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1.
Comput Biol Med ; 177: 108630, 2024 May 20.
Article En | MEDLINE | ID: mdl-38781643

Scaffolds are an essential component of bone tissue engineering to provide support and create a physiological environment for cells. Biomimetic scaffolds are a promising approach to fulfill the requirements. Bone allografts are widely used scaffolds due to their mechanical and structural characteristics. The scaffold geometry is well known to be an important determinant of induced mechanical stimulation felt by the cells. However, the impact of allograft geometry on permeability and wall shear stress distribution is not well understood. This information is essential for designing biomimetic scaffolds that provide a suitable environment for cells to proliferate and differentiate. The present study investigates the effect of geometry on the permeability and wall shear stress of bone allografts at both macroscopic and microscopic scales. Our results concluded that the wall shear stress was strongly correlated with the porosity of the allograft. The level of wall shear stress at a local scale was also determined by the surface curvature characteristics. The results of this study can serve as a guideline for future biomimetic scaffold designs that provide a mechanical environment favorable for osteogenesis and bone repair.

2.
Front Endocrinol (Lausanne) ; 15: 1362584, 2024.
Article En | MEDLINE | ID: mdl-38774228

Background: Previous observational studies have demonstrated a link between diabetes mellitus(DM) and primary biliary cholangitis (PBC). Nevertheless, since these relationships might be confused, whether there is any causal connection or in which direction it exists is unclear. Our investigation aimed to identify the causal associations between DM and PBC. Methods: We acquired genome-wide association study (GWAS) datasets for PBC, Type 1 diabetes(T1DM), and Type 2 diabetes(T2DM) from published GWASs. Inverse variance-weighted (IVW), MR-Egger, weighted median (WM), Simple mode, and weighted mode methods were used to determine the causal relationships between DM(T1DM or T2DM) and PBC. Sensitivity analyses were also carried out to ensure the results were robust. To determine the causal relationship between PBC and DM(T1DM or T2DM), we also used reverse MR analysis. Results: T1DM was associated with a higher risk of PBC (OR 1.1525; 95% CI 1.0612-1.2517; p = 0.0007) in the IVW method, but no evidence of a causal effect T2DM on PBC was found (OR 0.9905; 95% CI 0.8446-1.1616; p = 0.9071) in IVW. Results of the reverse MR analysis suggested genetic susceptibility that PBC was associated with an increased risk of T1DM (IVW: OR 1.1991; 95% CI 1.12-1.2838; p = 1.81E-07), but no evidence of a causal effect PBC on T2DM was found (IVW: OR 1.0101; 95% CI 0.9892-1.0315; p = 0.3420). Conclusion: The current study indicated that T1DM increased the risk of developing PBC and vice versa. There was no proof of a causal connection between PBC probability and T2DM. Our results require confirmation through additional replication in larger populations.


Diabetes Mellitus, Type 1 , Diabetes Mellitus, Type 2 , Genome-Wide Association Study , Liver Cirrhosis, Biliary , Mendelian Randomization Analysis , Humans , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Genetic Predisposition to Disease , Liver Cirrhosis, Biliary/genetics , Liver Cirrhosis, Biliary/epidemiology , Liver Cirrhosis, Biliary/complications , Polymorphism, Single Nucleotide , Risk Factors
3.
Foods ; 13(9)2024 May 01.
Article En | MEDLINE | ID: mdl-38731767

The diversity of alcohol beverage microorganisms is of great significance for improving the brewing process and the quality of alcohol beverage products. During the process of making alcoholic beverages, a group of microorganisms, represented by yeast and lactic acid bacteria, conducts fermentation. These microorganisms have complex synergistic or competitive relationships, and the participation of different microorganisms has a major impact on the fermentation process and the flavor and aroma of the product. Strain selection is one of the key steps. Utilizing scientific breeding technology, the relationship between strains can be managed, the composition of the alcoholic beverage microbial community can be improved, and the quality and flavor of the alcoholic beverage products can be increased. Currently, research on the microbial diversity of alcohol beverages has received extensive attention. However, the selection technology for dominant bacteria in alcohol beverages has not yet been systematically summarized. To breed better-quality alcohol beverage strains and improve the quality and characteristics of wine, this paper introduces the microbial diversity characteristics of the world's three major brewing alcohols: beer, wine, and yellow wine, as well as the breeding technologies of related strains. The application of culture selection technology in the study of microbial diversity of brewed wine was reviewed and analyzed. The strain selection technology and alcohol beverage process should be combined to explore the potential application of a diverse array of alcohol beverage strains, thereby boosting the quality and flavor of the alcohol beverage and driving the sustainable development of the alcoholic beverage industry.

4.
J Fungi (Basel) ; 10(5)2024 Apr 24.
Article En | MEDLINE | ID: mdl-38786661

Mining activities in the kaolin mining area have led to the disruption of the ecological health of the mining area and nearby soils, but the effects on the fungal communities in the rhizosphere soils of the plants are not clear. Three common plants (Conyza bonariensis, Artemisia annua, and Dodonaea viscosa) in kaolin mining areas were selected and analyzed their rhizosphere soil fungal communities using ITS sequencing. The alpha diversity indices (Chao1, Shannon, Simpson, observed-species, pielou-e) of the fungal communities decreased to different extents in different plants compared to the non-kauri mining area. The ß-diversity (PCoA, NMDS) analysis showed that the rhizosphere soil fungal communities of the three plants in the kaolin mine area were significantly differentiated from those of the control plants grown in the non-kaolin mine area, and the extent of this differentiation varied among the plants. The analysis of fungal community composition showed that the dominant fungi in the rhizosphere fungi of C. bonariensis and A. annua changed, with an increase in the proportion of Mycosphaerella (genus) by about 20% in C. bonariensis and A. annua. An increase in the proportion of Didymella (genus) by 40% in D. viscosa was observed. At the same time, three plant rhizosphere soils were affected by kaolin mining activities with the appearance of new fungal genera Ochrocladosporium and Plenodomus. Predictive functional potential analysis of the samples revealed that a significant decrease in the potential of functions such as biosynthesis and glycolysis occurred in the rhizosphere fungal communities of kaolin-mined plants compared to non-kaolin-mined areas. The results show that heavy metals and plant species are the key factors influencing these changes, which suggests that selecting plants that can bring more abundant fungi can adapt to heavy metal contamination to restore soil ecology in the kaolin mining area.

5.
Genes (Basel) ; 15(5)2024 Apr 23.
Article En | MEDLINE | ID: mdl-38790155

This study utilized 16S rRNA high-throughput sequencing technology to analyze the community structure and function of endophytic bacteria within the roots of three plant species in the vanadium-titanium-magnetite (VTM) mining area. The findings indicated that mining activities of VTM led to a notable decrease in both the biodiversity and abundance of endophytic bacteria within the root systems of Eleusine indica and Carex (p < 0.05). Significant reductions were observed in the populations of Nocardioides, concurrently with substantial increments in the populations of Pseudomonas (p < 0.05), indicating that Pseudomonas has a strong adaptability to this environmental stress. In addition, ß diversity analysis revealed divergence in the endophytic bacterial communities within the roots of E. indica and Carex from the VTM mining area, which had diverged to adapt to the environmental stress caused by mining activity. Functional enrichment analysis revealed that VTM mining led to an increase in polymyxin resistance, nicotinate degradation I, and glucose degradation (oxidative) (p < 0.05). Interestingly, we found that VTM mining did not notably alter the endophytic bacterial communities or functions in the root systems of Dodonaea viscosa, indicating that this plant can adapt well to environmental stress. This study represents the primary investigation into the influence of VTM mining activities on endophytic bacterial communities and the functions of nearby plant roots, providing further insight into the impact of VTM mining activities on the ecological environment.


Endophytes , Mining , Plant Roots , Titanium , Vanadium , Vanadium/pharmacology , Plant Roots/microbiology , Endophytes/genetics , Bacteria/genetics , Bacteria/classification , Bacteria/drug effects , RNA, Ribosomal, 16S/genetics , Soil Microbiology , Biodiversity
6.
BMC Genomics ; 25(1): 456, 2024 May 10.
Article En | MEDLINE | ID: mdl-38730418

In this study, we investigated the codon bias of twelve mitochondrial core protein coding genes (PCGs) in eight Pleurotus strains, two of which are from the same species. The results revealed that the codons of all Pleurotus strains had a preference for ending in A/T. Furthermore, the correlation between codon base compositions and codon adaptation index (CAI), codon bias index (CBI) and frequency of optimal codons (FOP) indices was also detected, implying the influence of base composition on codon bias. The two P. ostreatus species were found to have differences in various base bias indicators. The average effective number of codons (ENC) of mitochondrial core PCGs of Pleurotus was found to be less than 35, indicating strong codon preference of mitochondrial core PCGs of Pleurotus. The neutrality plot analysis and PR2-Bias plot analysis further suggested that natural selection plays an important role in Pleurotus codon bias. Additionally, six to ten optimal codons (ΔRSCU > 0.08 and RSCU > 1) were identified in eight Pleurotus strains, with UGU and ACU being the most widely used optimal codons in Pleurotus. Finally, based on the combined mitochondrial sequence and RSCU value, the genetic relationship between different Pleurotus strains was deduced, showing large variations between them. This research has improved our understanding of synonymous codon usage characteristics and evolution of this important fungal group.


Codon Usage , Genome, Mitochondrial , Pleurotus , Pleurotus/genetics , Codon/genetics , Base Composition , Species Specificity , Selection, Genetic , Evolution, Molecular , Genetic Variation
7.
Int Immunopharmacol ; 133: 112138, 2024 May 30.
Article En | MEDLINE | ID: mdl-38678670

BACKGROUND: Diabetic kidney disease (DKD) is a common microvascular complication and one of the main causes of death in diabetes. Ferroptosis, an iron-dependent mode of cell death characterized by lipid ROS accumulation, was found to be associated with a number of diseases and has great potential for kidney diseases. It has great value to identify potential ferroptosis-related genes and their biological mechanisms in DKD. METHODS: We obtained the GSE30122 dataset from Gene Expression Omnibus (GEO) database and ferroptosis-related genes from the Ferrdb database. After differential expression analysis, and three machine learning algorithms, the hub ferroptosis-related gene EZH2 was identified. In order to investigate the function of EZH2, Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA) and single cell analysis were conducted. The expression of EZH2 was validated in DKD patients, HK-2 cell models and DKD mouse models. EZH2 knockdown HK-2 cells and HK-2 cells treated with GSK126 were performed to verify whether EZH2 affected ferroptosis in DKD. CHIP assay was used to detect whether EZH2 regulated ferroptosis by suppressing SLC7A11. Molecular docking was performed to explore EZH2 and four traditional Chinese medicine (Sennoside A, Berberine, Umbelliferone, Platycodin D) related to ferroptosis in DKD treatment. RESULTS: According to the GSE30122 dataset in GEO and ferroptosis-related genes from the Ferrb database, we obtained the hub ferroptosis-related gene EZH2 in DKD via diversified machine learning methods. The increasing of EZH2 expression was shown in single cell analysis, DKD patients, DKD mouse models and high glucose induced DKD cell models. Further study showed that EZH2 knockdown and inhibition can alleviate HG-induced ferroptosis in vitro. CHIP assay showed EZH2-mediated epigenetic silencing regulated the expression of SLC7A11. Molecular docking results showed that EZH2 had strong binding stability with Sennoside A, Berberine, Umbelliferone, and Platycodin D. CONCLUSION: Overall, our data shouwed that histone H3K27 methyltransferase EZH2 could regulate the renal tubular epithelial cell ferroptosis by suppressing SLC7A11 in DKD, which may serve as a credible reliable indicator for diagnosing DKD and a potential target for treatment.


Amino Acid Transport System y+ , Diabetic Nephropathies , Enhancer of Zeste Homolog 2 Protein , Ferroptosis , Ferroptosis/genetics , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Diabetic Nephropathies/genetics , Animals , Humans , Mice , Amino Acid Transport System y+/genetics , Amino Acid Transport System y+/metabolism , Cell Line , Mice, Inbred C57BL , Male
8.
Neuroimage ; 291: 120583, 2024 May 01.
Article En | MEDLINE | ID: mdl-38554781

The data-driven approach of supervised learning methods has limited applicability in solving dipole inversion in Quantitative Susceptibility Mapping (QSM) with varying scan parameters across different objects. To address this generalization issue in supervised QSM methods, we propose a novel training-free model-based unsupervised method called MoDIP (Model-based Deep Image Prior). MoDIP comprises a small, untrained network and a Data Fidelity Optimization (DFO) module. The network converges to an interim state, acting as an implicit prior for image regularization, while the optimization process enforces the physical model of QSM dipole inversion. Experimental results demonstrate MoDIP's excellent generalizability in solving QSM dipole inversion across different scan parameters. It exhibits robustness against pathological brain QSM, achieving over 32 % accuracy improvement than supervised deep learning methods. It is also 33 % more computationally efficient and runs 4 times faster than conventional DIP-based approaches, enabling 3D high-resolution image reconstruction in under 4.5 min.


Brain , Felodipine , Humans , Brain/diagnostic imaging , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Brain Mapping/methods , Algorithms
9.
Med Image Anal ; 94: 103160, 2024 May.
Article En | MEDLINE | ID: mdl-38552528

Quantitative susceptibility mapping (QSM) is a post-processing technique for deriving tissue magnetic susceptibility distribution from MRI phase measurements. Deep learning (DL) algorithms hold great potential for solving the ill-posed QSM reconstruction problem. However, a significant challenge facing current DL-QSM approaches is their limited adaptability to magnetic dipole field orientation variations during training and testing. In this work, we propose a novel Orientation-Adaptive Latent Feature Editing (OA-LFE) module to learn the encoding of acquisition orientation vectors and seamlessly integrate them into the latent features of deep networks. Importantly, it can be directly Plug-and-Play (PnP) into various existing DL-QSM architectures, enabling reconstructions of QSM from arbitrary magnetic dipole orientations. Its effectiveness is demonstrated by combining the OA-LFE module into our previously proposed phase-to-susceptibility single-step instant QSM (iQSM) network, which was initially tailored for pure-axial acquisitions. The proposed OA-LFE-empowered iQSM, which we refer to as iQSM+, is trained in a simulated-supervised manner on a specially-designed simulation brain dataset. Comprehensive experiments are conducted on simulated and in vivo human brain datasets, encompassing subjects ranging from healthy individuals to those with pathological conditions. These experiments involve various MRI platforms (3T and 7T) and aim to compare our proposed iQSM+ against several established QSM reconstruction frameworks, including the original iQSM. The iQSM+ yields QSM images with significantly improved accuracies and mitigates artifacts, surpassing other state-of-the-art DL-QSM algorithms. The PnP OA-LFE module's versatility was further demonstrated by its successful application to xQSM, a distinct DL-QSM network for dipole inversion. In conclusion, this work introduces a new DL paradigm, allowing researchers to develop innovative QSM methods without requiring a complete overhaul of their existing architectures.


Brain , Image Processing, Computer-Assisted , Humans , Image Processing, Computer-Assisted/methods , Brain/diagnostic imaging , Neural Networks, Computer , Brain Mapping/methods , Magnetic Resonance Imaging/methods , Algorithms
10.
J Org Chem ; 89(5): 3345-3358, 2024 Mar 01.
Article En | MEDLINE | ID: mdl-38372225

In this study, a modular approach toward cyclic sulfoximines and sulfondiimines via palladium-catalyzed intramolecular C-H/C-C activation reactions was reported. Various 1,2-benzothiazines including bicyclic, tricyclic, highly fused ones, ones of the seven-membered ring, along with 1,2-benzothiazine 1-imines were accessed in good yields. KIE experiment demonstrated that the C-H bond cleavage at the position ortho to the sulfoximine group is not the rate-determining step in the coupling reaction.

11.
Nucleic Acids Res ; 52(D1): D882-D890, 2024 Jan 05.
Article En | MEDLINE | ID: mdl-37791883

The development of spatial transcriptome sequencing technology has revolutionized our comprehension of complex tissues and propelled life and health sciences into an era of spatial omics. However, the current availability of databases for accessing and analyzing spatial transcriptomic data is limited. In response, we have established CROST (https://ngdc.cncb.ac.cn/crost), a comprehensive repository of spatial transcriptomics. CROST encompasses high-quality samples and houses 182 spatial transcriptomic datasets from diverse species, organs, and diseases, comprising 1033 sub-datasets and 48 043 tumor-related spatially variable genes (SVGs). Additionally, it encompasses a standardized spatial transcriptome data processing pipeline, integrates single-cell RNA sequencing deconvolution spatial transcriptomics data, and evaluates correlation, colocalization, intercellular communication, and biological function annotation analyses. Moreover, CROST integrates the transcriptome, epigenome, and genome to explore tumor-associated SVGs and provides a comprehensive understanding of their roles in cancer progression and prognosis. Furthermore, CROST provides two online tools, single-sample gene set enrichment analysis and SpatialAP, for users to annotate and analyze the uploaded spatial transcriptomics data. The user-friendly interface of CROST facilitates browsing, searching, analyzing, visualizing, and downloading desired information. Collectively, CROST offers fresh and comprehensive insights into tissue structure and a foundation for understanding multiple biological mechanisms in diseases, particularly in tumor tissues.


Databases, Genetic , Gene Expression Profiling , Neoplasms , Humans , Genome , Neoplasms/genetics , Transcriptome
12.
Bioorg Chem ; 143: 106985, 2024 Feb.
Article En | MEDLINE | ID: mdl-38007892

A series of chromone derivatives bearing thiazolidine-2,4-dione moiety (5 âˆ¼ 37) were synthesized and evaluated for their PTP1B inhibitory activity, interaction analysis and effects on insulin pathway in palmitic acid (PA)-induced HepG2 cells. The results showed that all derivatives presented potential PTP1B inhibitory activity with IC50 values of 1.40 ± 0.04 âˆ¼ 16.83 ± 0.54 µM comparing to that of positive control lithocholic acid (IC50: 9.62 ± 0.14 µM). Among them, compound 9 had the strongest PTP1B inhibitory activity with the IC50 value of 1.40 ± 0.04 µM. Inhibition kinetic study revealed that compound 9 was a reversible mixed-type inhibitor against PTP1B. CD spectra results confirmed that compound 9 changed the secondary structure of PTP1B by their interaction. Molecular docking explained the detailed binding between compound 9 and PTP1B. Compound 9 also showed 19-fold of selectivity for PTP1B over TCPTP. Moreover compound 9 could recovery PA-induced insulin resistance by increasing the phosphorylation of IRSI and AKT. CETSA results showed that compound 9 significantly increased the thermal stability of PTP1B.


Enzyme Inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Thiazolidinediones , Molecular Docking Simulation , Structure-Activity Relationship , Thiazolidines , Enzyme Inhibitors/chemistry , Drug Design , Palmitic Acid/pharmacology
13.
Eur J Med Chem ; 264: 115957, 2024 Jan 15.
Article En | MEDLINE | ID: mdl-38029465

In order to develop potential α-glucosidase inhibitors with antidiabetic activity, twenty-six indole derivatives containing thiazolidine-2,4-dione were synthesized. All compounds presented potential α-glucosidase inhibitory activities with IC50 values ranging from 2.35 ± 0.11 to 24.36 ± 0.79 µM, respectively compared to acarbose (IC50 = 575.02 ± 10.11 µM). Especially, compound IT4 displayed the strongest α-glucosidase inhibitory activity (IC50 = 2.35 ± 0.11 µM). The inhibition mechanism of compound IT4 on α-glucosidase was clarified by the investigation of kinetics studies, fluorescence quenching, CD spectra, 3D fluorescence spectra, and molecular docking. In vivo antidiabetic experiments demonstrated that oral administration of compound IT4 would suppress fasting blood glucose level and ameliorate their glucose tolerance and dyslipidemia in diabetic mice.


Diabetes Mellitus, Experimental , Glycoside Hydrolase Inhibitors , Mice , Animals , Glycoside Hydrolase Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Structure-Activity Relationship , Molecular Docking Simulation , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , alpha-Glucosidases/metabolism , Thiazolidines , Indoles/pharmacology , Molecular Structure
14.
Nucleic Acids Res ; 52(D1): D909-D918, 2024 Jan 05.
Article En | MEDLINE | ID: mdl-37870433

Diverse individuals age at different rates and display variable susceptibilities to tissue aging, functional decline and aging-related diseases. Centenarians, exemplifying extreme longevity, serve as models for healthy aging. The field of human aging and longevity research is rapidly advancing, garnering significant attention and accumulating substantial data in recent years. Omics technologies, encompassing phenomics, genomics, transcriptomics, proteomics, metabolomics and microbiomics, have provided multidimensional insights and revolutionized cohort-based investigations into human aging and longevity. Accumulated data, covering diverse cells, tissues and cohorts across the lifespan necessitates the establishment of an open and integrated database. Addressing this, we established the Human Aging and Longevity Landscape (HALL), a comprehensive multi-omics repository encompassing a diverse spectrum of human cohorts, spanning from young adults to centenarians. The core objective of HALL is to foster healthy aging by offering an extensive repository of information on biomarkers that gauge the trajectory of human aging. Moreover, the database facilitates the development of diagnostic tools for aging-related conditions and empowers targeted interventions to enhance longevity. HALL is publicly available at https://ngdc.cncb.ac.cn/hall/index.


Aging , Databases, Factual , Longevity , Multiomics , Aged, 80 and over , Humans , Young Adult , Aging/genetics , Biomarkers , Disease Susceptibility , Genomics , Longevity/genetics
15.
Science ; 382(6677): 1399-1404, 2023 Dec 22.
Article En | MEDLINE | ID: mdl-37995210

The power conversion efficiency (PCE) of inverted perovskite solar cells (PSCs) is still lagging behind that of conventional PSCs, in part because of inefficient carrier transport and poor morphology of hole transport layers (HTLs). We optimized self-assembly of [4-(3,6-dimethyl-9H-carbazol-9-yl)butyl]phosphonic acid (Me-4PACz) onto nickel oxide (NiOx) nanoparticles as an HTL through treatment with hydrogen peroxide, which created a more uniform dispersion of nanoparticles with high conductivity attributed to the formation of Ni3+ as well as surface hydroxyl groups for bonding. A 25.2% certified PCE for a mask size of 0.074 square centimeters was obtained. This device maintained 85.4% of the initial PCE after 1000 hours of stabilized power output operation under 1 sun light irradiation at about 50°C and 85.1% of the initial PCE after 500 hours of accelerated aging at 85°C. We obtained a PCE of 21.0% for a minimodule with an aperture area of 14.65 square centimeters.

16.
Front Plant Sci ; 14: 1234866, 2023.
Article En | MEDLINE | ID: mdl-37746023

Chlorophyll content and fluorescence parameters are crucial indicators to evaluate the light use efficiency in rice; however, the correlations among these parameters and the underlying genetic mechanisms remain poorly understood. Here, to clarify these issues, we conducted a genome-wide association study (GWAS) on 225 rice accessions. In the phenotypic and Mendelian randomization (MR) analysis, a weak negative correlation was observed between the chlorophyll content and actual quantum yield of photosystem II (ΦII). The phenotypic diversity observed in SPAD, NPQt, ΦNPQ, and Fv/Fm among accessions was affected by genetic background. Furthermore, the GWAS identified 78 SNPs and 17 candidate genes significantly associated with SPAD, NPQt, ΦII, ΦNPQ, qL and qP. Combining GWAS on 225 rice accessions with transcriptome analysis of two varieties exhibiting distinct fluorescence characteristics revealed two potential candidate genes (Os03g0583000 from ΦII & qP traits and Os06g0587200 from NPQt trait), which are respectively associated with peroxisomes, and protein kinase catalytic domains might involve in regulating the chlorophyll content and chlorophyll fluorescence. This study provides novel insights into the correlation among chlorophyll content and fluorescence parameters and the genetic mechanisms in rice, and offers valuable information for the breeding of rice with enhanced photosynthetic efficiency.

17.
Eur J Med Chem ; 261: 115795, 2023 Dec 05.
Article En | MEDLINE | ID: mdl-37688939

In this study, we designed and synthesized a novel class of 1,3,4-oxadiazolyl-containing ß-carboline derivatives, i.e., compounds f1∼f35 as potential α-glucosidase inhibitors. All the synthesized compounds possessed outstanding α-glucosidase inhibitory activity with the IC50 values in the range of 3.07-15.49 µM, representing that they are 36∼183-fold more active than a positive control, acarbose (IC50 = 564.28 µM). Among them, compound f26 exhibited the highest α-glucosidase inhibitory activity (IC50 = 3.07 µM) and was demonstrated to function as a reversible and noncompetitive inhibitor. Mechanistic studies by means of 3D fluorescence spectra, CD spectra and molecular docking suggested that complexation of compound f26 with α-glucosidase through hydrogen bonds and hydrophobic interactions, led to changes in the conformation and secondary strictures of α-glucosidase and further the inhibition of the enzymatic activity. In vivo results showed that oral administration of compound f26 (50 mg/kg/day) could obviously reduce the levels of fasting blood glucose and improve glucose tolerance and dyslipidemia in diabetic mice. The present findings suggest that compound f26 is exploitable as a potential lead compound for the development of new α-glucosidase inhibitors with antidiabetic activity.


Diabetes Mellitus, Experimental , Glycoside Hydrolase Inhibitors , Mice , Animals , Glycoside Hydrolase Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/chemistry , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemistry , alpha-Glucosidases/metabolism , Structure-Activity Relationship , Molecular Docking Simulation , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Carbolines/pharmacology , Molecular Structure
18.
Cancers (Basel) ; 15(16)2023 Aug 14.
Article En | MEDLINE | ID: mdl-37627121

Immune checkpoint blockades (ICBs) have revolutionized cancer therapy by inducing durable clinical responses, but only a small percentage of patients can benefit from ICB treatments. Many studies have established various biomarkers to predict ICB responses. However, different biomarkers were found with diverse performances in practice, and a timely and unbiased assessment has yet to be conducted due to the complexity of ICB-related studies and trials. In this study, we manually curated 29 published datasets with matched transcriptome and clinical data from more than 1400 patients, and uniformly preprocessed these datasets for further analyses. In addition, we collected 39 sets of transcriptomic biomarkers, and based on the nature of the corresponding computational methods, we categorized them into the gene-set-like group (with the self-contained design and the competitive design, respectively) and the deconvolution-like group. Next, we investigated the correlations and patterns of these biomarkers and utilized a standardized workflow to systematically evaluate their performance in predicting ICB responses and survival statuses across different datasets, cancer types, antibodies, biopsy times, and combinatory treatments. In our benchmark, most biomarkers showed poor performance in terms of stability and robustness across different datasets. Two scores (TIDE and CYT) had a competitive performance for ICB response prediction, and two others (PASS-ON and EIGS_ssGSEA) showed the best association with clinical outcome. Finally, we developed ICB-Portal to host the datasets, biomarkers, and benchmark results and to implement the computational methods for researchers to test their custom biomarkers. Our work provided valuable resources and a one-stop solution to facilitate ICB-related research.

19.
Medicine (Baltimore) ; 102(31): e34443, 2023 Aug 04.
Article En | MEDLINE | ID: mdl-37543815

To study the anatomical orientation of the posterior group of calyces based on reconstructed images of computerized tomography urography (CTU) and provide a novel classification with its clinical significance. Clinical data of a total of 1321 patients, who underwent CTU examination in our hospital were retrospectively analyzed. Among these, a total of 2642 3-dimensional reconstructed images of CTU scans were considered in this study. Based on the morphology of the renal calyces and the influence on the establishment of surgical access, the posterior group renal calyces are classified into 3 major types including pot-belly type, classically branched and elongated branched. The classically branched type is further classified into 3 sub-types: a, b and c, based on the association of minor calyces of the posterior group to the major calyces. Type a is derived from 1 group of major calyces only, type b is derived from 2 groups of major calyces simultaneously, and type c is derived from 3 groups of major calyces simultaneously. Statistical findings revealed that all kidneys possess posterior group calyces. The percentage of occurrence of pot-belly type, classically branched and elongated branched is 8.06%, 73.13%, and 18.81%, respectively. The anatomical typing of the classical branching type occurred in 19.36%, 68.17%, and 12.47% for types a, b, and c, respectively. In this study, the posterior group calyces were found to be present across all patients. The posterior group calyces were highest in the classical branching type, of which anatomical typing was highest in type b. The typing of the posterior group of calyces could provide an anatomical basis for percutaneous nephrolithotomy (PCNL) puncture from the posterior group.


Kidney Calculi , Nephrostomy, Percutaneous , Humans , Kidney Calculi/surgery , Nephrostomy, Percutaneous/methods , Clinical Relevance , Retrospective Studies , Kidney/diagnostic imaging
20.
J Org Chem ; 88(13): 8379-8386, 2023 Jul 07.
Article En | MEDLINE | ID: mdl-37312277

Efficient access to the synthesis of lactam-derived quinoline through a bicyclic amidine-triggered cyclization reaction from readily prepared o-alkynylisocyanobenzenes has been developed. The reaction was initiated by nucleophilic attack of the bicyclic amidines to o-alkynylisocyanobenzenes, subsequently with intramolecular cyclization to produce a DBU-quinoline-based amidinium salt, followed by hydrolysis to afford the lactam-derived quinoline in moderate to good yields.


Lactams , Quinolines , Cyclization , Amidines , Hydrolysis
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