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The term “undruggable” is to describe molecules that are not targetable or at least hard to target pharmacologically. Unfortunately, some targets with potent oncogenic activity fall into this category, and currently little is known about how to solve this problem, which largely hampered drug research on human cancers. Ras, as one of the most common oncogenes, was previously considered “undruggable”, but in recent years, a few small molecules like Sotorasib (AMG-510) have emerged and proved their targeted anti-cancer effects. Further, myc, as one of the most studied oncogenes, and tp53, being the most common tumor suppressor genes, are both considered “undruggable”. Many attempts have been made to target these “undruggable” targets, but little progress has been made yet. This article summarizes the current progress of direct and indirect targeting approaches for ras, myc, two oncogenes, and tp53, a tumor suppressor gene. These are potential therapeutic targets but are considered “undruggable”. We conclude with some emerging research approaches like proteolysis targeting chimeras (PROTACs), cancer vaccines, and artificial intelligence (AI)-based drug discovery, which might provide new cues for cancer intervention. Therefore, this review sets out to clarify the current status of targeted anti-cancer drug research, and the insights gained from this review may be of assistance to learn from experience and find new ideas in developing new chemicals that directly target such “undruggable” molecules. 相似文献
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FENG ZHU QINQIN ZHANG YANGKAI ZHOU QIPING ZHANG MENGYAO CAO ZHAOLIN JI 《Biocell》2022,46(9):2123-2131
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WAN ZHANG GUIYAN YANG YUNLIN ZHAO ZHENGGANG XU HUANG HUIMIN JIAKANG ZHOU 《Biocell》2022,46(3):803-819
Broussonetia kazinoki × Broussonetia papyrifera (ZJGS) is a hybrid species in Moraceae family, which has a very complicated hybrid origin. The excellent characteristics of fast growth, strong soil and water conservation ability, high leaf protein content and stem fiber content in ZJGS make it both ecological benefits in the mining area and economically valuable. This study aims to further understand ZJGS and other Moraceae taxa through the ZJGS chloroplast (cp) genome structure and the comparison with 12 closely related Moraceae species. Among the 13 Moraceae species, the cp genome length of seven Broussonetia species (ranges from 160,239 bp to 162,594 bp) is larger than that of six Morus species (ranges from 158,459 bp to 159,265 bp). Among the 77 shared protein-coding genes (PCGs) in Moraceae species, the obvious positive selection of Ka/Ks ratios acted on petD and rpl16 genes of B. kazinoki and B. papyrifera, respectively. Phylogenetic analysis based on shared PCGs from 28 species shows that ZJGS is closely related to maternal B. kazinoki. These findings provide data support for the origin of ZJGS hybridization and provide genomic resources for future ZJGS resource development and molecular breeding. 相似文献
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QUANWEI LU YUZHEN SHI RUILI CHEN XIANGHUI XIAO PENGTAO LI JUWU GONG RENHAI PENG YOULU YUAN 《Biocell》2022,46(5):1347-1356
Aluminum-activated malate transporters (ALMT) are widely involved in plant growth and metabolic processes, including adaptation to acid soils, guard cell regulation, anion homeostasis, and seed development. Although ALMT genes have been identified in Arabidopsis, wheat, barley, and Lotus japonicus, little is known about its presence in Gossypium hirsutum L. In this study, ALMT gene recognition in diploid and tetraploid cotton were done using bioinformatics analysis that examined correlation between homology and evolution. Differentially regulated ALMT genetic profile in G. hirsutum was examined, using RNA sequencing and qRT-PCR, during six fiber developmental time-points, namely 5 d, 7 d, 10 d, 15 d, 20 d, and 25 d. We detected 36 ALMT genes in G. hirsutum, which were subsequently annotated and divided into seven sub-categories. Among these ALMT genes, 34 had uneven distribution across 14/26 chromosomes. Conserved domains and gene structure analysis indicated that ALMT genes were highly conserved and composed of exons and introns. The GhALMT gene expression profile at different DPA (days post anthesis) in different varieties of G. hirsutum is indicative of a crucial role of ALMT genes in fiber development in G. hirsutum. This study provides basis for advancements in the cloning and functional enhancements of ALMT genes in enhancing fiber development and augmenting high quality crop production. 相似文献
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SOHEILA HASANIAN NOUR AMIRMOZAFARI AHMAD FARAJZADEH SHEIKH IRAJ MEHREGAN 《Biocell》2020,44(3):411-419
Methicillin-resistant Staphylococcus aureus (MRSA) strains are the essential cause of infections in communities andhospitals. The present study was conducted to determine the molecular typing of MRSA, isolated from hospitalized patients,using the double-locus sequence typing (DLST). In total, 280 S. aureus isolated from clinical specimens by phenotypic(catalase, coagulase, DNase, oxacillin, vancomycin screening agar and antibiotic disk diffusion), and molecular methods(PCR for determining the mecA, vanA and nuc genes). The DLST and sequencing was performed for MRSA containingmecA. Out of 280 specimens, confirmed as Staphylococcus aureus (S. aureus), 123 (43.9%) strains were MRSA. Thehighest resistance toward the erythromycin (15 μg), followed by ciprofloxacin (5 μg), clindamycin (2 μg), tetracycline (30μg), gentamicin (10 μg) and rifampicin (5 μg), was 98.3%, 97.5%, 94.3%, 90.2%, 83.7% and 41.4%, respectively. Also, theleast resistance (0%) was observed in each of teicoplanin (30 μg), linzolide (30 μg), and vancomycin (30 μg). All (100%)of MRSA strains had the mecA, and none of them have had the vanA. The results of DLST showed that the mostcommon sequence types were BPH 2003 and 0217. The DLST type 18-32 was a significant cluster of MRSA. Bysequencing MRSA and comparing the dominant types via the DLST, it is possible to establish the etiology of the diseasein a much shorter time, and prevent the complications of the disease. Therefore, the combination of partial sequences ofclfB and spa can serve as useful genetic markers for MRSA typing. It concluded that the MRSA in our region wasrelatively high, but no vancomycin resistance was found. The majority of the MRSA DLST type was 18–32. 相似文献
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As sessile organisms, plants possess a complex system to cope with environmental changes. Ca2+ functions as a vital second messenger in the stress signaling of plants, and the CBL-interacting protein kinases (CIPKs) serve as essential elements in the plant Ca2+ signaling pathway. In this study, calcineurin B-like protein-interacting protein kinase 26 (BdCIPK26) from Brachypodium distachyon was characterized. Overexpression of BdCIPK26 enhanced tolerance to drought and salt stress of transgenic plants. Further investigations revealed that BdCIPK26 participated in abscisic acid (ABA) signaling, conferred hypersensitivity to exogenous ABA in transgenic plants, and promoted endogenous ABA biosynthesis. Moreover, BdCIPK26 was found to maintain ROS homeostasis in plants under stress conditions. Therefore, this study indicates that BdCIPK26 functions as a positive regulator in drought and salt stress response. 相似文献
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SANHUA LI QINGHONG KONG XIAOKE ZHANG XINTING ZHU CHUNBO YU CHANGYAN YU NIAN JIANG JING HUI LINGJIE MENG YUN LIU 《Biocell》2022,46(11):2425-2432
Traditional Chinese medicine (TCM) has been increasingly employed in the last decades in China for both preventing and treating a variety of cancers. 3-epi-bufotalin is an active ingredient of TCM “Chanpi” with anti-tumor potential. However, the effect and mechanism of 3-epi-bufotalin on colorectal cancers were not well disclosed. The present study demonstrated that 3-epi-bufotalin could reduce viability, trigger apoptosis, and block the cell cycle at the G2/M stage in colorectal cancer cell lines HT29, RKO, and COLO205 in vitro. Moreover, 3-epi-bufotalin inhibited the JAK1/STAT3 signaling pathway. These results indicated the anti-proliferation ability of 3-epi-bufotalin in colorectal cancer cells. 相似文献
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BICHUN ZHAO XUEQING WU YITONG YUAN YUANTAO GAO XIAO LI RUOCHEN DU SUMING XU RUXIN ZHANG CHUNFANG WANG 《Biocell》2020,44(4):487-499
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CARLOS ALBERTO-SILVA ANA CAROLINA DE ARAUJO RODRIGO SIMãO BONFIM JOYCE MEIRE GILIO 《Biocell》2023,47(2):289-295
Bothrops envenomation is complex and provokes prominent local tissue damage and systemic disturbances, but little is known about their effects on the male reproductive system. After intratesticular injection, the bioactive peptide fraction (Bj-PF) obtained from Bothrops jararaca snake venom changes the structure of different stages of the seminiferous epithelium cycle in adult mice. For the first time, we investigated whether local envenomation of Bj-PF induces toxicological effects on the male reproductive system, particularly on the seminiferous epithelium and Sertoli cells. Male adult mice were treated with 0.24 mg.kg−1 by intramuscular (i.m.) injection for 24 h. The testes samples were collected for morphological and morphometric evaluation. The toxicological effects of Bj-PF were also analyzed on mitochondrial metabolism and nitrite (NO2) production in 15P-1 Sertoli cell culture. Bj-PF changed the structure and function of the seminiferous epithelium, particularly the disruption of the epithelium and the presence of degenerated germ cells in the adluminal compartment, but there were no alterations in the basal compartment. Bj-PF increased the thickness of the seminiferous epithelium and decreased the lumen diameter of the tubule. Semiquantitative histological assessment of the degree of tubule degeneration revealed that Bj-PF also increased the number of hypospermatogenic tubules compared to control. Bj-PF reduced NO2 levels in 15P-1 Sertoli cells without changing the mitochondrial metabolism. Overall, the fact that Bj-PF alters the structure and function of the seminiferous epithelium suggests that bioactive peptides found in B. jararaca snake venom can have toxicological effects on the reproductive systems of affected male mice, providing new insight into the biological characteristics of snake venom and therapeutic strategies for envenomation inflammation. 相似文献
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Background: Although the GABAA receptor (GABAAR) has been proposed as the main action site for sevoflurane, isoflurane, halothane, enflurane, propofol, and benzodiazepines (BZDs), binding of these anesthetics with high-resolution structures of the GABAAR have been rarely examined by comparative docking analyses. Moreover, various combinations of ligands on more GABAARs with various subtypes need to be analyzed to understand the elaborate action mechanism of GABAARs better because some GABAA ligands showed specificity toward the distinct subtypes of the GABAAR. Methods: We performed in silico docking analysis to compare the binding modes of sevoflurane, isoflurane, halothane, enflurane, propofol, and BZDs to the GABAAR based on one of the most recently provided 3D structures. We performed the docking analysis and the affinity-based ranking of the binding sites. Results: Our docking studies revealed that isoflurane, halothane, and enflurane docked in an extracellular domain (ECD) on GABAARs, in contrast to sevoflurane. Conclusion: Our results supported a multi-site mechanism for the allosteric modulation of propofol. Propofol was bound to the pore or favored various subsites in the transmembrane domain (TMD). Our result confirmed that different chemically related BZD ligands interact via distinct binding modes rather than by using a common binding mode, as previously suggested. 相似文献
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The present study aims to explore the effects of p53 and its target gene Rap2B on the autophagy of U2OScells. U2OS cells were treated with siRNA against p53, Rap2B, and PLCε. Relative expressions of p53, Rap2B, and PLCεwere determined using quantitative polymerase chain reaction (qPCR) and Western blotting, respectively. Levels of IP3in the cells were determined using Enzyme-linked Immunosorbent Assay (ELISA). Levels of Ca2+ were detected using Flow cytometry. Fluorescence microscopy was used to observe the autophagy of cells. Knockdown of p53 significantlydecreased the expressions of Rap2B protein. Additionally, knockdown of p53 significantly decreased the mRNA levelsof PLCε. The knockdown of p53, Rap2B, and PLCε significantly decreased the levels of intracellular IP3 and Ca2+ and promoted autophagy of U2OS cells. Our results demonstrated that p53-Rap2B-PLCε-IP3 signaling pathway regulatedautophagy of U2OS cells. 相似文献
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NINGYU LI XIAOFANG CHEN SUXIA GENG PEILONG LAI LISI HUANG MINMING LI XIN HUANG CHENGXIN DENG YULIAN WANG JIANYU WENG XIN DU 《Biocell》2023,47(1):133-141
The pathogenesis of myelodysplastic syndrome (MDS) may be related to the abnormal expression of microRNAs(miRNAs), which could influence the differentiation capacity of mesenchymal stem cells (MSCs) towards adipogenic andosteogenic lineages. In this study, exosomes from bone marrow plasma were successfully extracted and identified.Assessment of miR-103-3p expression in exosomes isolated from BM in 34 MDS patients and 10 controls revealed its0.52-fold downregulation in patients with MDS compared with controls (NOR) and was downregulated 0.55-fold inMDS-MSCs compared with NOR-MSCs. Transfection of MDS-MSCs with the miR-103-3p mimic improved osteogenicdifferentiation and decreased adipogenic differentiation in vitro, while inhibition of miR-103-3p showed the oppositeresults in NOR-MSCs. Thus, the expression of miR-103-3p decreases in MDS BM plasma and MDS-MSCs, significantlyimpacting MDS-MSCs differentiation. The miR-103-3p mimics may boost MDS-MSCs osteogenic differentiation whileweakening lipid differentiation, thereby providing possible target for the treatment of MDS pathogenesis. 相似文献
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Sphingosine kinase 1 (SphK1) is an important synthetase during the synthesis of sphingosine-1-phosphate (S1P)from sphingosine (Sph). Previous studies demonstrated that arsenic trioxide (As2O3) could reduce the level of S1P in humangastric cancer cell line MGC-803, indicating that As2O3 may inhibit the activity of SphK1. In this study, the effect of As2O3on the SphK1 activation pathway was investigated. Western blot and quantitative real-time PCR analysis were used toevaluate the changes in protein and mRNA levels. The multi-dimensional mass spectrometry-based shotgun lipidomicsmethod (MDMS-SL) was used for the quantitative detection of phosphatidylserine (PS) and phosphatidic acid (PA). Theresults revealed that As2O3 did not affect the protein and mRNA expression of SphK1 in the MGC-803 cells. However,As2O3 increased the levels of p-ERK1/2 and CIB1 in the SphK1 activation pathway and decreased the levels of PS andPA in the MGC-803 cells. The outcomes suggested that As2O3 may enhance the activity of SphK1 by increasing thelevels of p-ERK1/2 and CIB1 and decrease the activity of SphK1 by decreasing the levels of PS and PA. It was suggestedthat the inhibition effect is stronger and resulting in an overall decrease in the activity of SphK1. 相似文献
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Hazelnut husk brown rot has been identified as a new disease in Liaoning Province in recent years. The objective of this study as to identify the pathogen. [Method] In this study, a standard sample of hazelnut husk brown rot was collected from Songmudao Base in Dalian City, Liaoning Province. The pathogen was identified by the studies of the morphology, pathogenicity, and analyses of ITS and LSU sequences. The pathogen was isolated and purified, which was confirmed by Koch’s postulates. The symptoms after inoculation were the same as those collected directly from a diseased tree, which showed that it was the pathogenic fungus. The cultural characteristics and conidia and the morphology of the pathogenic fungi were similar to those of Botrytis cinerea’s. The ITS sequences and LSU sequences were compared to the associated strain sequences in GenBank, with 100% identity to Botrytis cinerea (GenBank accession number: MN589848.1) and Botrytis cinerea (GenBank accession number: KU140653.1), respectively. The infection status of the pathogen on the hazelnut husks was also observed. The studies suggested that the pathogen leading to the hazelnut husk brown rot as a new disease in Liaoning Province was Botrytis cinerea. 相似文献