PubMed Health⌕ Search

Biomedical subjects

Wei Chen

Publications and source records attributed to Wei Chen.

At least 37 records · Page 2Linked to original sources
PubMed2025

RNA-DNA hybrid binding domain broadens the editing window of base editors.

Adenine base editors (ABEs) and cytosine base editors (CBEs) are prominent tools for precise genome editing but are hindered by limited editing activity at positions proximal to the protospacer adjacent motif (PAM). This study investigates the potential of enhancing base editors editing activity by fusing them with RNA-DNA hybrid binding domains (RHBDs). Specifically, fusing ABE8e with the RHBD of Homo sapiens RNaseH1 (RHBD1) significantly increased A-to-G editing efficiency in the PAM-proximal region (A9-A15) by up to 3.5-fold, while reducing off-target cytosine editing. Additionally, RHBD1 is compatible with ABEmax, BE4max, and dual base editor (eA&C-BEmax), enhancing their editing activity at the PAM-proximal bases. Notably, RHBD1-fused BE4max led to a 3.1-fold improvement in C-to-T editing efficiency at PAM-proximal region (C9-C12). Furthermore, we demonstrated that RHBD1-fused ABE8e could effectively edit disease-related single nucleotide variations (SNVs) in human cells and validated its efficacy in adult mouse liver. These findings highlight the significance of the RHBD in expanding editing window and the applicability of base editors for gene therapy and disease modeling.

Gene Editing↗
PubMed2025

NME2 modulates HCC progression through 4EBP1 phosphorylation and autophagy regulation independent of mTOR.

BACKGROUND: To investigate the role of nucleoside diphosphate kinase 2 (NME2) in HCC progression, assessing its therapeutic potential. METHODS: Utilizing transcriptome sequencing data from The Cancer Genome Atlas (TCGA) and immunohistochemical staining of tissue microarrays, we analyzed NME2 expression in HCC tumor tissues. The effects of NME2 on HCC cell proliferation and autophagy flux were assessed through knockdown and overexpression experiments. Additionally, the relationship between NME2 and 4EBP1 phosphorylation was explored through specific site mutation analysis. RESULTS: NME2 overexpression in HCC correlated with poor prognosis. NME2 knockdown significantly hindered HCC cell proliferation and induced autophagy flux. Notably, NME2 modulates 4EBP1 phosphorylation (Thr37/46) independently of mTOR, unveiling a novel axis in HCC pathogenesis. Additionally, NME2 modulates eukaryotic translation initiation factor 4F (eIF4F) complex formation and autophagy flux. CONCLUSIONS: NME2 plays a crucial role in HCC development by modulating 4EBP1 phosphorylation and autophagy through an mTOR-independent pathway. Our research underscores NME2's significance as a potential therapeutic target in HCC, meriting further exploration of its underlying mechanisms and clinical applicability.

Humans↗
PubMed2025

Identification and validation of the important role of KIF11 in the development and progression of endometrial cancer.

BACKGROUND: Human kinesin family member 11 (KIF11) plays a vital role in regulating the cell cycle and is implicated in the tumorigenesis and progression of various cancers, but its role in endometrial cancer (EC) is still unclear. Our current research explored the prognostic value, biological function and targeting strategy of KIF11 in EC through approaches including bioinformatics, machine learning and experimental studies. METHODS: The GSE17025 dataset from the GEO database was analyzed via the limma package to identify differentially expressed genes (DEGs) in EC. Functional enrichment analysis of the DEGs was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. DEGs were further screened for hub genes through protein-protein interaction (PPI) network analysis and machine learning. The role of the hub gene KIF11 in EC was analyzed using clinical data from the TCGA database. The expression of KIF11 in EC was subsequently validated in clinical samples. In vitro experiments were utilized to evaluate the effects of KIF11 on biological functions such as proliferation, migration, apoptosis, and the cell cycle in endometrial cancer cells. RESULTS: A total of 877 DEGs, which are widely involved in important biological processes such as cell division, tubulin binding, and the cell cycle, were identified. Through PPI network analysis and machine learning, KIF11 was selected as the hub gene for subsequent analysis and experimental validation. An analysis of TCGA data revealed that KIF11 is highly expressed in EC and is associated with tumor grade, stage, and a low survival rate. The overexpression of KIF11 in tumor tissues was further confirmed in EC patient samples. KIF11 knockdown had inhibitory effects on cell proliferation, migration and invasion. Flow cytometry analysis revealed that KIF11 knockdown induced G2/M phase arrest and promoted apoptosis in EC cells. CONCLUSION: Our study demonstrated that KIF11 was upregulated in EC and was strongly associated with a poor prognosis. Notably, we found that reduced KIF11 expression inhibited EC cell proliferation, migration and invasion. KIF11 knockdown caused more EC cells to arrest in the G2/M phase and undergo apoptosis. The findings of our study emphasized that KIF11 may be a promising prognostic biomarker and therapeutic target for EC patients.

Humans↗
PubMed2024

Gut microbial genomes with paired isolates from China illustrate probiotic and cardiometabolic effects.

The gut microbiome displays genetic differences among populations, and characterization of the genomic landscape of the gut microbiome in China remains limited. Here, we present the Chinese Gut Microbial Reference (CGMR) set, comprising 101,060 high-quality metagenomic assembled genomes (MAGs) of 3,707 nonredundant species from 3,234 fecal samples across primarily rural Chinese locations, 1,376 live isolates mainly from lactic acid bacteria, and 987 novel species relative to worldwide databases. We observed region-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. Preliminary mouse experiments suggest a probiotic effect of two Faecalibacillus intestinalis isolates in alleviating constipation, cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and isolates from the genera Parabacteroides and Lactobacillus in host lipid metabolism. Our study expands the current microbial genomes with paired isolates and demonstrates potential host effects, contributing to the mechanistic understanding of host-microbe interactions.

Probiotics↗
PubMed2024

The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism.

Renal interstitial fibrosis is an important mechanism in the progression of chronic kidney disease (CKD) to end-stage kidney disease. However, we lack specific treatments to slow or halt renal fibrosis. Ribosome profiling identified upregulation of a secreted micropeptide, C4orf48 (Cf48), in mouse diabetic nephropathy. Cf48 RNA and protein levels were upregulated in tubular epithelial cells in human and experimental CKD. Serum Cf48 levels were increased in human CKD and correlated with loss of kidney function, increasing CKD stage, and the degree of active interstitial fibrosis. Cf48 overexpression in mice accelerated renal fibrosis, while Cf48 gene deletion or knockdown by antisense oligonucleotides significantly reduced renal fibrosis in CKD models. In vitro, recombinant Cf48 (rCf48) enhanced TGF-β1-induced fibrotic responses in renal fibroblasts and epithelial cells independently of Smad3 phosphorylation. Cellular uptake of Cf48 and its profibrotic response in fibroblasts operated via the transferrin receptor. RNA immunoprecipitation-sequencing identified Cf48 binding to mRNA of genes involved in the fibrotic response, including Serpine1, Acta2, Ccn2, and Col4a1. rCf48 binds to the 3'UTR of Serpine1 and increases mRNA half-life. We identify the secreted Cf48 micropeptide as a potential enhancer of renal fibrosis that operates as an RNA-binding peptide to promote the production of extracellular matrix.

Animals↗
PubMed2007

Characterization of a 5.3 Mb deletion in 15q14 by comparative genomic hybridization using a whole genome "tiling path" BAC array in a girl with heart defect, cleft palate, and developmental delay.

High-resolution array CGH utilizing sets of overlapping BAC and PAC clones ("tiling path") covering the whole genome is a powerful novel tool for fast detection of submicroscopic chromosome deletions or duplications. We describe the successful application of a submegabase resolution whole genome "tiling path" BAC array to confirm and characterize a de novo interstitial deletion of chromosome 15. The deletion has a size of 5.3 Mb and is located within chromosome band 15q14, distal to the Prader-Willi/Angelman region. The affected girl had a heart defect, cleft palate, recurrent infections, and developmental delay. In contrast to GTG banding, array CGH determined the exact number of deleted genes and thus allowed the identification of candidate genes for cleft palate (GREM1, CX36, MEIS2), congenital heart defect (ACTC, GREM1, CX36, MEIS2), and mental retardation (ARHGAP11A, CHRNA7, CHRM5).

Adult↗
PubMed2007

Concentration-dependent effects of a selective estrogen receptor modulator raloxifene on proliferation and apoptosis in human uterine leiomyoma cells cultured in vitro.

BACKGROUND: This study was conducted to elucidate the effects of raloxifene on proliferation and apoptosis in cultured human uterine leiomyoma cells. METHODS: The monolayer cultures were treated with graded concentrations (10(-9), 10(-8) and 10(-7) M) of raloxifene and 10(-7) M 17beta-estradiol (E(2)). Cell viability, percentage of proliferating cell nuclear antigen (PCNA)-positive cells, percentage of terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labelling (TUNEL)-positive cells and the expression of PCNA and Bcl-2 proteins were assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxylphenyl)-2-(4-sulphophenyl)-2H-tetraz olium assay, immunocytochemistry, TUNEL assay and western blot analysis, respectively. RESULTS: Compared with untreated cultures, the number of viable cultured cells, percentage of PCNA-positive cells and PCNA protein expression were significantly decreased by treatment with 10(-9) M raloxifene, but increased by treatment with either 10(-8) M or 10(-7) M raloxifene. In contrast, the percentage of TUNEL-positive cells was significantly increased and Bcl-2 protein expression was significantly decreased by treatment with 10(-9) M raloxifene, whereas they were not affected by treatment with either 10(-8) or 10(-7) M raloxifene. CONCLUSIONS: In cultured leiomyoma cells, low concentration (10(-9) M) of raloxifene may inhibit the growth of leiomyoma cells, whereas high concentrations (10(-8) M, 10(-7) M) of raloxifene may promote their growth.

Adult↗
PubMed2007

A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing.

Adult cancers may derive from stem or early progenitor cells. Epigenetic modulation of gene expression is essential for normal function of these early cells but is highly abnormal in cancers, which often show aberrant promoter CpG island hypermethylation and transcriptional silencing of tumor suppressor genes and pro-differentiation factors. We find that for such genes, both normal and malignant embryonic cells generally lack the hypermethylation of DNA found in adult cancers. In embryonic stem cells, these genes are held in a 'transcription-ready' state mediated by a 'bivalent' promoter chromatin pattern consisting of the repressive mark, histone H3 methylated at Lys27 (H3K27) by Polycomb group proteins, plus the active mark, methylated H3K4. However, embryonic carcinoma cells add two key repressive marks, dimethylated H3K9 and trimethylated H3K9, both associated with DNA hypermethylation in adult cancers. We hypothesize that cell chromatin patterns and transient silencing of these important regulatory genes in stem or progenitor cells may leave these genes vulnerable to aberrant DNA hypermethylation and heritable gene silencing during tumor initiation and progression.

Adult↗
PubMed2007

Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence.

Pycnodysostosis is a genetic bone disease featuring the unique bone homeostasis disorders of osteolysis and osteopetrosis in the same organism. The pathomechanism for pycnodysostosis has been largely unknown due to the unavailability of a pycnodysostosis mouse model with all the traits of the disease. We generated cathepsin K(-/-) mouse strains in the 129/Sv and C57BL/6J backgrounds and found that, only in the 129/Sv background, cathepsin K(-/-) mice exhibit many characteristics of the human pycnodysostosis-like phenotype. Our data indicated that 129/Sv cathepsin K(-/-) osteoclasts (OCs) lacked normal apoptosis and senescence and exhibited over-growth both in vitro and in vivo. These abnormalities resulted in an unusually high OC number, which is consistent with a recent case study of human pycnodysostosis. Our results show that cathepsin K function has different effects around the skeleton due to site-specific variations in bone homeostasis, such as phenotypes of osteopetrosis in tibiae and osteolysis in calvariae as a result of cathepsin K mutation. Our data demonstrated that the expression levels of p19, p53 and p21 were significantly reduced in 129/Sv cathepsin K(-/-) OCs and forced expression of cathepsin K in pre-OCs induced premature senescence and increased expression of p19, p53 and p21. This is the first evidence that cathepsin K plays a key role in OC apoptosis and senescence, revealing the importance of OC senescence in bone homeostasis. The finding of this novel cathepsin K function provides insight into the pathomechanism of pycnodysostosis and may provide new drug targets for diseases involved in OC-related abnormal bone homeostasis.

Animals↗
PubMed2007

Osteoclast differentiation and gene regulation.

Osteoclasts, the bone resorbing cells, play a key role both in normal bone remodeling and in the skeletal osteopenia of arthritis, osteoporosis, periodontal disease and certain malignancies. Osteoclast cellular commitment, differentiation and function depend upon the establishment of specific patterns of gene expression achieved through networks of transcription factors activated by osteoclastogenic cytokines. This review is an updated look at the various transcription factors and cytokines that have been demonstrated to play critical roles in osteoclast differentiation and function, along with their known animal models, such as: PU.1, Mcsf, RANKL, NF-kappaB, AP-1, NFATc1, Mitf, Myc, and Src. Further studies on these transcription factors and cytokines will not only expand our basic understanding of the molecular mechanisms of osteoclast differentiation, but will also aid our ability to develop therapeutic means of intervention in osteoclast-related diseases.

Animals↗
PubMed2007

Targets of genome copy number reduction in primary breast cancers identified by integrative genomics.

The identification of specific oncogenes and tumor suppressor genes in regions of recurrent aneuploidy is a major challenge of molecular cancer research. Using both oligonucleotide single-nucleotide polymorphism and mRNA expression arrays, we integrated genomic and transcriptional information to identify and prioritize candidate cancer genes in regions of increased and decreased chromosomal copy number in a cohort of primary breast cancers. Confirming the validity of this approach, several regions of previously-known copy number (CN) alterations in breast cancer could be successfully reidentified. Focusing on regions of decreased CN, we defined a prioritized list of eighteen candidate genes, which included ARPIN, FBN1, and LZTS1, previously shown to be associated with cancers in breast or other tissue types, and novel genes such as P29, MORF4L1, and TBC1D5. One such gene, the RUNX3 transcription factor, was selected for further study. We show that RUNX3 is present at reduced CNs in proportion to the rest of the tumor genome and that RUNX3 CN reductions can also be observed in a breast cancer series from a different center. Using tissue microarrays, we demonstrate in an independent cohort of over 120 breast tissues that RUNX3 protein is expressed in normal breast epithelium but not fat and stromal tissue, and widely down-regulated in the majority of breast cancers (>85%). In vitro, RUNX3 overexpression suppressed the invasive potential of MDA-MB-231 breast cancer cells in a matrigel assay. Our results demonstrate the utility of integrative genomic approaches to identify novel potential cancer-related genes in primary tumors. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.

Breast Neoplasms↗
PubMed2007

Efficient in vivo 31P magnetization transfer approach for noninvasively determining multiple kinetic parameters and metabolic fluxes of ATP metabolism in the human brain.

ATP metabolism is controlled mainly by ATP synthase (ATP(ase)) and creatine kinase (CK) reactions that regulate cerebral ATP production, transportation, and utilization. These coupled reactions constitute a chemical exchange metabolic network of PCr<-->ATP<-->Pi characterized by two forward and two reverse reaction fluxes, which can be studied noninvasively by in vivo (31)P MRS combined with magnetization transfer (MT). However, it is still debated whether current MT approaches can precisely determine all of these fluxes. We developed and tested a modified in vivo (31)P MT approach based on a multiple single-site saturation (MSS) technique to study the entire PCr<-->ATP<-->Pi network in human occipital lobe at 7T. Our results reveal that 1) the MSS MT approach can explicitly determine all four reaction fluxes with a minimal number of (31)P spectra; 2) the three-spin exchange model accurately determines reverse reaction fluxes, resulting in equal forward and reverse fluxes for both CK and ATP(ase) reactions; and 3) the ATP synthesis rate (8.8 +/- 1.9 micromol/g/min, N = 11) measured in the human brain reflects cerebral oxidative phosphorylation. The MSS MT approach should provide an important modality for noninvasively studying the essential roles of ATP metabolism in brain bioenergetics, function, and diseases.

Adenosine Triphosphate↗
PubMed2007

Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier.

Production of short-chain fatty acids (SCFA) in the intestinal lumen may play an important role in the maintenance of the intestinal barrier. However, overproduction/accumulation of SCFA in the bowel may be toxic to the intestinal mucosa and has been hypothesized to play a role in the pathogenesis of neonatal necrotizing enterocolitis (NEC). By using a Caco-2 cell monolayer model of intestinal barrier, we report here that the effect of butyrate on the intestinal barrier is paradoxical. Butyrate at a low concentration (2 mM) promotes intestinal barrier function as measured by a significant increase in transepithelial electrical resistance (TER) and a significant decrease in inulin permeability. Butyrate at a high concentration (8 mM) reduces TER and increases inulin permeability significantly. Butyrate induces apoptosis and reduces the number of viable Caco-2 cells in a dose-dependent manner. Intestinal barrier function impairment induced by high concentrations of butyrate is most likely related to butyrate-induced cytotoxicity due to apoptosis. We conclude that the effect of butyrate on the intestinal barrier is paradoxical; i.e. whereas low concentrations of butyrate may be beneficial in promoting intestinal barrier function, excessive butyrate may induce severe intestinal epithelial cell apoptosis and disrupt intestinal barrier.

Apoptosis↗
PubMed2006

Tuning the hole injection barrier at the organic/metal interface with self-assembled functionalized aromatic thiols.

Self-assembled functionalized aromatic thiols (oligophenylenes composed of building blocks of dimethoxy-substituted phenylenes, perfluoro-substituted phenylenes, and a terminal thiol group) were used to tune the hole injection barrier (Delta(h)) of copper(II) phthalocyanine (CuPc) on Au(111). Synchrotron-based high-resolution photoemission spectroscopy study reveals a significant reduction of Delta(h) by as much as 0.75 eV from Delta(h) = 0.9 eV for CuPc/Au(111) to Delta(h) = 0.15 eV for CuPc/BOF/Au(111), where BOF represents 4-pentafluorophenyl-1-(p-thiophenyl)-2,5-dimethoxybenzene. The delocalized pi orbitals of these functionalized aromatic thiols greatly facilitate effective charge transfer (hole or electron) across the SAM interface as compared to alkanethiols, hence making this novel interface modification scheme a simple and effective way to tune the hole injection barrier. This method has potential applications in molecular electronics, organic light-emitting diodes (OLED), organic field-effect transistors (OFETs), and organic solar cells.

Journal Article↗
PubMed2006

Synthesis and characterization of ultrathin WO3 nanodisks utilizing long-chain poly(ethylene glycol).

Metal oxide nanostructures hold great potential for photovoltaic (PV), photoelectrochemical (PEC), and photocatalytic applications. Whereas thin films of various materials of both nanoparticle and nanorod morphologies have been widely investigated, there have been few inquiries into nanodisk structures. Here, we report the synthesis of ultrathin WO3 nanodisks using a wet chemical route with poly(ethylene glycol) (PEG) as a surface modulator. The reported nanodisk structure is based on the interaction of the nonionic 10000 g/mol PEG molecules with tungsten oxoanion precursors. The WO3 nanostructures formed are dominated by very thin disks with dimensions on the nanometer to micrometer scale. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images reveal the structures to have dimensions on the order of 350-1000 nm in length, 200-750 nm in width, and 7-18 nm in thickness and possessing textured single-crystalline features. A number of analytical techniques were used to characterize the WO3 nanodisks, including selected-area electron diffraction (SAED), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDX), atomic force microscopy (AFM), Raman scattering spectroscopy, UV-visible spectrophotometry, and cyclic voltammetry (CV). The growth of the WO3 nanodisks was inhibited in the [010] crystal direction, leading to ultrathin morphologies in the monoclinic crystal phase. The large flat surface area and high aspect ratio of the WO3 nanodisks are potentially useful in PEC cells for hydrogen production via direct water splitting, as has been demonstrated in a preliminary experiment with external bias.

Electrochemistry↗
PubMed2006

Synthesis of chiral 3-substituted hexahydropyrroloindoline via intermolecular cyclopropanation.

[Structure: see text] A new and efficient synthetic route to chiral 3-substituted hexahydropyrroloindoline 18 possessing absolute configurations in accordance with indole alkaloids has been developed from readily available L-tryptophan. The key step relies on the one-pot cascade reaction of oxazolidinone 17 with diazoester, which proceeds through intermolecular cyclopropanation, ring opening, and cyclization.

Cyclopropanes↗
PubMed2006

Mutation screening of brain-expressed X-chromosomal miRNA genes in 464 patients with nonsyndromic X-linked mental retardation.

MiRNAs are small noncoding RNAs that control the expression of target genes at the post-transcriptional level and have been reported to modulate various biological processes. Their function as regulatory factors in gene expression renders them attractive candidates for harbouring genetic variants with subtle effects on IQ. In an attempt to investigate the potential role of miRNAs in the aetiology of X-linked mental retardation, we have examined all 13 known, brain-expressed X-chromosomal miRNAs in a cohort of 464 patients with non-syndromic X-linked MR and found four nucleotide changes in three different pre-miRNA hairpins. All the observed changes appear to be functionally neutral which, taken together with the rarity of detected nucleotide changes in miRNA genes, may reflect strong selection and thus underline the functional importance of miRNAs.

Base Sequence↗