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Chemical Science May 2024The synthesis and scale-up of high quality covalent organic frameworks (COFs) remains a challenge due to slow kinetics of the reversible bond formation and the need for...
The synthesis and scale-up of high quality covalent organic frameworks (COFs) remains a challenge due to slow kinetics of the reversible bond formation and the need for precise control of reaction conditions. Here we report the rapid synthesis of faceted single crystals of two-dimensional (2D) COFs using a continuous flow reaction process. Two imine linked materials were polymerized to the hexagonal CF-TAPB-DMPDA and the rhombic CF-TAPPy-PDA COF, respectively. The reaction conditions were optimized to produce single crystals of micrometer size, which notably formed when the reaction was cooling to room temperature. This indicated a growth mechanism consistent with the fusion of smaller COF particles. The optimized conditions were used to demonstrate the scalability of the continuous approach by synthesizing high quality, faceted COFs at a rate of more than 1 g h. The materials showed high crystallinity and porosity with surface areas exceeding 2000 m g. Additionally, the versatility of the continuous flow reaction approach was demonstrated on a post-synthetic single crystal to single crystal demethylation of CF-TAPB-DMPDA to afford a hydroxyl functionalized COF CF-TAPB-DHPDA. Throughout the modification process, the material maintained its hexagonal morphology, crystallinity, and porosity. This work reports the first example of synthesizing and post-synthetically modifying imine linked COF single crystals in continuous flow and will prove a first step towards scaling high quality COFs to industrial levels.
PubMed: 38784733
DOI: 10.1039/d4sc01128g -
IScience Jun 2024The development of tyrosine kinase inhibitors (TKIs) has revolutionarily increased the overall survival of patients with chronic myeloid leukemia (CML). However, drug...
The development of tyrosine kinase inhibitors (TKIs) has revolutionarily increased the overall survival of patients with chronic myeloid leukemia (CML). However, drug resistance remains a major obstacle. Here, we demonstrated that a BCR-ABL1-independent long non-coding RNA, , is constitutively expressed at low levels in CML, resulting in imatinib resistance. knockdown decreased the sensitivity of CD34 CML blasts and cell lines to imatinib, whereas overexpression significantly increased sensitivity. Mechanistically, downregulates CD44, a membrane receptor favorably affecting TKI resistance, by binding to the nuclear factor kappa B subunit p65 to reduce the expression of p65 and phosphorylated p65. Therefore, the demethylating drug decitabine, which upregulates , combined with imatinib, formed a dual therapy strategy which can be applied to CML with resistance to TKIs.
PubMed: 38784023
DOI: 10.1016/j.isci.2024.109851 -
BMC Plant Biology May 2024Proper flower development is essential for plant reproduction, a crucial aspect of the plant life cycle. This process involves precisely coordinating transcription...
BACKGROUND
Proper flower development is essential for plant reproduction, a crucial aspect of the plant life cycle. This process involves precisely coordinating transcription factors, enzymes, and epigenetic modifications. DNA methylation, a ubiquitous and heritable epigenetic mechanism, is pivotal in regulating gene expression and shaping chromatin structure. Fagopyrum esculentum demonstrates anti-hypertensive, anti-diabetic, anti-inflammatory, cardio-protective, hepato-protective, and neuroprotective properties. However, the heteromorphic heterostyly observed in F. esculentum poses a significant challenge in breeding efforts. F. tataricum has better resistance to high altitudes and harsh weather conditions such as drought, frost, UV-B radiation damage, and pests. Moreover, F. tataricum contains significantly higher levels of rutin and other phenolics, more flavonoids, and a balanced amino acid profile compared to common buckwheat, being recognised as functional food, rendering it an excellent candidate for functional food applications.
RESULTS
This study aimed to compare the DNA methylation profiles between the Pin and Thrum flower components of F. esculentum, with those of self-fertile species of F. tataricum, to understand the potential role of this epigenetic mechanism in Fagopyrum floral development. Notably, F. tataricum flowers are smaller than those of F. esculentum (Pin and Thrum morphs). The decline in DNA methylation levels in the developed open flower components, such as petals, stigmas and ovules, was consistent across both species, except for the ovule in the Thrum morph. Conversely, Pin and Tartary ovules exhibited a minor decrease in DNA methylation levels. The highest DNA methylation level was observed in Pin stigma from closed flowers, and the most significant decrease was in Pin stigma from open flowers. In opposition, the nectaries of open flowers exhibited higher levels of DNA methylation than those of closed flowers. The decrease in DNA methylation might correspond with the downregulation of genes encoding methyltransferases.
CONCLUSIONS
Reduced overall DNA methylation and the expression of genes associated with these epigenetic markers in fully opened flowers of both species may indicate that demethylation is necessary to activate the expression of genes involved in floral development.
Topics: Fagopyrum; DNA Methylation; Flowers; Epigenesis, Genetic; Gene Expression Regulation, Plant
PubMed: 38783206
DOI: 10.1186/s12870-024-05162-w -
Communications Biology May 2024Understanding how to increase soybean yield is crucial for global food security. The genetic and epigenetic factors influencing seed size, a major crop yield...
Understanding how to increase soybean yield is crucial for global food security. The genetic and epigenetic factors influencing seed size, a major crop yield determinant, are not fully understood. We explore the role of DNA demethylase GmDMEa in soybean seed size. Our research indicates that GmDMEa negatively correlates with soybean seed size. Using CRISPR-Cas9, we edited GmDMEa in the Dongnong soybean cultivar, known for small seeds. Modified plants had larger seeds and greater yields without altering plant architecture or seed nutrition. GmDMEa preferentially demethylates AT-rich transposable elements, thus activating genes and transcription factors associated with the abscisic acid pathway, which typically decreases seed size. Chromosomal substitution lines confirm that these modifications are inheritable, suggesting a stable epigenetic method to boost seed size in future breeding. Our findings provide insights into epigenetic seed size control and suggest a strategy for improving crop yields through the epigenetic regulation of crucial genes. This work implies that targeted epigenetic modification has practical agricultural applications, potentially enhancing food production without compromising crop quality.
Topics: Glycine max; Seeds; DNA Methylation; DNA Transposable Elements; Epigenesis, Genetic; Gene Expression Regulation, Plant; Plant Proteins; Plants, Genetically Modified
PubMed: 38773248
DOI: 10.1038/s42003-024-06306-2 -
Scientific Reports May 2024Despite growing evidence implicating the calcium-activated chloride channel anoctamin1 (ANO1) in cancer metastasis, its direct impact on the metastatic potential of...
Despite growing evidence implicating the calcium-activated chloride channel anoctamin1 (ANO1) in cancer metastasis, its direct impact on the metastatic potential of prostate cancer and the possible significance of epigenetic alteration in this process are not fully understood. Here, we show that ANO1 is minimally expressed in LNCap and DU145 prostate cancer cell lines with low metastatic potential but overexpressed in high metastatic PC3 prostate cancer cell line. The treatment of LNCap and DU145 cells with DNMT inhibitor 5-aza-2'-deoxycytidine (5-Aza-CdR) potentiates ANO1 expression, suggesting that DNA methylation is one of the mechanisms controlling ANO1 expression. Consistent with this notion, hypermethylation was detected at the CpG island of ANO1 promoter region in LNCap and DU145 cells, and 5-Aza-CdR treatment resulted in a drastic demethylation at promoter CpG methylation sites. Upon 5-Aza-CdR treatment, metastatic indexes, such as cell motility, invasion, and metastasis-related gene expression, were significantly altered in LNCap and DU145 cells. These 5-Aza-CdR-induced metastatic hallmarks were, however, almost completely ablated by stable knockdown of ANO1. These in vitro discoveries were further supported by our in vivo observation that ANO1 expression in xenograft mouse models enhances the metastatic dissemination of prostate cancer cells into tibial bone and the development of osteolytic lesions. Collectively, our results help elucidate the critical role of ANO1 expression in prostate cancer bone metastases, which is epigenetically modulated by promoter CpG methylation.
Topics: Male; Anoctamin-1; DNA Methylation; Humans; Prostatic Neoplasms; Promoter Regions, Genetic; Animals; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Bone Neoplasms; Neoplasm Proteins; Mice; CpG Islands; Decitabine; Cell Movement; Epigenesis, Genetic; Azacitidine
PubMed: 38773164
DOI: 10.1038/s41598-024-62478-1 -
Molecular Cancer May 2024Breast cancer (BC) is the most frequent malignant cancer diagnosis and is a primary factor for cancer deaths in women. The clinical subtypes of BC include estrogen... (Review)
Review
Breast cancer (BC) is the most frequent malignant cancer diagnosis and is a primary factor for cancer deaths in women. The clinical subtypes of BC include estrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) positive, and triple-negative BC (TNBC). Based on the stages and subtypes of BC, various treatment methods are available with variations in the rates of progression-free disease and overall survival of patients. However, the treatment of BC still faces challenges, particularly in terms of drug resistance and recurrence. The study of epigenetics has provided new ideas for treating BC. Targeting aberrant epigenetic factors with inhibitors represents a promising anticancer strategy. The KDM5 family includes four members, KDM5A, KDM5B, KDM5C, and KDMD, all of which are Jumonji C domain-containing histone H3K4me2/3 demethylases. KDM5 proteins have been extensively studied in BC, where they are involved in suppressing or promoting BC depending on their specific upstream and downstream pathways. Several KDM5 inhibitors have shown potent BC inhibitory activity in vitro and in vivo, but challenges still exist in developing KDM5 inhibitors. In this review, we introduce the subtypes of BC and their current therapeutic options, summarize KDM5 family context-specific functions in the pathobiology of BC, and discuss the outlook and pitfalls of KDM5 inhibitors in this disease.
Topics: Humans; Female; Breast Neoplasms; Histone Demethylases; Molecular Targeted Therapy; Animals; Antineoplastic Agents; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Jumonji Domain-Containing Histone Demethylases; Biomarkers, Tumor
PubMed: 38769556
DOI: 10.1186/s12943-024-02011-0 -
Proceedings of the National Academy of... May 2024Spontaneous gain or loss of DNA methylation occurs in plant and animal genomes, and DNA methylation changes can lead to meiotically stable epialleles that generate...
Spontaneous gain or loss of DNA methylation occurs in plant and animal genomes, and DNA methylation changes can lead to meiotically stable epialleles that generate heritable phenotypic diversity. However, it is unclear whether transgenerational epigenetic stability may be regulated by any cellular factors. Here, we examined spontaneously occurring variations in DNA methylation in wild-type and mutant Arabidopsis plants that were propagated for ten generations from single-seed descent. We found that the mutant, which is defective in active DNA demethylation, showed an increased transgenerational epimutation rate. The mutation led to more spontaneously gained methylation than lost methylation at individual cytosines, compared to the wild type which had similar numbers of spontaneously gained and lost methylation cytosines. Consistently, transgenerational differentially methylated regions were also biased toward hypermethylation in the mutant. Our results reveal a genetic contribution of the ROS1 DNA demethylase to transgenerational epigenetic stability and suggest that ROS1 may have an unexpected surveillance function in preventing transgenerational DNA methylation increases.
Topics: Arabidopsis; DNA Methylation; Arabidopsis Proteins; Epigenesis, Genetic; Mutation; DNA Demethylation; Gene Expression Regulation, Plant; DNA, Plant; Nuclear Proteins
PubMed: 38768356
DOI: 10.1073/pnas.2320468121 -
PeerJ 2024Promoter hypermethylation of the tumor suppressor gene is one of the well-studied causes of cancer development. The drugs that reverse the process by driving...
BACKGROUND
Promoter hypermethylation of the tumor suppressor gene is one of the well-studied causes of cancer development. The drugs that reverse the process by driving demethylation could be a candidate for anticancer therapy. This study was designed to investigate the effects of arsenic disulfide on methylation in diffuse large B cell lymphoma (DLBCL).
METHODS
We knocked down the expression of in two DLBCL cell lines (, DB and SU-DHL-4 cells) using siRNA. Then the DLBCL proliferation was determined in the presence of knockdown. The methylation of in DLBCL cells was analyzed by methylation specific PCR (MSPCR). The effect of arsenic disulfide on the methylation was determined in DLBCL cell lines in the presence of different concentrations of arsenic disulfide (5 µM, 10 µM and 20 µM), respectively. To investigate the potential mechanism on the arsenic disulfide-mediated methylation, the mRNA expression of , and was determined.
RESULTS
functioned as a tumor suppressor gene in DLBCL cells, which was featured by the fact that knockdown promoted the proliferation of DLBCL cells. was found hypermethylated in DLBCL cells. Arsenic disulfide promoted the demethylation in a dose-dependent manner, which was related to the inhibition of DNMTs and the increase of MBD2.
CONCLUSION
Experimental evidence shows that functions as a tumor suppressor gene in DLBCL progression. hyper-methylation could be reversed by arsenic disulfide in a dose-dependent manner.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Cell Line, Tumor; DNA Methylation; Cell Proliferation; Arsenicals; DNA Methyltransferase 3B; Disulfides; DNA (Cytosine-5-)-Methyltransferases; DNA (Cytosine-5-)-Methyltransferase 1; DNA-Binding Proteins; Gene Knockdown Techniques; Promoter Regions, Genetic; Gene Expression Regulation, Neoplastic
PubMed: 38766487
DOI: 10.7717/peerj.17363 -
Clinical and Translational Medicine May 2024Human dermal fibroblasts (HDFs) are essential in the processes of skin ageing and wound healing. However, the underlying mechanism of HDFs in skin healing of the elderly...
BACKGROUND
Human dermal fibroblasts (HDFs) are essential in the processes of skin ageing and wound healing. However, the underlying mechanism of HDFs in skin healing of the elderly has not been well defined. This study aims to elucidate the mechanisms of HDFs senescence and how senescent HDFs affect wound healing in aged skin.
METHODS
The expression and function of sperm equatorial segment protein 1 (SPESP1) in skin ageing were evaluated via in vivo and in vitro experiments. To delve into the potential molecular mechanisms by which SPESP1 influences skin ageing, a combination of techniques was employed, including proteomics, RNA sequencing, immunoprecipitation, chromatin immunoprecipitation and liquid chromatography-mass spectrometry analyses. Clearance of senescent cells by dasatinib plus quercetin (D+Q) was investigated to explore the role of SPESP1-induced senescent HDFs in wound healing.
RESULTS
Here, we define the critical role of SPESP1 in ameliorating HDFs senescence and retarding the skin ageing process. Mechanistic studies demonstrate that SPESP1 directly binds to methyl-binding protein, leading to Decorin demethylation and subsequently upregulation of its expression. Moreover, SPESP1 knockdown delays wound healing in young mice and SPESP1 overexpression induces wound healing in old mice. Notably, pharmacogenetic clearance of senescent cells by D+Q improved wound healing in SPESP1 knockdown skin.
CONCLUSIONS
Taken together, these findings reveal the critical role of SPESP1 in skin ageing and wound healing, expecting to facilitate the development of anti-ageing strategies and improve wound healing in the elderly.
Topics: Animals; Humans; Male; Mice; Cellular Senescence; Down-Regulation; Fibroblasts; Quercetin; Skin Aging; Wound Healing; Carrier Proteins; Seminal Plasma Proteins
PubMed: 38764260
DOI: 10.1002/ctm2.1660 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Feb 2024Hypoxia is a common pathological phenomenon, usually caused by insufficient oxygen supply or inability to use oxygen effectively. Hydroxylated and methoxylated...
OBJECTIVES
Hypoxia is a common pathological phenomenon, usually caused by insufficient oxygen supply or inability to use oxygen effectively. Hydroxylated and methoxylated flavonoids have significant anti-hypoxia activity. This study aims to explore the synthesis, antioxidant and anti-hypoxia activities of 6-hydroxygenistein (6-OHG) and its methoxylated derivatives.
METHODS
The 6-OHG and its methoxylated derivatives, including 4',6,7-trimethoxy-5-hydroxyisoflavone (compound 3), 4',5,6,7-tetramethoxyisoflavone (compound 4), 4',6-imethoxy-5,7-dihydroxyisoflavone (compound 6), and 4'-methoxy-5,6,7-trihydroxyisoflavone (compound 7), were synthesized by methylation, bromination, methoxylation, and demethylation using biochanin A as raw material. The structure of these products were characterized by hydrogen-nuclear magnetic resonance spectroscopy (H-NMR) and mass spectrometry (MS). The purity of these compounds was detected by high pressure chromatography (HPLC). The antioxidant activity in vitro was investigated by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) free radical scavenging assay. PC12 cells were divided into a normal group, a hypoxia model group, rutin (1×10-1×10 mol/L) groups, and target compounds (1×10-1×10 mol/L) groups under normal and hypoxic conditions. Cell viability was detected by cell counting kit-8 (CCK-8) assay, the target compounds with excellent anti-hypoxia activity and the drug concentration at the maximum anti-hypoxia activity were screened. PC12 cells were treated with the optimal concentration of the target compound or rutin with excellent anti-hypoxia activity, and the cell morphology was observed under light microscope. The apoptotic rate was determined by flow cytometry, and the expressions of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were detected by Western blotting.
RESULTS
The structure of 6-OHG and its 4 methylated derivatives were correct, and the purity was all more than 97%. When the concentration was 4 mmol/L, the DPPH free radical removal rates of chemical compounds 7 and 6-OHG were 81.16% and 86.94%, respectively, which were higher than those of rutin, the positive control. The removal rates of chemical compounds 3, 4, and 6 were all lower than 20%. Compared with the normal group, the cell viability of the hypoxia model group was significantly decreased (<0.01). Compared with the hypoxia model group, compounds 3, 4, and 6 had no significant effect on cell viability under hypoxic conditions. At all experimental concentrations, the cell viability of the 6-OHG group was significantly higher than that of the hypoxia model group (all <0.05). The cell viability of compound 7 group at 1×10 and 1×10 mol/L was significantly higher than that of the hypoxia model group (both <0.05). The anti-hypoxia activity of 6-OHG and compound 7 was excellent, and the optimal drug concentration was 1×10 and 1×10 mol/L. After PC12 cells was treated with 6-OHG (1×10 mol/L) and compound 7 (1×10 mol/L), the cell damage was reduced, the apoptotic rate was significantly decreased (<0.01), and the protein expression levels of HIF-1α and VEGF were significantly decreased in comparison with the hypoxia model group (both <0.01).
CONCLUSIONS
The optimized synthesis route can increase the yield of 6-OHG and obtain 4 derivatives by methylation and selective demethylation. 6-OHG and compound 7 have excellent antioxidant and anti-hypoxia activities, which are related to the structure of the A-ring ortho-triphenol hydroxyl group in the molecule.
Topics: Antioxidants; Rats; Animals; PC12 Cells; Methylation; Cell Hypoxia; Vascular Endothelial Growth Factor A; Isoflavones; Flavones
PubMed: 38755719
DOI: 10.11817/j.issn.1672-7347.2024.230228