Biomedical subjects

Jianjun Chen

Publications and source records attributed to Jianjun Chen.

At least 19 recordsLinked to original sources

PubMed2026

Targeting the METTL1/m7G axis as a therapeutic strategy in myeloid leukemia.

N7-methylguanosine (m7G), a prevalent modification in transfer RNAs (tRNAs), is primarily catalyzed by the methyltransferase METTL1. Although growing evidence supports a role for METTL1 in various tumors, its therapeutic potential and precise function in leukemia stem cell (LSC) homeostasis remain largely unexplored. Here, we identify METTL1 as a key regulator of LSC self-renewal and homing within bone marrow (BM) microenvironment through catalyzing m7G formation on a specific tRNA, tRNAPheGAA, thereby promoting leukemogenesis. Mechanistically, METTL1 loss significantly reduces m7G abundance and steady-state levels of tRNAPheGAA, leading to translation suppression and degradation of transcripts enriched with tRNAPheGAA-related codons, such as hematopoietic cell kinase (HCK). Decreased HCK expression disrupts CXCR4 signaling, impairing LSC self-renewal and BM homing. Therapeutically, we characterized a small-molecule METTL1 inhibitor (M1i; NSC137443), through high-throughput screening. Pharmacological inhibition of METTL1 demonstrated potent antitumor efficacy by reducing tRNA m7G levels and disrupting the tRNAPheGAA/HCK/CXCR4 cascade. Notably, targeting METTL1 significantly reduces LSC frequency, delays leukemogenesis, and prolongs survival in multiple acute myeloid leukemia models. Together, our findings establish a previously unrecognized role for METTL1 and its target tRNAPheGAA in LSC homeostasis and provide compelling proof-of-concept evidence that METTL1 is a druggable epitranscriptomic target for antileukemia therapy.

Humans↗

PubMed2007

MicroRNA and cancer: Current status and prospective.

Gene expression in normal cells is highly regulated by complex gene regulatory networks. Disruption of these networks may lead to cancer. Recent studies have revealed the existence of an abundant class of small nonprotein-coding regulatory RNAs, known as microRNAs (miRNAs). MiRNAs may regulate diverse biological processes including development, cell proliferation, differentiation and apoptosis, through suppressing the expression of their target genes. Posttranscriptional silencing of target genes by miRNAs occurs either by cleavage of homologous target messenger RNAs (mRNAs), or by inhibition of target protein synthesis. Computational predictions indicate that 1 miRNA may target on hundreds of genes, and suggest that over 50% of human protein-coding genes might be regulated by miRNAs. MiRNAs are receiving increased attention in cancer genomic research. We are beginning to understand that miRNAs may act as oncogenes and/or tumor suppressor genes within the molecular architecture of gene regulatory networks, thereby contributing to the development of cancer. MiRNAs may provide useful diagnostic and prognostic markers for cancer diagnosis and treatment, as well as serving as potential therapeutic targets or tools.

Animals↗

PubMed2007

Five novel mutations of RNA-specific adenosine deaminase gene with dyschromatosis symmetrica hereditaria.

Dyschromatosis symmetrica hereditaria (OMIM127400) is a rare autosomal dominant pigmentary genodermatosis caused by mutations in the RNA-specific adenosine deaminase (ADAR) gene. This study investigated 5 families and 3 sporadic patients with dyschromatosis symmetrica hereditaria in the Chinese Han population from Anhui province, China. By direct sequencing, 5 novel ADAR gene mutations (c.982C>T, c.1491insA, c.2568_2571delTAAC, c.2969C>G and c.3040G>T) and 3 mutations described previously (c.3203-2A>G, c.3247C>T and c.3286C>T) were identified, all of which were heterozygous. We reviewed a total of 48 mutations in the ADAR gene in patients with dyschromatosis symmetrica hereditaria by previous reports and speculated that the mutation hotspots on the ADAR gene might be located in exons 9-15. The tRNA-specific and double-stranded RNA adenosine deaminase domain is essential for the deaminase activity of the ADAR encoded protein.

Adenosine Deaminase↗

PubMed2006

Evidence for variation in abundance of antisense transcripts between multicellular animals but no relationship between antisense transcriptionand organismic complexity.

Given that humans have about the same number of genes as mice and not so many more than worm, what makes us more complex? Antisense transcripts are implicated in many aspects of gene regulation. Is there a functional connection between antisense transcription and organismic complexity, that is, is antisense regulation especially prevalent in humans? We used the same robust protocol to identify antisense transcripts in humans and five other metazoan genomes (mouse, rat, chicken, fruit fly, and nematode), and found that the estimated proportions of genes involved in antisense transcription are highly sensitive to the number of transcripts included in the analysis. By controlling for transcript abundance, we find that the probability that any given transcript is putatively involved in sense-antisense regulation is no higher in humans than in other vertebrates but appears unusually high in flies and especially low in nematodes. Similarly, there is no evidence that the proportion of sense-antisense transcripts is especially higher in humans than other vertebrates in a given subset of transcript sequences such as mRNAs, coding sequences, conserved, or nonconserved transcripts. Although antisense transcription might be enriched in mammalian brains compared with nonbrain tissues, it is no more enriched in human brain than in mouse brain. Overall, therefore, while we see striking variation between multicellular animals in the abundance of antisense transcripts, there is no evidence for a link between antisense transcription and organismic complexity. More particularly, we see no evidence that humans are in any way unusual among the vertebrates in this regard. Instead, our results suggest that antisense transcription might be prevalent in almost all metazoan genomes, nematodes being an unexplained exception.

Animals↗

PubMed2006

Contact acoustic nonlinearity in a bonded solid-solid interface.

We have conducted research on the contact acoustic nonlinearity (CAN) produced by a bonded solid-solid interface in order to find a nondestructive and quantitative method to evaluate the bonding strength of the interface. A CAN model is used to depict a bonded state from the relationship between the CAN parameter and the bonding strength and the crack width in the interface. According to this model, a nondestructive evaluation of the bonding strength can be established. When the CAN parameter and the crack width are measured, the bonding strength can be calculated from the model. In this paper, the bonding strengths of some samples are evaluated based on the CAN method. The results well agree with the bonding strengths measured by hanging clogs (weights) to destroy their interfaces.

Journal Article↗

PubMed2006

Internalization of CD40 regulates its signal transduction in vascular endothelial cells.

The CD40 ligand (CD40L)-CD40 dyad can ignite proinflammatory and procoagulatory activities of the vascular endothelium in the pathogenesis and progression of atherosclerosis. Besides being expressed on the activated CD4(+) T cell surface (mCD40L), the majority of circulating CD40L reservoir (sCD40L) in plasma is released from stimulated platelets. It remains debatable which form of CD40L triggers endothelial inflammation. Here, we demonstrate that the agonistic antibody of CD40 (G28.5), which mimics the action of sCD40L, induces rapid endocytosis of CD40 independent of TRAF2/3/6 binding while CD40L expressed on the surface of HEK293A cells captures CD40 at the cell conjunction. Forced internalization of CD40 by constitutively active mutant of Rab5 preemptively activates NF-kappaB pathway, suggesting that CD40 was able to form an intracellular signal complex in the early endosomes. Internalized CD40 exhibits different patterns of TRAF2/3/6 recruitment and Akt phosphorylation from the membrane anchored CD40 complex. Finally, mCD40L but not sCD40L induces the upregulation of proinflammatory cytokines and cell adhesion factors in the primary human vascular endothelial cells in vitro, although both forms of CD40L activate NF-kappaB pathway. These results therefore may help understand the molecular mechanism of CD40L signaling that contributes to the pathophysiology of atherosclerosis.

Animals↗

PubMed2006

Synthesis of phospholipase A2 inhibitory biflavonoids.

A series of C-C biflavones was designed to investigate the relationship between structural array of different flavone-flavone subunit linkage and the inhibitory activity against phospholipase A2 (PLA2). Among six classes of C-C biflavones designed, four classes of C-C biflavones, which have flavone-flavone subunit linkages at A ring-A ring, A ring-B ring, B ring-B ring, and B ring-C ring, were synthesized. The synthetic biflavones exhibited somewhat different inhibitory activities against sPLA2-IIA. Among them, the biflavone a having a C-C 4'-4' linkage showed comparable inhibitory activity with that of the natural biflavonoid, ochnaflavone, and 7-fold stronger activity than that of amentoflavone. Further chemical modification is being carried out in order to obtain the chemically optimized biflavonoids.

Biflavonoids↗

PubMed2006

Gene expression profiles in acute myeloid leukemia with common translocations using SAGE.

Identification of the specific cytogenetic abnormality is one of the critical steps for classification of acute myeloblastic leukemia (AML) which influences the selection of appropriate therapy and provides information about disease prognosis. However at present, the genetic complexity of AML is only partially understood. To obtain a comprehensive, unbiased, quantitative measure, we performed serial analysis of gene expression (SAGE) on CD15(+) myeloid progenitor cells from 22 AML patients who had four of the most common translocations, namely t(8;21), t(15;17), t(9;11), and inv(16). The quantitative data provide clear evidence that the major change in all these translocation-carrying leukemias is a decrease in expression of the majority of transcripts compared with normal CD15(+) cells. From a total of 1,247,535 SAGE tags, we identified 2,604 transcripts whose expression was significantly altered in these leukemias compared with normal myeloid progenitor cells. The gene ontology of the 1,110 transcripts that matched known genes revealed that each translocation had a uniquely altered profile in various functional categories including regulation of transcription, cell cycle, protein synthesis, and apoptosis. Our global analysis of gene expression of common translocations in AML can focus attention on the function of the genes with altered expression for future biological studies as well as highlight genes/pathways for more specifically targeted therapy.

Apoptosis↗

PubMed2006

[Safety analysis of Allergovit immunotherapy in patients of allergic rhinitis].

OBJECTIVE: To analyse the safety of Allergovit immunotherapy in patients of allergic rhinitis. METHOD: Two hundred and fifty-six patients with allergic rhinitis received Allergovit immunotherapy, their local and systemic side-effect were observed, recorded and analyzed during the treatment. RESULT: The number of patients who got local side-effect was 84 cases, the percent of local side-effect was 4.45%; the number of patients who got systemic side-effect were 21 cases, the percent of systemic side-effect was 0.31%. Both side-effects were slight. CONCLUSION: Allergovit immunotherapy is a safe and feasible choice for allergic rhinitis. While the schedule fit for Chinese or individually is needed to be mended in practice.

Adolescent↗

PubMed2006

[Effect of immunostimulatory sequence on the expression of EOTAXIN of experimental allergic rhinitis].

OBJECTIVE: To investigate the effect of CpG DNA applied intraperitoneally on the expression of EOTAXIN of allergic rhinitis model. METHOD: CpG DNA was injected intraperitoneally to rat at the same time of the basic intraperitoneal immunized. The symptoms, expression of eosinophil (EOS) in nasal cavity and expression of EOTAXIN in the nasal mucosa were measured. RESULT: After the CpG DNA was applied, the symptom scores, eosinophil (EOS) in nasal cavity and expression of EOTAXIN were weaken. CONCLUSION: There was great reverse effect of CpG DNA on the foundation of rat model of experimental allergic rhinitis, suppression of EOTAXIN may be one of the mechanisms.

Animals↗

PubMed2006

[The concentration and expression of IL-4, IL-5, IL-6, IL-8 in human nasal polyps tissues].

OBJECTIVE: To study the concentration and expression of IL-4, IL-5, IL-6, IL-8 in human nasal polyps tissues, and to explore the relationship between cytokines and the formative mechanism of nasal polyps. METHOD: The concentration and expression of IL-4, IL-5, IL-6, IL-8 in 54 cases with nasal polyps were determined by enzyme linked immunosorbent assay (ELISA) and immunohistochemistry, and the middle turbinate mucosa from 22 patients with the deviation of nasal septum were used as the control. RESULT: The concentration of IL-5, IL-8 in nasal polyps tissues were significantly higher than that in normal middle turbinate mucosa (P < 0.01). There was no significant difference between the concentration of IL-6 in nasal polyps and that in normal control group (P > 0.05). No significant difference was found between the concentration of IL-4 in nasal polyps tissues with negative allergic skin test and that in control group, but the concentration of IL-4 was significantly higher in nasal polyps tissues with positive allergic skin test than in control group (P < 0.05). IL-4 was mostly found in lymphocytes and plasma cells in nasal polyps and IL-5 in eosinophils and lymphocytes. IL-6 and IL-8 were mostly found in nasal polyps epithelium and inflammatory cells, as was no difference between positive allergic skin test and negative one. CONCLUSION: IL-5 and IL-8 are the key cytokines in the formation of nasal polyps, and IL-4 is a key cytokine in nasal polyps with positive allergic skin test. IL-6 isn't an important cytokine in the formative mechanism of nasal polyps.

Adolescent↗

PubMed2005

Coal fly ash as an amendment to container substrate for Spathiphyllum production.

Coal fly ash, possessing alkalinity and containing some essential mineral elements, could be an alternative to lime amendment and a nutrient source of container substrates for ornamental plant growth. This study examined physiochemical properties of three fly ashes collected from Florida, Michigan, and North Carolina and container substrates formulated by incorporating commercial dolomite and the three fly ashes, respectively into a soilless basal substrate. The basal, dolomite- and fly ash-amended substrates were used to grow peace lily (Spathiphyllum Schott 'Ty's Pride'), a popular ornamental foliage plant, in 15-cm diameter containers in a shaded greenhouse. Electrical conductivities and pH of the substrates were monitored monthly. Plant canopy heights and widths, shoot fresh and dry weights were recorded five months after transplanting, and tissue nutrient contents were measured. Three fly ashes and the commercial dolomite were able to raise pH of the basal substrate from 3.8 to about 6.8. Canopy heights and widths as well as shoot fresh and dry weights of plants produced from fly ash-amended substrates were comparable to those produced from dolomite-amended substrate but significantly different from those produced from the basal substrate. On an average, five necrotic leaves appeared from plants produced in the basal substrate; however, less than one necrotic leaf occurred on plants produced in either dolomite- or fly ash-amended substrates. As a result, the quality grade of plants grown in the basal substrate was low, and plants were not marketable. Additionally, electrical conductivities of fly ash-amended substrates were consistently higher during the course of plant growth, suggesting that, in addition to neutralizing pH, the amended fly ashes provide nutrients for peace lily growth, which was confirmed by high nutrient contents in plant shoots. This study demonstrates that the three fly ashes can be alternatives to commercial dolomites used as amendments to soilless substrates for ornamental plant production. Utilization of fly ashes as container substrate amendments should represent a new market for the beneficial use of coal combustion byproducts.

Araceae↗

PubMed2005

Evidence for a preferential targeting of 3'-UTRs by cis-encoded natural antisense transcripts.

Although both the 5'- and 3'-untranslated regions (5'- and 3'-UTRs) of eukaryotic mRNAs may play a crucial role in posttranscriptional gene regulation, we observe that cis-encoded natural antisense RNAs have a striking preferential complementarity to the 3'-UTRs of their target genes in mammalian (human and mouse) genomes. A null neutral model, evoking differences in the rate of 3'-UTR and 5'-UTR extension, could potentially explain high rates of 3'-to-3' overlap compared with 5'-to-5' overlap. However, employing a simulation model we show that this null model probably cannot explain the finding that 3'-to-3' overlapping pairs have a much higher probability (>5 times) of conservation in both mouse and human genomes with the same overlapping pattern than do 5'-to-5' overlaps. Furthermore, it certainly cannot explain the finding that overlapping pairs seen in both genomes have a significantly higher probability of having co-expression and inverse expression (i.e. characteristic of sense-antisense regulation) than do overlapping pairs seen in only one of the two species. We infer that the function of many 3'-to-3' overlaps is indeed antisense regulation. These findings underscore the preference for, and conservation of, 3'-UTR-targeted antisense regulation, and the importance of 3'-UTRs in gene regulation.

3' Untranslated Regions↗

PubMed2005

The small introns of antisense genes are better explained by selection for rapid transcription than by "genomic design".

Several models have been proposed to explain why expression parameters of a gene might be related to the size of the gene's introns. These include the idea that an energetic cost of transcription should favor smaller introns in highly expressed genes (the "economy selection" argument) and that tissue-specific genes reside in genomic locations with complex chromatin level control requiring large amounts of noncoding DNA (the "genomic design" hypothesis). We recently proposed a modification of the economy model arguing that, for some genes, the time that expression takes is more important than the energetic cost, such that some weakly but rapidly expressed genes might also have small introns. We suggested that antisense genes might be such a class and showed that the data appear to be consistent with this. We now reexamine this model to ask (a) whether the effects described were owing solely to the fact that antisense genes are often noncoding RNA and (b) whether we can confidently reject the "genomic design" model as an explanation for the facts. We show that the effects are not specific to noncoding RNAs and that the predictions of the "genomic design" model for the most part are not upheld.

Antisense Elements (Genetics)↗

PubMed2005

Protection against influenza virus infection in BALB/c mice immunized with a single dose of neuraminidase-expressing DNAs by electroporation.

The ability of a single dose of plasmid DNA encoding neuraminidase (NA) or hemagglutinin (HA) from influenza virus A/PR/8/34 (PR8) (H1N1) to protect against homologous virus infection was examined in BALB/c mice. In the present study, mice were immunized once with 30 microg of NA or HA DNA by electroporation. Four weeks or 28 weeks after immunization, mice were challenged with a lethal dose of homologous virus and the ability of NA or HA DNA to protect the mice from influenza was evaluated. We found that a single inoculation of NA DNA could provide protection against influenza virus challenge as well as long-term protection against viral infection. Whereas, the mice immunized with a single dose of HA DNA could not be protected. In addition, neonatal mice immunized with a single dose of 30 microg of NA DNA could be provided with significant protection against viral infection.

Animals↗

PubMed2005

Human antisense genes have unusually short introns: evidence for selection for rapid transcription.

We suggest that small introns are favored in genes requiring a minimal response time ('nimble' genes), and that antisense genes might be prime candidates for such nimble genes. In this article, we show that antisense genes have significantly shorter introns than all other gene categories, which supports our proposal that the short introns of antisense genes might be functionally important and integrally related to their potential role in efficient gene regulation.

DNA, Antisense↗

PubMed2005

Genome-wide analysis of coordinate expression and evolution of human cis-encoded sense-antisense transcripts.

Is sense-antisense (SA) pairing of transcripts a common mode of gene regulation in the human genome? Although >20% of human genes might form SA pairs, the extent to which they are involved in antisense regulation is unknown. Simultaneous expression of paired sense and antisense genes is an essential step and an important indicator of antisense regulation. In this article, we demonstrate that human SA pairs tend to be co-expressed and/or inversely expressed more frequently than expected by chance. Moreover, co-expressed and inversely expressed SA pairs exhibit a striking pattern of evolutionary conservation. These findings suggest that antisense regulation is a common and important mechanism of gene regulation in the human genome.

Animals↗

PubMed2005

Maternal immunization with both hemagglutinin- and neuraminidase-expressing DNAs provides an enhanced protection against a lethal influenza virus challenge in infant and adult mice.

Maternal immunization is the major form of protection against many infectious diseases in early life. In this report, transmission of vaccine-specific maternal antibodies and protection of offspring against a lethal influenza virus challenge were studied. Adult female BALB/c mice were immunized intramuscularly with plasmid DNAs encoding influenza virus hemagglutinin (HA), neuraminidase (NA), or mixture of the two plasmids. The levels of specific antibodies in sera of offspring at different ages and the survival rates following the lethal viral challenge were valued. The results showed effective transmission of maternal antibodies and long-lasting protection in offspring. Along with the growth of offspring, the antibody titers in vivo decreased and the ability against virus infection decreased accordingly. The HA-specific maternal antibodies protected the offspring from a lethal influenza infection up to 2 weeks old, and the NA-specific maternal antibodies protected offspring up to 4 weeks old. Furthermore, antibodies transferred by the mother immunized with the mixture of HA and NA DNAs protected the offspring up to 6 weeks old. This suggests that maternal immunization with a mixture of HA and NA DNAs provide the most effective protection against the virus challenge for the offspring of mice.

Animals↗