Combinatorial chemistry & high throughput screening最新文献

Purpose: miR-122 is upregulated in non-alcoholic fatty liver disease (NAFLD) liver tissue, and knockdown of miR-122 protects hepatocytes from lipid metabolism disorders. This study aimed to investigate whether Huazhi Rougan Granule (HRG) alleviates NAFLD liver and intestinal injury by regulating the miR-122-mediated TLR4/MyD88/NF-κB pathway.

Methods: Rats with NAFLD were constructed by high-fat feeding. Serum levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured using a fully automated biochemical instrument. Histopathological changes in the liver and small intestine were observed by HE staining. QRT-PCR detected the expression level of miR-122 in the liver tissues. The protein expression of TLR4, MyD88, NF- κB p65, and p-p65 in liver tissues was detected by western blotting.

Results: HRG slowed down the weight gain of NAFLD rats, decreased (P<0.05) the levels of TC, TG, ALT, AST, TNF-α, IL-1β, IL-6, LPS, and Hpt, improved the pathological status of liver and small intestine tissues, upregulated (P<0.05) the expression of ZO-1 and Occludin, downregulated (P<0.05) the protein expression of TLR4, MyD88, and p-p65, and inhibited (P<0.05) the expression of miR-122.

Conclusion: HRG may alleviate hepatic and intestinal injuries in rats with NAFLD by regulating the miR-122-mediated TLR4/MyD88/NF-κB pathway.

Purpose: The purpose of this study is to investigate the underlying relationship of diagnosis and therapy between glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and various cancers.

Methods: The Cancer Genome Atlas (TCGA) database was utilized to get gene expression RNAseq and clinical data for 33 tumors. The immunotherapeutic cohorts, including GSE35640, GSE78220, GSE67501, GSE181815, and IMvigor210, were derived from the Gene Expression Omnibus database (GEO) and a previously released article. Differential expression analysis of GFPT2 was performed using several clinical factors, and prognostic analysis was performed using Cox proportional hazard regression. In addition, the Cell type Identification By Estimating Relative Subsets Of RNA transcripts (CIBERSORT) and the Estimation of STromal and Immune cells in MAlignant Tumor tissues utilizing Expression data (ESTIMATE) algorithms were used to investigate the connection between GFPT2 and the tumor microenvironment. This approach additionally incorporated dynamic immunological indicators, such as tumor mutational burden (TMB) and microsatellite instability (MSI). In addition, a correlation between GFPT2 expression and the effectiveness of anticancer drugs was plotted for discussion.

Results: GFPT2 expression significantly differed in 11 out of 33 cancers. Although the distinct correlation between GFPT2 expression and clinical parameters had no wide distribution in pan-cancer, it demonstrated the potential prognostic validity of gene expression. GFPT2 demonstrated a strong correlation with immune infiltration, immune modulators, and immunerelated biomarkers. Furthermore, a variance analysis demonstrated a significant relationship between GFPT2 and the efficacy of immunotherapy. In addition, GFPT2 was associated with increased sensitivity of drugs such as Olaparib and Lenvatinib and decreased sensitivity of drugs such as Nilotinib.

Conclusion: Collectively, GFPT2 is potentially useful as a biomarker for prognostic prediction and immune infiltration in a variety of malignancies ,and could lead to exciting new approaches to personalized oncotherapy.

Objective: This study aimed to develop and characterize DOX-TPP/HA-ss-OA nanoparticles, utilizing the mitochondria-targeting prodrug doxorubicin-triphenylphosphine (DOXTPP) and a reduction-sensitive amphiphilic polymer, hyaluronic acid-disulfide-oleic acid (HAss- OA). The research focused on evaluating the drug release behavior of these nanoparticles under varying glutathione (GSH) concentrations and their anti-tumor activity in vitro.

Methods: DOX-TPP/HA-ss-OA nanoparticles were prepared using probe ultrasound technology. The study examined the impact of different organic solvents on drug loading capacity and encapsulation efficiency to determine the optimal conditions. A single-factor experimental design was used to optimize the formulation process. Key parameters, including particle size and zeta potential, were measured to assess nanoparticle stability and performance. The dynamic dialysis method was employed to evaluate the reduction-sensitive drug release characteristics in media with different GSH concentrations. The MTT assay was used to analyze the growth-inhibitory effects of the nanoparticles on human breast cancer cells (MCF-7) and drug-resistant cells (MCF-7/ADR).

Results: The optimized preparation process for DOX-TPP/HA-ss-OA nanoparticles included a drug dosage of 2.0 mg, an oil-to-water volume ratio of 1:5, ultrasonic power of 500 W, and ultrasonic time of 15 minutes. The nanoparticles had an average particle size of 203.72 ± 2.30 nm and a zeta potential of 25.82 ± 0.58 mV, indicating favorable stability and effective drug delivery properties. The nanoparticles exhibited a slow, sustained release of DOX-TPP in pH 7.4 phosphate buffer solution (PBS) and accelerated release in high GSH concentrations, demonstrating reduction-responsive drug release. In vitro studies showed that DOX-TPP/HA-ss-OA nanoparticles significantly inhibited the proliferation of MCF-7 and MCF-7/ADR cells in a dosedependent manner, with enhanced efficacy compared to free DOX and other formulations.

Conclusion: DOX-TPP/HA-ss-OA nanoparticles demonstrate excellent reduction sensitivity, effective tumor cell growth inhibition in vitro, and the ability to overcome drug resistance. Including particle size and zeta potential measurements supports their suitability as drug carriers, highlighting their potential for targeted cancer therapy and further development.

Cardiovascular diseases (CVDs) remain a key contributor to global morbidity and mortality. Being a vital regulator of hypoxia, hypoxia-inducible factor-1α (HIF-1α) is a crucial player in CVD treatment. Recently, increasing attention has been paid to the effect of natural drugs on CVDs. According to some studies, HIF-1α is a potential target for CVD treatment in traditional Chinese medicine. In this study, we describe the mechanism underlying the regulatory role of HIF-1α in CVDs and summarize 30 natural drugs and 3 formulations for CVD treatment through HIF-1α and its signaling pathway. The study provides new ideas for CVD prevention and treatment.

Background: Colorectal cancer is one of the common malignant tumors in clinical practice, and traditional Chinese medicine, as an important adjuvant treatment method, plays important roles in the treatment of malignant tumors.

Objective: This study aims to explore the mechanism of action of the Qizhu anti-cancer recipe on colorectal cancer through transcriptome sequencing.

Methods: The control group and Qizhu anti-cancer recipe group were established separately, and sequencing of the cells of the two groups was performed using the Illumina sequencing platform. Two sets of Differentially Expressed Genes (DEGs) were screened using the DESeq2 algorithm, and Principal Component Analysis (PCA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, Disease Ontology (DO), and Protein-Protein Interaction (PPI) were used to comprehensively analyze the molecular functions and signaling pathways enriched by DEGs.

Result: A total of 122 DEGs were identified through differential analysis, including 24 upregulated genes and 98 downregulated genes. GO analysis showed that DEGs were mainly enriched in functions such as alkaline phase activity, ion transport, cell differentiation, etc.; KEGG analysis showed that DEGs were mainly enriched in pathways such as Thiamine metabolism, apoptosis, signaling pathways regulating pluripotency of stem cells, cellular senescence and so on. Reactom analysis showed that DEGs were mainly enriched in response pathways such as EGR1,2,3 bind to the NAB2 promoter, EGR binds ARC gene, EGR-dependent NAB2 gene expression, etc.; DO analysis showed that differentially expressed genes were mainly enriched in diseases such as disease of cellular proliferation, disease of anatomical entity, organ system cancer, etc.; PPI analysis identified key differentially expressed genes, including DDIT3, CHAC1, TRIB3, and ASNS.

Conclusion: Based on transcriptome sequencing and bioinformatics analysis, it was found that the Qizhu anti-cancer recipe may involve DEGs and signaling pathways in the treatment of colorectal cancer. Our study may provide potential drug targets for developing new treatment strategies for colorectal cancer.

Introduction: In this research, 3-(triethoxysilyl)propyl isocyanate (TESPIC) functionalized chitosan was successfully synthesized to fabricate silica-coated magnetite nanoparticles (Fe3O4@SiO2-CS MNPs).

Method: The synthesized MNPs were characterized using XRD, FT-IR, SEM, and TEM instruments and were utilized for the decolorization of Crystal Violet cationic dye (CV). The affecting variables controlling CV removal efficiency were investigated using the Taguchi fractional factorial design method (L16 array).

Result: Under the optimized removal conditions (adsorbent amount = 0.12 g (4.8 g L-1), pH = 4, ionic strength = 0.05 mol L-1 NaCl, and 30 min stirring), 98.2% of the CV dye was eliminated. The kinetic and equilibrium adsorption isotherms were explained by the pseudo-second-order kinetic (R2 = 0.999) and Freundlich isotherm models, respectively. MATLAB's fmincon function as an efficient solution was applied in order to compare the Redlich-Peterson three-parametric isotherm model with two-parametric models. Moreover, the Fe3O4@SiO2-CS-TESPIC MNPs showed recyclability and reusability for subsequent runs.

Conclusion: The findings confirmed that these functional MNPs can be considered as proper adsorbents for the removal of CV dye from the aqueous solutions.

Introduction: Omacetaxine, a semisynthetic form of Homoharringtonine (HHT), was approved for the treatment of Chronic Myeloid Leukemia (CML). Previously, we have published the synthesis of this natural alkaloid and three of its derivatives: Deoxyharringtonine (DHT), Deoxyhomoharringtonine (DHHT), and Bis(demethyl)-deoxyharringtonine (BDHT), and reported its refractory activity against the HL-60/RV+ cells over-expressing P-glycoprotein 1 (MDR1).

Methods: In this study, we have explored the extent of this resistance by first expanding the panel of established cell lines and using a panel of 21 leukemia patient-derived primary cells.

Results: Herein, we have reported consistent resistance to HTT of K562-derived cells and to mitoxantrone of MES-SA/MX2-derived cells; all of them have been found to overexpress MDR1, while we have found U87MG-ABCG2 and H69AR cells to be very sensitive to HTT. In contrast, DHT, DHHT, and BDHT seemingly overcame this resistance due to the changes made to the acyl chain of HTT, rendering the derivatives less susceptible to efflux. Surprisingly, the leukemia primary cells were very sensitive to HHT and its derivatives with low nanomolar potencies, followed by a new class of CDC7 kinase inhibitors, the anthracycline class of topoisomerase inhibitors, the DNA intercalator actinomycin-D, and the vinca alkaloid class of microtubule inhibitors. The mechanism of cell death induced by HTT and DHHT was found to be mediated via caspase 3 cleavage, leading to apoptosis.

Conclusion: Taken together, our results confirm that HHT is a substrate for MDR1. It opens the door to a new opportunity to clinically evaluate HHT and its derivatives for the treatment of AML and other cancers.

Introduction: The You-gui pill (YGP) is a classical compound used for treating antidiabetic erectile dysfunction (DMED). However, the specific active ingredients responsible for its effects on DMED and their mechanisms remain unclear.

Methods: In this paper, we used data mining techniques to analyze high-frequency herbs and herb combinations used in Chinese medicine for the treatment of DMED based on existing literature. Using network pharmacology to study the active components and mechanism of action of YGP against DMED, molecular docking was used to analyze the interactions of the active components with major structural proteins, nonstructural proteins, and mutants. Also, the therapeutic effect of YGP on hyperglycemic modelling and its underlying mechanisms were experimentally validated in CCEC cells by analyzing the expression of its relevant target mRNAs.

Results: Network pharmacological analysis identified the three core components of YGP as quercetin, kaempferol, and β-sitosterol, and constructed a PPI network map of common targets of YGP and DMED, which included HIF-1α, ALB, Bcl-2, INS, IL-1β, IL-6, TNF-α, CASP3, and TP53. Combined with molecular docking results, these targets had a strong binding affinity between them and the active ingredient compounds, with the highest affinity for HIF-1α and TNF-α. During the in vitro cellular assay validation, the HIF-1α, ALB, Bcl-2, TNF-α, and IL-6 mRNA in CCECs cells showed positive regulation after YGP intervention.

Conclusion: The combination of "data mining - network pharmacology - molecular docking - experimental validation" provides a powerful methodological basis for the study of the main active components and mechanism of action of YGP against DMED, as well as the development and application of the drug.

Purpose: This study aimed to initially clarify the potential mechanism of quercetin in the treatment of non-small cell lung cancer (NSCLC) based on network pharmacology, molecular docking and in vitro experiments.

Method: TCMSP, SwissTargetPrediction, TCMIP, STITCH, and ETCM databases were applied to obtain the targets of quercetin. NSCLC-related targets were retrieved from GeneCards, OMIM, PharmGKB, TTD, and NCBI databases. Their intersection targets were imported into the STRING database to construct a protein-protein interaction (PPI) network and core targets were identified through the Cytoscape 3.10.0 soft and the CytoHubba tool. Furthermore, Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the intersection targets. A compound-targetspathways network was subsequently constructed to screen for key targets and pathways. Molecular docking was performed with Discovery Studio software to verify the interactions between quercetin and core targets. In vitro validations were conducted employing CCK-8 assays, flow cytometry, and Western blotting (WB).

Results: 193 potential targets of quercetin for treating NSCLC were obtained. The top ten core targets identified within the PPI network included TP53, HSP90AA1, AKT1, JUN, SRC, EGFR, ACTB, TNF, MAPK1, and VEGFA. GO analysis yielded 2319 items, and KEGG analysis resulted in 211 enriched pathways. Molecular docking results demonstrated a high affinity of quercetin towards the core targets. Based on the compound-targets-pathways network and molecular docking, the PI3K/AKT/P53 pathway and its key-related proteins (PIK3R1, AKT1, and TP53) were selected for further validation. Quercetin(20 and 40 μg/mL) significantly decreased the viability of A549 NSCLC cells but not BEAS-2B normal cells via CCK-8 assays. Flow cytometry and WB analyses further corroborated that quercetin could promote apoptosis of A549 cells by downregulating and upregulating the expression of Bcl-2 and Bax (P<0.05), respectively. Notably, quercetin did not significantly alter the total protein levels of PI3K, AKT, and P53 but downregulated the phosphorylation levels of PI3K and AKT (P<0.05) and upregulated the phosphorylation level of P53 (P<0.05).

Conclusion: Quercetin exhibits therapeutic potential in NSCLC by regulating the PI3K/AKT/P53 pathway to promote cell apoptosis.

Background: Let G be a connected graph and S be a k element subset of the vertex set V(G) of G. Steiner distance is a natural generalization of the usual graph distance. The Steiner-k distance dG(S) between the vertices of S is the minimum size among all connected subgraphs whose vertex set contains S. The generalized indices based on Steiner distances have several applications in the real world. It is a well-known fact that "Steiner Problem" is NP-complete and hence any parameter based on Steiner distance is also an NP problem.

Objective: The objective of this work is to determine the Steiner 3-Wiener index for an important chemical structure called the zigzag polyhex nanotube.

Methods: In this paper, we present an algorithm for computing the Steiner 3-Wiener index (SW3) for zigzag polyhex nanotubes. The developed algorithm addresses the complexities associated with exponential increments in the number of vertices as the nanotube's circumference or length expands. The obtained SW3 values for zigzag polyhex nanotubes can be used for Quantitative Structure-Activity Relationship (QSAR) and Quantitative Structure-Property Relationship (QSPR) analyses.

Results: We have presented an algorithm and listed the numerical values of SW3 for various parameters of circumference and length of a zigzag polyhex nanotube to facilitate their utilization in QSAR/ QSPR analyses. We have obtained the time complexity for the algorithm, which shows that the SW3 values are computationally intensive. To explain this complex nature, we have used multiple linear regression to fit log SW3 values corresponding to log p and log q, the radius and length of a nanotube.

Conclusion: The algorithm addresses the complexities associated with the exponential increase in vertices as the nanotube's circumference or length expands. Furthermore, we provide SW3 values for various parameter combinations up to circumference or length 17, and a general relation to determine the value of SW3, facilitating its utilization in real-world applications. These values serve as crucial descriptors for understanding the structural nuances of zigzag polyhex nanotubes, that find applications in material science, drug design, drug discovery, etc.