Biomedical subjects

Jin Chen

Publications and source records attributed to Jin Chen.

At least 19 recordsLinked to original sources

PubMed2025

Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions.

Understanding how genes influence drug responses is critical for advancing personalized cancer treatments. However, identifying these gene-drug interactions in a physiologically relevant human system remains a challenge, as it requires a model that reflects the complexity and heterogeneity among individuals. Here we show that large-scale CRISPR-based genetic screens, including knockout, interference (CRISPRi), activation (CRISPRa), and single-cell approaches, can be applied in primary human 3D gastric organoids to systematically identify genes that affect sensitivity to cisplatin. Our screens uncover genes that modulate cisplatin response. By combining CRISPR perturbations with single-cell transcriptomics, we resolve how genetic alterations interact with cisplatin at the level of individual cells and uncover an unexpected link between fucosylation and cisplatin sensitivity. We identify TAF6L as a regulator of cell recovery from cisplatin-induced cytotoxicity. These results highlight the utility of human organoid models for dissecting gene-drug interactions and offer insights into therapeutic vulnerabilities in gastric cancer.

Humans↗

PubMed2007

Wnt signaling and human diseases: what are the therapeutic implications?

Wnt signaling plays an important role in regulating cell proliferation and differentiation. De-regulation of these signaling pathways has been implicated in many human diseases, ranging from cancers to skeletal disorders. Wnt proteins are a large family of secreted factors that bind to the Frizzled receptors and LRP5/6 co-receptors and initiate complex signaling cascades. Over the past two decades, our understanding of Wnt signaling has been significantly improved due to the identification of many key regulators and mediators of these pathways. Given that Wnt signaling is tightly regulated at multiple cellular levels, these pathways themselves offer ample nodal points for targeted therapeutics. Here, we focus on our current understanding of these pathways, the associations of Wnt signaling with human disorders, and the opportunities to target key components of Wnt signaling for rational drug discovery.

Cell Differentiation↗

PubMed2006

Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation.

Endocytosis of Eph receptors is critical for a number of biological processes, including modulating axon growth cone collapse response and regulating cell surface levels of receptor in epithelial cells. In particular, ephrin-A ligand stimulation of tumor cells induces EphA2 receptor internalization and degradation, a process that has been explored as a means to reduce tumor malignancy. However, the mechanism and regulation of ligand-induced Eph receptor internalization are not well understood. Here we show that SHIP2 (Src homology 2 domain-containing phosphoinositide 5-phosphatase 2) is recruited to activated EphA2 via a heterotypic sterile alpha motif (SAM)-SAM domain interaction, leading to regulation of EphA2 internalization. Overexpression of SHIP2 inhibits EphA2 receptor endocytosis, whereas suppression of SHIP2 expression by small interfering RNA-mediated gene silencing promotes ligand-induced EphA2 internalization and degradation. SHIP2 regulates EphA2 endocytosis via phosphatidylinositol 3-kinase-dependent Rac1 activation. Phosphatidylinositol 3,4,5-trisphosphate levels are significantly elevated in SHIP2 knockdown cells, phosphatidylinositol 3-kinase inhibitor decreases phosphatidylinositol 3,4,5-trisphosphate levels and suppresses increased EphA2 endocytosis. Ephrin-A1 stimulation activates Rac1 GTPase, and the Rac1-GTP levels are further increased in SHIP2 knockdown cells. A dominant negative Rac1 GTPase effectively inhibited ephrin-A1-induced EphA2 endocytosis. Together, our findings provide evidence that recruitment of SHIP2 to EphA2 attenuates a positive signal to receptor endocytosis mediated by phosphatidylinositol 3-kinase and Rac1 GTPase.

Animals↗

PubMed2006

Search for invisible decays of eta and eta' in J/psi --> phi eta and phi eta'.

Using a data sample of 58 x 10(6) J/psi decays collected with the Beijing Spectrometer II detector at the Beijing Electron Positron Collider, searches for invisible decays of eta and eta' in J/psi to phi eta and phi eta' are performed. The phi signals, which are reconstructed in K+K- final states, are used to tag the eta and eta' decays. No signals are found for the invisible decays of either eta or eta', and upper limits at the 90% confidence level are determined to be 1.65 x 10(-3) for the ratio B(eta-->invisible)/B(eta --> gamma gamma) and 6.69 x 10(-2) for B(eta' --> invisible)/B(eta' --> gammagamma). These are the first searches for eta and eta' decays into invisible final states.

Journal Article↗

PubMed2006

Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice.

Ephrin-A1, the prototypic ligand for EphA receptor tyrosine kinases, is overexpressed in vascularized tumors relative to normal tissue. Moreover, ephrin-A1-Fc fusion proteins induce endothelial cell sprouting, migration, and assembly in vitro, and s.c. vascular remodeling in vivo. Based on these data, we hypothesized that native, membrane-bound ephrin-A1 regulates tumor angiogenesis and progression. We tested this hypothesis using a transplantable mouse mammary tumor model. Small interfering RNA-mediated ephrin-A1 knockdown in metastatic mammary tumor cells significantly diminishes lung metastasis without affecting tumor volume, invasion, intravasation, or lung colonization upon i.v. injection in vivo. Ephrin-A1 knockdown reduced tumor-induced endothelial cell migration in vitro and microvascular density in vivo. Conversely, overexpression of ephrin-A1 in nonmetastatic mammary tumor cells elevated microvascular density and vascular recruitment. Overexpression of ephrin-A1 elevated wild-type but not EphA2-deficient endothelial cell migration toward tumor cells, suggesting that activation of EphA2 on endothelial cells is one mechanism by which ephrin-A1 regulates angiogenesis. Furthermore, ephrin-A1 knockdown diminished, whereas overexpression of ephrin-A1 elevated, vascular endothelial growth factor (VEGF) levels in tumor cell-conditioned medium, suggesting that ephrin-A1-mediated modulation of the VEGF pathway is another mechanism by which membrane-tethered ephrin-A1 regulates angiogenic responses from initially distant host endothelium. These data suggest that ephrin-A1 is a proangiogenic signal, regulating VEGF expression and facilitating angiogenesis-dependent metastatic spread.

Adenocarcinoma↗

PubMed2006

Observation of a broad 1-- resonant structure around 1.5 GeV/c2 in the K+K- mass spectrum in J/psi-->K+K-pi0.

A broad peak is observed at low K+K- invariant mass in J/psi-->K+K-pi(0) decays found in a sample of 5.8x10(7) J/psi events collected with the BESII detector. The statistical significance of the broad resonance is much larger than 5sigma. A partial wave analysis shows that the J;{PC} of this structure is 1--. Its pole position is determined to be [1576(-55)(+49)(stat)-91+98(syst)] MeV/c(2)-i/2[818(-23)(+22)(stat)-133+64(syst)] MeV/c(2). These parameters are not compatible with any known meson resonances.

Journal Article↗

PubMed2006

Ezetimibe analogs with a reorganized azetidinone ring: Design, synthesis, and evaluation of cholesterol absorption inhibitions.

The underlying principle of drug design in this paper is that the maximum retention of the functional groups that exist in the marketed drug would provide a higher probability for comparable safety while the conformational changes in the newly created analogs should not constitute a significant structural variation to adversely affect biological activity. Four individual isomers of backbone re-organized ezetimibe analogs were designed and synthesized. Their effects on the cholesterol levels in rat serum were evaluated by a high-cholesterol and high-fat diet feeding experiment. All the new analogs showed significant effect in lowering the levels of total cholesterol in serum.

Absorption↗

PubMed2006

Measurements of the branching fractions for psi(3770)-->D(0)D[over ](0), D+D-, DD[over ], and the resonance parameters of psi(3770) and psi(2S).

We measure the branching fractions for psi(3770)-->D(0)D[over ](0), D+D-, DD[over ], and non-DD[over ] to be (46.7+/-4.7+/-2.3)%, (36.9+/-3.7+/-2.8)%, (83.6+/-7.3+/-4.2)%, and (16.4+/-7.3+/-4.2)%, respectively. The resonance parameters of psi(3770) and psi(2S) are measured to be M_(psi(3770))=3772.2+/-0.7+/-0.3 MeV, Gamma_(psi(3770))(tot)=26.9+/-2.4+/-0.3 MeV, and Gamma_(psi(3770))(ee)=251+/-26+/-11 eV; M_(psi(2S))=3685.5+/-0.0+/-0.3 MeV, Gamma_(psi(2S))(tot)=331+/-58+/-2 keV, and Gamma_(psi(2S))(ee)=2.330+/-0.036+/-0.110 keV. We also measure the light hadron R value to be R(uds)=2.262+/-0.054+/-0.109 in the energy region from 3.660 to 3.872 GeV.

Journal Article↗

PubMed2006

Observation of two new N* peaks in J/psi-->ppi-n and ppi+n decays.

The decay J/psi-->NNpi provides an effective isospin 1/2 filter for the piN system due to isospin conservation. Using 58x10(6) J/psi decays collected with the Beijing Electromagnetic Spectrometer at the Beijing Electron Positron Collider, more than 100 thousand J/psi-->ppi-n+c.c. events are obtained. Besides the two well-known N* peaks at around 1500 MeV/c2 and 1670 MeV/c2, there are two new, clear N* peaks in the ppi invariant mass spectrum around 1360 MeV/c2 and 2030 MeV/c2 with statistical significance of 11sigma and 13sigma, respectively. We identify these as the first direct observation of the N*(1440) peak and a long-sought missing N* peak above 2 GeV/c2 in the piN invariant mass spectrum.

Journal Article↗

PubMed2006

Genetic diversity and geographic differentiation in Tacca chantrieri (Taccaceae): an autonomous selfing plant with showy floral display.

BACKGROUND AND AIMS: Despite considerable investment in elaborate floral displays, Tacca chantrieri populations are predominantly selfing. It is hypothesized that this species might possess considerable spatial or temporal variation in outcrossing rates among populations. To test this hypothesis, genetic variability and genetic differentiation within and among T. chantrieri populations were investigated to find out if they are in agreement with expectations based on a predominantly inbred mating system. METHODS: Genetic diversity was quantified using inter-simple sequence repeats (ISSR) in 303 individuals from 13 populations taken from known locations of T. chantrieri in China, and from one population in Thailand. KEY RESULTS: Of the 113 primers screened, 24 produced highly reproducible ISSR bands. Using these primers, 160 discernible DNA fragments were generated, of which 145 (90.62 %) were polymorphic. This indicated considerable genetic variation at the species level. However, there were relatively low levels of polymorphism at population levels, with percentages of polymorphic bands (PPB) ranging from 8.75 % to 55 %. A high level of genetic differentiation among populations was detected based on different measures (Nei's genetic diversity analysis: G(ST) = 0.5835; AMOVA analysis: F(ST) = 0.6989). Furthermore, based on levels of genetic differentiation, the 14 populations clustered into two distinct groups separated by the Tanaka Line. CONCLUSIONS: High levels of differentiation among populations and low levels of diversity within populations at large spatial scales are consistent with earlier small-scale studies of mating patterns detected by allozymes which showed that T. chantrieri populations are predominantly selfing. However, it appears that T. chantrieri has a mixed-mating system in which self-fertilization predominates, but there is occasional outcrossing. Significant genetic differences between the two distinct regions might be attributed to vicariance along the Tanaka Line. Finally, possible mechanisms of geographic patterns based on genetic differentiation of T. chantrieri are discussed.

Dioscoreaceae↗

PubMed2006

Increasing confidence of protein interactomes using network topological metrics.

MOTIVATION: Experimental limitations in high-throughput protein-protein interaction detection methods have resulted in low quality interaction datasets that contained sizable fractions of false positives and false negatives. Small-scale, focused experiments are then needed to complement the high-throughput methods to extract true protein interactions. However, the naturally vast interactomes would require much more scalable approaches. RESULTS: We describe a novel method called IRAP* as a computational complement for repurification of the highly erroneous experimentally derived protein interactomes. Our method involves an iterative process of removing interactions that are confidently identified as false positives and adding interactions detected as false negatives into the interactomes. Identification of both false positives and false negatives are performed in IRAP* using interaction confidence measures based on network topological metrics. Potential false positives are identified amongst the detected interactions as those with very low computed confidence values, while potential false negatives are discovered as the undetected interactions with high computed confidence values. Our results from applying IRAP* on large-scale interaction datasets generated by the popular yeast-two-hybrid assays for yeast, fruit fly and worm showed that the computationally repurified interaction datasets contained potentially lower fractions of false positive and false negative errors based on functional homogeneity. AVAILABILITY: The confidence indices for PPIs in yeast, fruit fly and worm as computed by our method can be found at our website http://www.comp.nus.edu.sg/~chenjin/fpfn.

Animals↗

PubMed2006

The anti-nociceptive effect of BmK AS, a scorpion active polypeptide, and the possible mechanism on specifically modulating voltage-gated Na+ currents in primary afferent neurons.

In the present study, we investigated the anti-nociceptive effect and the underlying mechanism of BmK AS, an active peptide purified from scorpion Buthus martensi Karsch. The results showed that BmK AS can significantly relieve formalin-induced two-phase spontaneous flinching response and carrageenan-induced mechanical hyperalgesia. Using the whole-cell patch-clamp recording, exposure of acutely isolated sensory neurons to 500 nM BmK AS produced a one-fold decrease in the number of action potentials (APs) evoked by a ramp of depolarizing current. To investigate the mechanism of action of BmK AS, isolated membrane current and Ca2+ influx on rat primary sensory neurons were examined. BmK AS produced insignificant effect on voltage-dependent I(K) and KCl or caffeine-induced Ca2+ influx, but caused remarkable suppressive effect on tetrodotoxin-resistant (TTX-R) and tetrodotoxin-sensitive (TTX-S) I(Na). Further experiments showed that BmK AS reduced the peak TTX-R and TTX-S Na+ conductance in a dose-dependent manner, prompted the voltage-dependent activation, and caused a negative shift of the steady-state inactivation of TTX-R and TTX-S I(Na). Thus, the present results indicate the anti-nociceptive response of BmK AS may be ascribed to its specific modulation of voltage-gated Na+ channels of sensory neurons.

Action Potentials↗

PubMed2006

Observation of a near-threshold enhancement in the omega(phi) mass spectrum from the doubly OZI-suppressed decay J/psi-->gamma(omega)phi.

An enhancement near threshold is observed in the omega(phi) invariant mass spectrum from the doubly Okubo-Zweig-Iizuka-suppressed decays of J/psi-->gamma(omega)phi, based on a sample of 5.8 x 10(7) J/psi events collected with the BESII detector. A partial wave analysis shows that this enhancement favors JP=0+, and its mass and width are M=1812(+19)(-26)(stat)+/-18(syst) MeV/c2 and Gamma=105+/-20(stat)+/-28(syst) MeV/c2. The product branching fraction is determined to be B(J/psi-->gammaX)B(X-->omega(phi))=[2.61+/-0.27(stat)+/-0.65(syst)]x10(-4).

Journal Article↗

PubMed2006

Pathogenomic sequence analysis of Bacillus cereus and Bacillus thuringiensis isolates closely related to Bacillus anthracis.

Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis are closely related gram-positive, spore-forming bacteria of the B. cereus sensu lato group. While independently derived strains of B. anthracis reveal conspicuous sequence homogeneity, environmental isolates of B. cereus and B. thuringiensis exhibit extensive genetic diversity. Here we report the sequencing and comparative analysis of the genomes of two members of the B. cereus group, B. thuringiensis 97-27 subsp. konkukian serotype H34, isolated from a necrotic human wound, and B. cereus E33L, which was isolated from a swab of a zebra carcass in Namibia. These two strains, when analyzed by amplified fragment length polymorphism within a collection of over 300 of B. cereus, B. thuringiensis, and B. anthracis isolates, appear closely related to B. anthracis. The B. cereus E33L isolate appears to be the nearest relative to B. anthracis identified thus far. Whole-genome sequencing of B. thuringiensis 97-27and B. cereus E33L was undertaken to identify shared and unique genes among these isolates in comparison to the genomes of pathogenic strains B. anthracis Ames and B. cereus G9241 and nonpathogenic strains B. cereus ATCC 10987 and B. cereus ATCC 14579. Comparison of these genomes revealed differences in terms of virulence, metabolic competence, structural components, and regulatory mechanisms.

Amino Acids↗

PubMed2006

Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis.

Angiogenesis, the process by which new blood vessels are formed from preexisting vasculature, is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Prior studies from our laboratory demonstrate that the EphA2 receptor tyrosine kinase is a key regulator of angiogenesis in vivo. The EphA receptor-mediated angiogenic response is dependent on activation of Rho family GTPase Rac1 and is regulated by phosphatidylinositol 3-kinase. Here we report the identification of Vav2 and Vav3 as guanine nucleotide exchange factors (GEFs) that link the EphA2 receptor to Rho family GTPase activation and angiogenesis. Ephrin-A1 stimulation recruits the binding of Vav proteins to the activated EphA2 receptor. The induced association of EphA receptor and Vav proteins modulates the activity of Vav GEFs, leading to activation of Rac1 GTPase. Overexpression of either Vav2 or Vav3 in primary microvascular endothelial cells promotes Rac1 activation, cell migration, and assembly in response to ephrin-A1 stimulation. Conversely, loss of Vav2 and Vav3 GEFs inhibits Rac1 activation and ephrin-A1-induced angiogenic responses both in vitro and in vivo. In addition, embryonic fibroblasts derived from Vav2-/- Vav3-/- mice fail to spread on an ephrin-A1-coated surface and exhibit a significant decrease in the formation of ephrin-A1-induced lamellipodia and filopodia. These findings suggest that Vav GEFs serve as a molecular link between EphA2 receptors and the actin cytoskeleton and provide an important mechanism for EphA2-mediated angiogenesis.

Animals↗

PubMed2006

Mechanism underlying mitochondrial protection of asiatic acid against hepatotoxicity in mice.

Asiatic acid (AA) is one of the triterpenoid components of Terminalia catappa L., which has antioxidative, anti-inflammatory and hepatoprotective activity. This research focused on the mitochondrial protection of AA against acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) in mice. It was found that pretreatment with 25, 50 or 100 mg kg(-1) AA significantly blocked the LPS + D-GalN-induced increase in both serum aspartate aminotransferase (sAST) and serum alanine aminotransferase (sALT) levels, which was confirmed by ultrastructural observation under an electron microscope, showing improved nuclear condensation, ameliorated mitochondrion proliferation and less lipid deposition. Meanwhile, different doses of AA could decrease both the transcription and the translation level of voltage-dependent anion channels (VDACs), the most important mitochondrial PTP component protein, and block the translocation of cytochrome c from mitochondria to cytosol. On the other hand, pre-incubation with 25, 50 and 100 microg mL(-1) AA inhibited the Ca(2+)-induced mitochondrial permeability transition (MPT), including mitochondrial swelling, membrane potential dissipation and releasing of matrix Ca(2+) in liver mitochondria separated from normal mice, indicating the direct role of AA on mitochondria. Collectively, the above data suggest that AA could protect liver from damage and the mechanism might be related to up-regulating mitochondrial VDACs and inhibiting the process of MPT.

Alanine Transaminase↗

PubMed2006

Pancreatic islet production of vascular endothelial growth factor--a is essential for islet vascularization, revascularization, and function.

To investigate molecular mechanisms controlling islet vascularization and revascularization after transplantation, we examined pancreatic expression of three families of angiogenic factors and their receptors in differentiating endocrine cells and adult islets. Using intravital lectin labeling, we demonstrated that development of islet microvasculature and establishment of islet blood flow occur concomitantly with islet morphogenesis. Our genetic data indicate that vascular endothelial growth factor (VEGF)-A is a major regulator of islet vascularization and revascularization of transplanted islets. In spite of normal pancreatic insulin content and beta-cell mass, mice with beta-cell-reduced VEGF-A expression had impaired glucose-stimulated insulin secretion. By vascular or diffusion delivery of beta-cell secretagogues to islets, we showed that reduced insulin output is not a result of beta-cell dysfunction but rather caused by vascular alterations in islets. Taken together, our data indicate that the microvasculature plays an integral role in islet function. Factors modulating VEGF-A expression may influence islet vascularity and, consequently, the amount of insulin delivered into the systemic circulation.

Animals↗

PubMed2006

[Equivalent cardioprotective effect of "half-conditioning" and post-conditioning in a canine model of myocardial ischemia and reperfusion].

OBJECTIVE: To study the effects of "half-conditioning", a modified postconditioning process, on myocardial injury induced by severe myocardial ischemia/reperfusion (I/R) in anesthetized dogs. METHODS: Mongrel dogs of both sexes were subjected to 40 min ischemia (coronary blood flow reduced by 80% via controlled coronary stenosis). At the end of ischemia, dogs were randomly received one of the following treatments: (1) control, reperfusion for 3 h (n = 7); (2) post-conditioning, three cycles of ischemia 30 s followed by reperfusion for 30 s and then reperfusion for 3 h (n = 7); (3) half-conditioning, coronary blood flow recovered to 50% for 2 min, then 80% for 2 min, thereafter 100% for 3 h (n = 7). Electrocardiogram (ECG), arterial blood pressure and left ventricular pressure were monitored throughout the experiment. Plasma creatine kinase (CK) and lactate dehydrogenase (LDH) activity were measured spectrophotometrically. Myocardial necrosis was defined by TTC-staining. RESULTS: Compared with control animals, arrhythmia incidence, LVEDP at 2 and 3 h reperfusion, CK and LDH were significantly reduced in animals received post-conditioning and half-conditioning treatments, infarct size as a percentage (%) of the area at risk was also significantly reduced by post-conditioning and half-conditioning treatments. No differences were observed in the post-conditioning and half-conditioning groups. CONCLUSION: Half-conditioning exerts the same cardioprotective effects on post-ischemic hearts as postconditioning.

Animals↗