exchange bias, a 16 Boolean logic operation is successfully demonstrated. With both memory and logic functionalities integrated into our electrically controllable antiferromagnetic-based tunnel junction, we chart the course toward high-performance antiferromagnetic logic-in-memory.

10.
Hum Mol Genet ; 31(13): 2109-2120, 2022 07 07.
Article in English | MEDLINE | ID: mdl-35038734

ABSTRACT

Noise-induced hearing loss (NIHL) is a multifactorial disease caused by environmental, genetic and epigenetic variables. SUMOylation is a post-translational modification that regulates biological processes. The objective of this study was to determine the link between genetic variation in the chromobox 4 (CBX4) and the risk of NIHL. This study applied a case-control design with 588 cases and 582 controls, and the sample was predominantly male (93.76%). The T allele of CBX4 rs1285250 was found to be significantly linked with NIHL (P = 0.002) and showed strong associations in both the codominant and recessive models (TT versus CC, P = 0.005; TT/TC versus CC, P = 0.009). By constructing a mouse model of hearing loss because of noise exposure, changes in hearing thresholds were observed in noise-exposed mice, along with a decrease in the number of cochlear hair cells. Furthermore, noise promotes cochlear hair cell apoptosis by inducing SP1/CBX4 pathway activation. Further functional studies demonstrated that SP1 has an influence on the promoter activity of the CBX4 rs1285250 intron, with the promoter activity of the T allele being higher than that of the C allele. Knockdown of transcription factor SP1 reduced the expression of CBX4 expression and simultaneously reduced apoptosis in HEI-OC1 cells. Together, our findings have shown that CBX4 genetic polymorphism rs1285250 T-allele was associated with increased risk of NIHL and might be used as biomarkers for male workers exposed to noise. Furthermore, we speculate that the CBX4 of rs1285250 T-allele leads to a stronger potential enhancer activity from a predicted gain of stronger SP1 binding.


Subject(s)
Hearing Loss, Noise-Induced , Ligases/metabolism , Polycomb Repressive Complex 1/metabolism , Animals , Case-Control Studies , China , Female , Genetic Predisposition to Disease , Genotype , Hearing Loss, Noise-Induced/genetics , Male , Mice , Polymorphism, Single Nucleotide/genetics , SUMO-1 Protein/genetics , Ubiquitin-Protein Ligases/genetics
11.
Development ; 148(13)2021 07 01.
Article in English | MEDLINE | ID: mdl-34027990

ABSTRACT

Polycomb repressive complex 2 (PRC2) deposits H3K27me3 on chromatin to silence transcription. PRC2 broadly interacts with RNAs. Currently, the role of the RNA-PRC2 interaction in human cardiogenesis remains elusive. Here, we found that human-specific heart brake lncRNA 1 (HBL1) interacted with two PRC2 subunits, JARID2 and EED, in human pluripotent stem cells (hPSCs). Loss of JARID2, EED or HBL1 significantly enhanced cardiac differentiation from hPSCs. HBL1 depletion disrupted genome-wide PRC2 occupancy and H3K27me3 chromatin modification on essential cardiogenic genes, and broadly enhanced cardiogenic gene transcription in undifferentiated hPSCs and later-on differentiation. In addition, ChIP-seq revealed reduced EED occupancy on 62 overlapped cardiogenic genes in HBL1-/- and JARID2-/- hPSCs, indicating that the epigenetic state of cardiogenic genes was determined by HBL1 and JARID2 at pluripotency stage. Furthermore, after cardiac development occurs, the cytosolic and nuclear fractions of HBL1 could crosstalk via a conserved 'microRNA-1-JARID2' axis to modulate cardiogenic gene transcription. Overall, our findings delineate the indispensable role of HBL1 in guiding PRC2 function during early human cardiogenesis, and expand the mechanistic scope of lncRNA(s) that cytosolic and nuclear portions of HBL1 could coordinate to orchestrate human cardiogenesis.


Subject(s)
Genome , Organogenesis , Pluripotent Stem Cells/metabolism , Polycomb Repressive Complex 2/genetics , RNA, Long Noncoding/metabolism , Cell Differentiation , Chromatin , Embryonic Stem Cells/metabolism , Gene Expression Regulation, Developmental , Heart/growth & development , Histones/genetics , Humans , MicroRNAs
12.
Small ; 20(27): e2309661, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38268235

ABSTRACT

Soft robots based on flexible materials have attracted the attention due to high flexibility and great environmental adaptability. Among the common driving modes, electricity, light, and magnetism have the limitations of wiring, poor penetration capability, and sophisticated equipment, respectively. Here, an emerging wireless driving mode is proposed for the soft crawling robot based on wireless power transfer (WPT) technology. The receiving coil at the robot's tail, as an energy transfer station, receives energy from the transmitting coil and supplies the electrothermal responsiveness to drive the robot's crawling. By regulating the WPT's duration to control the friction between the robot and the ground, bidirectional crawling is realized. Furthermore, the receiving coil is also employed as a sensory organ to equip the robot with localization, ID recognition, and sensing capabilities based on electromagnetic coupling. This work provides an innovative and promising strategy for the design and integration of soft crawling robots, exhibiting great potential in the field of intelligent robots.

13.
Small ; : e2310469, 2024 Jan 28.
Article in English | MEDLINE | ID: mdl-38282141

ABSTRACT

Water splitting (or, water electrolysis) is considered as a promising approach to produce green hydrogen and relieve the ever-increasing energy consumption as well as the accompanied environmental impact. Development of high-efficiency, low-cost practical water-splitting systems demands elegant design and fabrication of catalyst-loaded electrodes with both high activity and long-life time. To this end, dimensional engineering strategies, which effectively tune the microstructure and activity of electrodes as well as the electrochemical kinetics, play an important role and have been extensively reported over the past years. Here, a type of most investigated electrode configurations is reviewed, combining particulate catalysts with 3D porous substrates (aerogels, metal foams, hydrogels, etc.), which offer special advantages in the field of water splitting. It is analyzed the design principles, structural and interfacial characteristics, and performance of particle-3D substrate electrode systems including overpotential, cycle life, and the underlying mechanism toward improved catalytic properties. In particular, it is also categorized the catalysts as different dimensional particles, and show the importance of building hybrid composite electrodes by dimensional control and engineering. Finally, present challenges and possible research directions toward low-cost high-efficiency water splitting and hydrogen production is discussed.

14.
Small ; : e2400205, 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38676331

ABSTRACT

The conventional membranes used for separating oil/water emulsions are typically limited by the properties of the membrane materials and the impact of membrane fouling, making continuous long-term usage unachievable. In this study, a filtering electrode with synchronous self-cleaning functionality is devised, exhibiting notable antifouling ability and an extended operational lifespan, suitable for the continuous separation of oil/water emulsions. Compared with the original Ti foam, the in situ growth of NiTi-LDH (Layered double hydroxide) nano-flowers endows the modified Ti foam (NiTi-LDH/TF) with exceptional superhydrophilicity and underwater superoleophobicity. Driven by gravity, a rejection rate of over 99% is achieved for various emulsions containing oil content ranging from 1% to 50%, as well as oil/seawater emulsions. The flux recovery rate exceeds 90% after one hundred cycles and a 4-h filtration period. The enhanced separation performance is realized through the "gas bridge" effect during in situ aeration and electrochemical anodic oxidation. The internal aeration within the membrane pores contributes to the removal of oil foulants. This study underscores the potential of coupling foam metal filtration materials with electrochemical technology, providing a paradigm for the exploration of novel oil/water separation membranes.

15.
Plant Physiol ; 193(1): 821-839, 2023 08 31.
Article in English | MEDLINE | ID: mdl-37311207

ABSTRACT

Soil acidification in apple (Malus domestica) orchards results in the release of rhizotoxic aluminum ions (Al3+) into soil. Melatonin (MT) participates in plant responses to abiotic stress; however, its role in AlCl3 stress in apple remains unknown. In this study, root application of MT (1 µM) substantially alleviated AlCl3 stress (300 µM) in Pingyi Tiancha (Malus hupehensis), which was reflected by higher fresh and dry weight, increased photosynthetic capacity, and longer and more roots compared with plants that did not receive MT treatment. MT functioned mainly by regulating vacuolar H+/Al3+ exchange and maintaining H+ homeostasis in the cytoplasm under AlCl3 stress. Transcriptome deep sequencing analysis identified the transcription factor gene SENSITIVE TO PROTON RHIZOTOXICITY 1 (MdSTOP1) was induced by both AlCl3 and MT treatments. Overexpressing MdSTOP1 in apple increased AlCl3 tolerance by enhancing vacuolar H+/Al3+ exchange and H+ efflux to the apoplast. We identified 2 transporter genes, ALUMINUM SENSITIVE 3 (MdALS3) and SODIUM HYDROGEN EXCHANGER 2 (MdNHX2), as downstream targets of MdSTOP1. MdSTOP1 interacted with the transcription factor NAM ATAF and CUC 2 (MdNAC2) to induce MdALS3 expression, which reduced Al toxicity by transferring Al3+ from the cytoplasm to the vacuole. Furthermore, MdSTOP1 and MdNAC2 coregulated MdNHX2 expression to increase H+ efflux from the vacuole to the cytoplasm to promote Al3+ compartmentalization and maintain cation balance in the vacuole. Taken together, our findings reveal an MT-STOP1 + NAC2-NHX2/ALS3-vacuolar H+/Al3+ exchange model for the alleviation of AlCl3 stress in apple, laying a foundation for practical applications of MT in agriculture.


Subject(s)
Malus , Melatonin , Malus/metabolism , Melatonin/metabolism , Aluminum/toxicity , Aluminum/metabolism , Aluminum Chloride/metabolism , Protons , Ions/metabolism , Transcription Factors/metabolism , Soil
16.
Theor Appl Genet ; 137(3): 67, 2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38441674

ABSTRACT

KEY MESSAGE: A major stable QTL, qKl-1BL, for kernel length of wheat was narrowed down to a 2.04-Mb interval on chromosome 1BL; the candidate genes were predicated and the genetic effects on yield-related traits were characterized. As a key factor influencing kernel weight, wheat kernel shape is closely related to yield formation, and in turn affects both wheat processing quality and market value. Fine mapping of the major quantitative trait loci (QTL) for kernel shape could provide genetic resources and a theoretical basis for the genetic improvement of wheat yield-related traits. In this study, a major QTL for kernel length (KL) on 1BL, named qKl-1BL, was identified from the recombinant inbred lines (RIL) in multiple environments based on the genetic map and physical map, with 4.76-21.15% of the phenotypic variation explained. To fine map qKl-1BL, the map-based cloning strategy was used. By using developed InDel markers, the near-isogenic line (NIL) pairs and eight key recombinants were identified from a segregating population containing 3621 individuals derived from residual heterozygous lines (RHLs) self-crossing. In combination with phenotype identification, qKl-1BL was finely positioned into a 2.04-Mb interval, KN1B:698.15-700.19 Mb, with eight differentially expressed genes enriched at the key period of kernel elongation. Based on transcriptome analysis and functional annotation information, two candidate genes for qKl-1BL controlling kernel elongation were identified. Additionally, genetic effect analysis showed that the superior allele of qKl-1BL from Jing411 could increase KL, thousand kernel weight (TKW), and yield per plant (YPP) significantly, as well as kernel bulk density and stability time. Taken together, this study identified a QTL interval for controlling kernel length with two possible candidate genes, which provides an important basis for qKl-1BL cloning, functional analysis, and application in molecular breeding programs.


Subject(s)
Quantitative Trait Loci , Triticum , Humans , Triticum/genetics , Chromosome Mapping , Alleles , DNA Shuffling
17.
Analyst ; 149(13): 3585-3595, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38767148

ABSTRACT

The main protease of SARS-CoV-2 (SARS-CoV-2 Mpro) plays a critical role in the replication and life cycle of the virus. Currently, how to screen SARS-CoV-2 Mpro inhibitors from complex traditional Chinese medicine (TCM) is the bottleneck for exploring the pharmacodynamic substances of TCM against SARS-CoV-2. In this study, a simple, cost-effective, rapid, and selective fluorescent sensor (TPE-S-TLG sensor) was designed with an AIE (aggregation-induced emission) probe (TPE-Ph-In) and the SARS-CoV-2 Mpro substrate (S-TLG). The TPE-S-TLG sensor was characterized using UV-Vis absorption spectroscopy, fluorescence spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), zeta potential, and Fourier transform infrared (FTIR) spectroscopy techniques. The limit of detection of this method to detect SARS-CoV-2 Mpro was measured to be 5 ng mL-1. Furthermore, the TPE-S-TLG sensor was also successfully applied to screen Mpro inhibitors from Xuebijing injection using the separation and collection of the HPLC-fully automatic partial fraction collector (HPLC-FC). Six active compounds, including protocatechualdehyde, chlorogenic acid, hydroxysafflower yellow A, caffeic acid, isoquercetin, and pentagalloylglucose, were identified using UHPLC-Q-TOF/MS that could achieve 90% of the Mpro inhibition rate for the Xuebijing injection. Accordingly, the strategy can be broadly applied in the detection of disease-related proteases as well as screening active substances from TCM.


Subject(s)
Coronavirus 3C Proteases , Fluorescent Dyes , Medicine, Chinese Traditional , SARS-CoV-2 , Spectrometry, Fluorescence , SARS-CoV-2/isolation & purification , SARS-CoV-2/drug effects , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Humans , Fluorescent Dyes/chemistry , Spectrometry, Fluorescence/methods , Antiviral Agents/pharmacology , Antiviral Agents/analysis , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/analysis , COVID-19/virology , COVID-19/diagnosis , Limit of Detection , COVID-19 Drug Treatment
18.
Acta Pharmacol Sin ; 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38605180

ABSTRACT

Antibody drug conjugate (ADC) therapy has become one of the most promising approaches in cancer immunotherapy. Bispecific targeting could enhance the efficacy and safety of ADC by improving its specificity, affinity and internalization. In this study we constructed a HER2/HER3-targeting bispecific ADC (BsADC) and characterized its physiochemical properties, target specificity and internalization in vitro, and assessed its anti-tumor activities in breast cancer cell lines and in animal models. The HER2/HER3-targeting BsADC had a drug to antibody ratio (DAR) of 2.89, displayed a high selectivity against the target JIMT-1 breast cancer cells in vitro, as well as a slightly higher level of internalization than HER2- or HER3-monospecific ADCs. More importantly, the bispecific ADC potently inhibited the viability of MCF7, JIMT-1, BT474, BxPC-3 and SKOV-3 cancer cells in vitro. In JIMT-1 breast cancer xenograft mice, a single injection of bispecific ADC (3 mg/kg, i.v.) significantly inhibited the tumor growth with an efficacy comparable to that caused by combined injection of HER2 and HER3-monospecific ADCs (3 mg/kg for each). Our study demonstrates that the bispecific ADC concept can be applied to development of more potent new cancer therapeutics than the monospecific ADCs.

19.
Biol Pharm Bull ; 47(5): 978-987, 2024 May 18.
Article in English | MEDLINE | ID: mdl-38631865

ABSTRACT

Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis and evidence of hepatocyte injury (ballooning) and inflammation, with or without liver fibrosis. In this study, after 12 weeks of induction, the mice were treated with emodin succinyl ethyl ester (ESEE) for four weeks at doses of 10/30/90 mg/kg/d. The blood analysis of experimental endpoints showed that ESEE exhibited significant therapeutic effects on the progression of disorders of glycolipid metabolism and the induced liver injury in the model animals. Histopathological diagnosis of the liver and total triglyceride measurements revealed that ESEE had a significant therapeutic effect on the histopathological features of nonalcoholic fatty liver disease/hepatitis, such as cellular steatosis and activation of intrahepatic inflammation. Additionally, ESEE was able to improve hepatocyte fat deposition, steatosis, and the course of intrahepatic inflammatory activity. Furthermore, it showed some inhibitory effect on liver fibrosis in the model animals. In summary, this study confirms the therapeutic effects of ESEE on the NAFLD/NASH model in C57BL/6J mice induced by a high-fat, high cholesterol, and fructose diet. These effects were observed through improvements in liver function, inhibition of fibrosis, and inflammatory responses. Changes in blood glucose levels, blood lipid metabolism, liver histopathological staining, liver fibrosis staining, and related pathological scores further supported the therapeutic effects of ESEE. Therefore, this study has important implications for the exploration of novel drugs for nonalcoholic fatty liver disease.


Subject(s)
Diet, High-Fat , Emodin , Fructose , Liver , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease , Animals , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/etiology , Male , Emodin/pharmacology , Emodin/therapeutic use , Emodin/analogs & derivatives , Liver/drug effects , Liver/pathology , Liver/metabolism , Diet, High-Fat/adverse effects , Mice , Triglycerides/blood , Cholesterol/blood , Disease Models, Animal , Blood Glucose/drug effects
20.
BMC Pregnancy Childbirth ; 24(1): 9, 2024 Jan 02.
Article in English | MEDLINE | ID: mdl-38166803

ABSTRACT

BACKGROUND: Intractable postpartum hemorrhage (PPH) during cesarean section has been a significant concern for obstetricians. We aimed to explore the effectiveness and safety of a new type of uterine compression suture, the step-wise surgical technique of knapsack-like sutures for treating intractable PPH caused by uterine atony and placenta factors in cesarean section. METHODS: The step-wise surgical technique of knapsack-like sutures was established on the basis of the artful combination of vertical strap-like sutures and an annular suture-ligation technique. This novel surgical technique was applied to 34 patients diagnosed with PPH during cesarean section due to severe uterine atony and placental factors in our department. The hemostatic effects, clinical outcomes and follow-up visit results were all reviewed and analyzed. RESULTS: This new uterine compression suture successfully stopped bleeding in 33 patients, and the effective rate was 97.06%. Only 1 patient failed and was changed to use bilateral uterine arterial embolization and internal iliac artery embolization. The follow-up visits indicated that 33 patients restored menstruation except for 1 who was diagnosed with amenorrhea. The gynecological ultrasound tests of all the patients suggested good uterine involutions, and they had no obvious complaints such as hypogastralgia. CONCLUSIONS: This step-wise surgical technique of knapsack-like uterine compression sutures can compress the uterus completely. It is a technique that can conserve the uterus and fertility function without special equipment in caesarean section for PPH, with the characteristics of being safe, simple and stable (3 S) with rapid surgery, reliable hemostasis and resident doctor to operation (3R).


Subject(s)
Postpartum Hemorrhage , Uterine Inertia , Female , Humans , Pregnancy , Postpartum Hemorrhage/surgery , Postpartum Hemorrhage/etiology , Cesarean Section/adverse effects , Uterine Inertia/surgery , Hemostasis, Surgical/methods , Placenta/surgery , Uterus/surgery , Uterus/blood supply , Sutures/adverse effects , Suture Techniques/adverse effects
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