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Yi Zhao - Top 30 Publications

Expression and correlation analysis of RegIV and vascular endothelial growth factors (VEGF-A and VEGF-C) in metastatic spinal tumors.

The expression and correlation analysis of the regenerating gene family member 4 (RegIV) and vascular endothelial growth factors (VEGF-A and VEGF-C) in metastatic spinal tumors were studied. Fifteen patients with metastatic spinal tumors who underwent operation in our hospital from January 2011 to January 2013 were selected into this study. The expression level of tumor tissues in patients with spinal metastasis and RegIV, VEGF-A and VEGF-C of the corresponding paracancer normal tissue samples were evaluated by immunohistochemical staining method and the correlation between the expression of RegIV, VEGF-A and VEGF-C was analyzed. qRT-PCR results showed that the expression of RegIV was increased (P<0.05) in paracancer normal tissues and spinal metastatic tumor tissues. Compared with normal tissues, expression of RegIV, VEGF-A and VEGF-C was higher in metastatic spinal tumor tissues and the difference had statistical difference (P<0.05). Spearman's correlation analysis showed that the expression of RegIV was positively correlated with VEGF-A (r=0.683, P<0.05); the expression of RegIV positively correlated with VEGF-C (r=0.717, P<0.05). Cox regression analysis showed that RegIV, VEGF-A, VEGF-C expression and microvessel density counts are prognostic factors affecting spine metastasis (P<0.05), RegIV expression affected the survival of patients with relative risk. The high expression of RegIV in spinal metastatic tumors may promote the expression of VEGF-A and VEGF-C to increase the microvascular density, promote angiogenesis, and accelerate the occurrence and progression of spinal metastatic tumors.

Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11β hydroxysteroid dehydrogenase type 1 inhibitor.

A potent, in vivo efficacious 11β hydroxysteroid dehydrogenase type 1 (11β HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11β HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.

Cervical spine involvement risk factors in rheumatoid arthritis: a meta-analysis.

This study aims to discuss risk factors associated with cervical spine involvement (CSI) in patients with rheumatoid arthritis (RA).

Dynamic model of vascular-targeted photodynamic therapy.

Vascular-targeted photodynamic therapy has shown efficiency in treating port wine stains. A dynamic model that incorporates blood flow, kinetic diffusion, oxygen and photosensitizer consumption and reaction, and light modulation is proposed to reveal the interactions among light, photosensitizer, and oxygen. Simulation results show that pulse light modulation synchronized with heartbeats hold the advantage of increased singlet oxygen accumulation, higher oxygen concentration and lower temperature. Meanwhile, constant light treatment is advantageous in terms of higher temperature, lower total oxygen concentration and singlet oxygen accumulation. Therefore, the optimized treatment protocol may involve a balance among the phototoxicity, hypoxia, and photothermolysis.

Expression of YAP/TAZ in Keratocystic Odontogenic Tumors and Its Possible Association with Proliferative Behavior.

The aim of this study is to clarify whether YAP/TAZ is involved in the pathogenesis and proliferative growth of keratocystic odontogenic tumor (KCOT). The expression levels of YAP/TAZ and downstream proteins and genes in normal oral mucosa (OM) and KCOT were determined and compared by immunohistochemistry and real-time quantitative PCR. The results showed that the expression of YAP/TAZ and downstream proteins (Cyr61, CTGF) was significantly upregulated in KCOT with upregulation of Ki-67 compared to OM. Importantly, the mRNA levels of transcription factors (TEAD1, TEAD4, and RUNX2) and cell cycle related genes (CDK2, PCNA), which interact with the transcriptional coactivators YAP/TAZ, are also upregulated in the KCOT. In addition, the results from Spearman rank correlation test revealed the close relationship between YAP/TAZ and Ki-67, which was further evidenced by double-labelling immunofluorescence that revealed a synchronous distribution for YAP/TAZ with Ki-67 in KCOT samples. All the data suggested YAP/TAZ might be involved in the proliferative behavior of KCOT.

Inosine Released from Dying or Dead Cells Stimulates Cell Proliferation via Adenosine Receptors.

Many antitumor therapies induce apoptotic cell death in order to cause tumor regression. Paradoxically, apoptotic cells are also known to promote wound healing, cell proliferation, and tumor cell repopulation in multicellular organisms. We aimed to characterize the nature of the regenerative signals concentrated in the micromilieu of dead and dying cells.

Ampicillin-incorporated alginate-chitosan fibers from microfluidic spinning and for vitro release.

The fibrous drug-loading capability, degradation profile, drug release behavior and mechanical performance were found to be controlled by regulating the amount of IPA and chitosan, which delayed the degradable time-scale and improved the drug loading capacity. Six types of alginate fibers were spun by combining two distinct core flows with deionized water-based, ethanol-based and isopropyl alcohol-based sheath fluid, respectively. The as prepared fibers were analyzed and compared by the characterization of SEM, mass loss, ICP, FTIR, XRD, UV, mechanics performance testing and antibacterial activity tests. The results showed that fibers in the isopropyl alcohol with low polarity sheath flow exhibited higher-ordered structure. Also, incorporation of chitosan for the core stream strengthened the degree of crosslinking among the molecular chain, and thus made the fiber entrapped more drug of ampicillin molecular. The fibers, possessing superior mechanical properties, preferable drug loading capability, more prolonged drug release behavior and outstanding antibiotic activity, may offer a promising candidate for biomaterials, such as fibrous drug carrier and antibacterial sutures.

Small molecule p300/catenin antagonist enhances hematopoietic recovery after radiation.

There is currently no FDA approved therapeutic agent for ARS mitigation post radiation exposure. Here we report that the small molecule YH250, which specifically antagonizes p300/catenin interaction, stimulates hematopoiesis in lethally or sublethally irradiated mice. A single administration of YH250 24 hours post irradiation can significantly stimulate HSC proliferation, improve survival and accelerate peripheral blood count recovery. Our studies suggest that promotion of the expansion of the remaining HSC population via stimulation of symmetric non-differentiative proliferation is at least part of the mechanism of action.

Podocyte-specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury.

Podocytes play an important role in maintaining glomerular function, and podocyte injury is a significant component in the pathogenesis of proteinuria. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme whose genetic deficiency and pharmacological inhibition have beneficial effects on renal function, but its role in podocytes remains unexplored. The objective of this study was to investigate the contribution of sEH in podocytes to lipopolysaccharide (LPS)-induced kidney injury. We report increased sEH transcript and protein expression in murine podocytes upon LPS challenge. To determine the function of sEH in podocytes in vivo we generated podocyte-specific sEH-deficient (pod-sEHKO) mice. Following LPS challenge, podocyte sEH-deficient mice exhibited lower kidney injury, proteinuria, and blood urea nitrogen concentrations than controls suggestive of preserved renal function. Also, renal mRNA and serum concentrations of inflammatory cytokines IL-6, IL-1β and TNFα were significantly lower in LPS-treated pod-sEHKO than control mice. Moreover, podocyte sEH deficiency was associated with decreased LPS-induced NF-κB and MAPK activation and attenuated endoplasmic reticulum stress. Further, the protective effects of podocyte sEH deficiency in vivo were recapitulated in E11 murine podocytes treated with a selective sEH pharmacological inhibitor. Altogether, these findings identify sEH in podocytes as a contributor to signaling events in acute renal injury and suggest that sEH inhibition may be of therapeutic value in proteinuria. This article is protected by copyright. All rights reserved.

Structural insights into the binding of buckwheat glutaredoxin with GSH and regulation of its catalytic activity.

Glutaredoxins (Grxs) are ubiquitous thioltransferases and members of the thioredoxin (Trx) fold superfamily. They have multiple functions in cells including oxidative stress responses and cell signaling. A novel glutaredoxin from buckwheat (rbGrx) with higher catalytic activity was identified, cloned, and purified. The structures of glutathionylated rbGrx and an rbGrx mutant, in which cysteine 39 was mutated to alanine, were solved by x-ray diffraction at a resolution of 2.05Å and 2.29Å, respectively. In rbGrx, GSH (glutathione) is bound at the conserved GSH-binding site, and its structure shows that it has the potential to function as a scaffold protein for the assembly and delivery of GSH. The crystal structure shows that GSH does not bind to the C39A rbGrx mutant, and the C39A mutant had no catalytic activity, indicating that C39 is a key residue that is involved in both the binding of rbGrx to GSH and the regulation of its catalytic activity. The model showing the binding of GSH with rbGrx provides a basis for understanding its molecular function and its potential future applications in medicinal food science.

Hierarchy of stochastic Schrödinger equation towards the calculation of absorption and circular dichroism spectra.

A theoretically solid and numerically exact method is presented for the calculation of absorption and circular dichroism (CD) spectra of molecular aggregates immersed in a harmonic bath constituted as the combination of some prominent quantized vibrational modes and continuous overdamped Brownian oscillators. The feasibility and the validity of newly proposed method are affirmed in the analytical monomer spectra. To go beyond the independent local bath approximation, all the correlations of site energy fluctuations and excitonic coupling fluctuations are included in our strategy, and their influence on the absorption and CD spectra is investigated based on the Frenkel exciton model of homodimer. In the end, a good fit of the absorption and part of CD spectra for the entire B800-B850 ring in the light-harvesting complexes 2 of purple bacteria to the experimental data is given, and the simulation results suggest that the asymmetry in the 800 nm region of CD spectra is actually an indication of B800-B850 inter-ring coupling.

Disrupted-in-Schizophrenia-1 (DISC1) protein disturbs neural function in multiple disease-risk pathways.

Although the genetic contribution is under debate, biological studies in multiple mouse models have suggested that the Disrupted-in-Schizophrenia-1 (DISC1) protein may contribute to susceptibility to psychiatric disorders. In the present study, we took the advantages of Drosophila model to dissect molecular pathways that can be affected by DISC1 in the context of pathology-related phenotypes. We found that three pathways that include the homologs of Drosophila Dys, Trio, and Shot were downregulated by introducing a C-terminal truncated mutant DISC1. Consistently, these three molecules were downregulated in the induced pluripotent stem cell-derived forebrain neurons from the subjects carrying a frameshift deletion in DISC1 C-terminus. Importantly, the three pathways were underscored in the pathophysiology of psychiatric disorders in bioinformatics analysis. Taken together, our findings are in line with the polygenic theory of psychiatric disorders.

Vernodalol enhances TRAIL-induced apoptosis in diffuse large B-cell lymphoma cells.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent anti-tumor agent that triggers apoptosis in cells from multiple types of carcinoma but not in normal cells. However, diverse mechanisms are associated with insensitivity to TRAIL in various cancers. TRAIL efficacy may be enhanced by combining TRAIL with a sensitizer. In this study, vernodalol, a sesquiterpene lactone, sensitized diffuse large B-cell lymphoma (DLBCL) cells to TRAIL-induced apoptosis. Vernodalol increased the expression of death receptor (DR) 5, and silencing of DR5 with a small interfering RNA (siRNA) reduced the effect of vernodalol on TRAIL-mediated apoptosis. Additionally, vernodalol up-regulated the expression of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), a transcription factor. Inhibition of CHOP with a siRNA diminished DR5 expression and vernodalol-induced sensitization to the TRAIL treatment. In addition, a c-Jun N-terminal kinase (JNK) inhibitor blocked the vernodalol-induced up-regulation of DR5, indicating that the effect depended on JNK activation. Furthermore, the down-regulation of induced myeloid leukaemia cell differentiation protein (Mcl-1) played an important role in vernodalol/TRAIL-induced apoptosis, as Mcl-1 overexpression prevented this apoptotic effect. Moreover, the vernodalol/TRAIL combination inhibited tumor growth in a xenograft model. Based on our results, vernodalol enhanced TRAIL-induced apoptosis by down-regulating Mcl-1 and up-regulating DR5, and the effects of DR5 depended on JNK activation and CHOP induction. Therefore, combining TRAIL with vernodalol, a naturally occurring agent, may represent a promising therapeutic approach for DLBCL.

Berberine displays antitumor activity in esophageal cancer cells in vitro.

To investigate the effects of berberine on esophageal cancer (EC) cells and its molecular mechanisms.

Land scale biogeography of arsenic biotransformation genes in estuarine wetland.

As an analog of phosphorus, arsenic (As) has a biogeochemical cycle coupled closely with other key elements on the Earth, such as iron, sulfate and phosphate. It has been documented that microbial genes associated with As biotransformation are widely present in As-rich environments. Nonetheless, their presence in natural environment with low As levels remains unclear. To address this issue, we investigated the abundance levels and diversities of aioA, arrA, arsC and arsM genes in estuarine sediments at low As levels across Southeastern China to uncover biogeographic patterns at a large spatial scale. Unexpectedly, genes involved in As biotransformation were characterized by high abundance and diversity. The functional microbial communities showed a significant decrease in similarity along the geographic distance, with higher turnover rates than taxonomic microbial communities based on the similarities of 16S rRNA genes. Further investigation with niche-based models showed that deterministic processes played primary roles in shaping both functional and taxonomic microbial communities. Temperature, pH, total nitrogen concentration, carbon/nitrogen ratio and ferric iron concentration rather than As content in these sediments were significantly linked to functional microbial communities, while sediment temperature and pH were linked to taxonomic microbial communities. We proposed several possible mechanisms to explain these results. This article is protected by copyright. All rights reserved.

Study of recombinant human interleukin-12 for treatment of complications after radiotherapy for tumor patients.

To evaluate the treatment effects of recombinant human interleukin-12 (rhIL-12) on radiotherapy complications, such as severe myelosuppression or pancytopenia, the decline or imbalance of immune function, etc.

Multiband selective absorbers made of 1D periodic Ag/SiO<sub>2</sub>/Ag core/shell coaxial cylinders horizontally lying on a planar substrate.

In this paper, we present a one-dimensional periodic microstructure for multiband selective absorbers of thermal radiation. The microstructure is made of Ag/SiO<sub>2</sub>/Ag core/shell coaxial cylinders horizontally lying on top of a SiO<sub>2</sub> dielectric spacer and an opaque silver substrate. The spectral-directional absorptivity of the proposed structure was numerically investigated with the finite element based Comsol Multiphysics software. Multiband selective absorption in the wavenumber range from 2500 to 20000 cm<sup>-1</sup> for TM-wave incidence was obtained. Physical mechanisms responsible for the multiband selective absorption were elucidated due to the resonance of magnetic polaritons in the SiO<sub>2</sub> spacer shell, excitation of surface plasmon polaritons at the SiO<sub>2</sub>/Ag interface, and the effect of Wood's anomaly. Furthermore, the effects of a silver core radius, spacer shell thickness, a confocal elliptical core/shell cylinder on the property of multiband absorption, and the absorptivity of the structure with one core/four shells coaxial cylinders were explored.

Varied pathological and therapeutic response effects associated with CHCHD2 mutant and risk variants.

Mutations and polymorphic risk variant of coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) have been associated with late-onset Parkinson disease. In vivo pathological evidence of CHCHD2 mutations is currently lacking. Utilizing transgenic Drosophila model, we examined the relative pathophysiologic effect of the pathogenic (c.182C>T, p.Thr61Ile and c.434G>A, p.Arg145Gln) and the risk (c.5C>T, p.Pro2Leu) CHCHD2 variants. All the transgenic models exhibited locomotor dysfunction which could be exacerbated by rotenone exposure, dopaminergic neuron degeneration, reduction in lifespan, mitochondrial dysfunction, oxidative stress and impairment in synaptic transmission. However, both mutants showed more severe early motor dysfunction, dopaminergic neuronal loss and higher hydrogen peroxide production compared to risk variant. p.Thr61Ile (co-segregated in three independent PD families) displayed the most severe phenotype followed by p.Arg145Gln (present only in index patient). We treated the transgenic flies with Ebselen, a mitochondrial hydrogen peroxide scavenger compound and Ebselen appears to be more effective in ameliorating motor function in the mutant than the risk variant models. We provide the first in vivo evidence of the pathological effects associated with CHCHD2 mutations. There was a difference in the pathological and drug response effects between the pathogenic and the risk variants. Ebselen may be a useful neuroprotective drug for carriers of CHCHD2 mutations. This article is protected by copyright. All rights reserved.

A genome-wide association study identifies six novel risk loci for primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

The long non-coding RNA NONHSAG026900 predicts prognosis as a favorable biomarker in patients with diffuse large B-cell lymphoma.

Long non-coding RNAs are known to be involved in cancer progression, but their biological functions and prognostic values are still largely unexplored in diffuse large B-cell lymphoma. In this study, long non-coding RNAs expression was characterized in 1,403 samples including normal and diffuse large B-cell lymphoma by repurposing 7 microarray datasets. Compared with any stage of normal B cells, NONHSAG026900 expression was significantly decreased in tumor samples. And in germinal center B-cell subtype, the significantly higher expression of NONHSAG026900 indicated it was a favorable prognosis biomarker. Then the prognostic power of NONHSAG026900 was validated with another independent dataset and NONHSAG026900 improved the predictive power of International Prognostic Index as an independent factor. Moreover, functional prediction and validation demonstrated that NONHSAG026900 could inhibit cell cycle activity to restrain tumor proliferation. These findings identified NONHSAG026900 as a novel prognostic biomarker and offered a new therapeutic target for diffuse large B-cell lymphoma patients.

Elevated levels of TL1A are associated with disease activity in patients with systemic sclerosis.

TL1A is a member of the TNF superfamily. It performs significantly in the pathogenesis of rheumatic and autoimmune diseases partly through regulating the Th17 pathway. The clinical implication of circulating TL1A in patients with systemic sclerosis (SSc) remains unclear, and correlation between TL1A and Th17-related cytokines in the pathogenesis of SSc needs to be discussed. We measured serum levels of TL1A and Th17-related cytokines by ELISA in 47 patients with SSc, 56 patients with SLE, and 53 healthy subjects, and investigated association of these cytokines with clinical manifestations and laboratory variables. TL1A in relation to Th17-related cytokines were examined. In addition, the transcript level of TL1A in peripheral blood mononuclear cells (PBMCs) was determined by real-time reverse transcription polymerase chain reaction (real-time PCR). Serum TL1A levels were higher in patients with SSc than in healthy controls (P = 0.001), but were lower compared with SLE patients (P = 0.004). Diffuse cutaneous SSc or limited cutaneous SSc patients reported elevated expression of TL1A than those in healthy controls (P = 0.002, P = 0.007). Patients with active disease showed significantly higher expression of TL1A when compared with less active disease (P = 0.014). SSc patients with arthritis, elevated IgG titer, ESR >30 mm/h, and CRP >5 mg/l displayed elevated expression of TL1A, respectively. Serum levels of IL-17 and IL-21 were increased in SSc patients compared with healthy controls and positively related to TL1A levels (r s = 0.373, P = 0.010; r s = 0.370, P = 0.011, respectively). Moreover, TL1A mRNA expression in PBMCs was significantly higher in patients with SSc compared with healthy controls (P < 0.001). TL1A may play a role in the development of SSc.

AZD0530 sensitizes drug-resistant ALK-positive lung cancer cells by inhibiting SRC signaling.

Most tumors develop resistance to targeted cancer drugs, even though these drugs have produced substantial clinical responses. Here we established anaplastic lymphoma kinase (ALK)-positive drug-resistant lung cancer cell lines, which are resistant to ceritinib (LDK378). We found that ceritinib treatment resulted in robust upregulation of SRC activity, as measured by the phosphorylation of the SRC substrate paxillin. Knockdown of SRC alone with siRNA effectively sensitized ceritinib resistance in ALK-positive cells. Furthermore, SRC inhibition by AZD0530 was effective in ALK-resistant cancer cells. Thus, ALK inhibition by ceritinib may lead to upregulation of SRC signaling, and AZD0530 could serve as a potential drug in the clinic to treat ALK-resistant lung cancer patients.

Generation of a human induced pluripotent stem cell (iPSC) line carrying the Parkinson's disease linked LRRK2 variant S1647T.

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 64-year old male Parkinson's disease (PD) patient with S1647T variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model will be useful for further function studies and therapeutic screening.

Development of a human induced pluripotent stem cell (iPSC) line from a Parkinson's disease patient carrying the N551K variant in LRRK2 gene.

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 64-year old male Parkinson's disease (PD) patient with N551K variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model can complement in vivo PD models for pathophysiological studies and drug screening.

Derivation of human induced pluripotent stem cell (iPSC) line with LRRK2 gene R1398H variant in Parkinson's disease.

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 72-year old female Parkinson's disease (PD) patient with R1398H variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model provides a good platform for studying the mechanism of PD, and also for drug testing and gene therapy studies.

Reprogramming of a human induced pluripotent stem cell (iPSC) line from a Parkinson's disease patient with a R1628P variant in the LRRK2 gene.

Peripheral blood mononuclear cells (PBMCs) were collected from a clinically diagnosed 59-year old male Parkinson's disease (PD) patient with R1628P variant in the LRRK2 gene. The PMBCs were reprogrammed with the human OSKM transcription factors using the Sendai-virus reprogramming system. The transgene-free iPSC showed pluripotency confirmed by immunofluorescent staining for pluripotency markers and differentiated into the 3 germ layers in vivo. The iPSC line also showed normal karyotype. This cellular model will provide a good resource for further pathophysiological studies of PD.

Astragaloside IV inhibits PMA-induced EPCR shedding through MAPKs and PKC pathway.

Astragaloside IV (AS-IV), a main active substance isolated from Astragalus membranaceus Bunge, has been shown to have multiple pharmacological effects. Endothelial cell protein C receptor (EPCR) is a marker of inflammation, and is also a major member of protein C (PC) anti-coagulation system. EPCR can be cut off from the cell surface by tumor necrosis factor-α converting enzyme (TACE), which is controlled through mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) pathways. To develop novel therapeutic drug for EPCR shedding, the effect of AS-IV was studied in phorbol-12-myristate 13-acetate (PMA)-induced human umbilical vein endothelial cells (HUVECs) and the potential molecular mechanism of AS-IV action was investigated. The results showed that AS-IV could significantly inhibit PMA-induced EPCR shedding. In further study, AS-IV suppressed the expression and activity of TACE. In addition, AS-IV could decrease the phosphorylation of MAPK such as janus kinase (JNK) and p38, and inhibit activation of PKC through the prevention of non-phosphorylation and phosphorylation of specific PKC isoforms in PMA-stimulated HUVECs. These findings indicate that AS-IV may be used as a natural medicine to treat EPCR-related systemic inflammation and cardiovascular diseases by targeting MAPK and PKC pathway.

Mechanism of immune evasion in breast cancer.

Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body's immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail.

Bilirubin augments Ca(2+) load of developing bushy neurons by targeting specific subtype of voltage-gated calcium channels.

Neonatal brain is particularly vulnerable to pathological levels of bilirubin which elevates and overloads intracellular Ca(2+), leading to neurotoxicity. However, how voltage-gated calcium channels (VGCCs) are functionally involved in excess calcium influx remains unknown. By performing voltage-clamp recordings from bushy cells in the ventral cochlear nucleus (VCN) in postnatal rat pups (P4-17), we found the total calcium current density was more than doubled over P4-17, but the relative weight of VGCC subtypes changed dramatically, being relatively equal among T, L, N, P/Q and R-type at P4-6 to predominantly L, N, R over T and P/Q at P15-17. Surprisingly, acute administration of bilirubin augmented the VGCC currents specifically mediated by high voltage-activated (HVA) P/Q-type calcium currents. This augment was attenuated by intracellular loading of Ca(2+) buffer EGTA or calmodulin inhibitory peptide. Our findings indicate that acute exposure to bilirubin increases VGCC currents, primarily by targeting P/Q-type calcium channels via Ca(2+) and calmodulin dependent mechanisms to overwhelm neurons with excessive Ca(2+). Since P/Q-subtype calcium channels are more prominent in neonatal neurons (e.g. P4-6) than later stages, we suggest this subtype-specific enhancement of P/Q-type Ca(2+) currents likely contributes to the early neuronal vulnerability to hyperbilirubinemia in auditory and other brain regions.

Characterization of the B Cell Receptor Repertoire in the Intestinal Mucosa and of Tumor-Infiltrating Lymphocytes in Colorectal Adenoma and Carcinoma.

The B cells inhabited in mucosa play a vital role in mediating homeostasis with autoantigens and external Ags. Tumor-infiltrating lymphocytes are potential prognostic markers and therapeutic agents for cancer. However, the spatial heterogeneity of the B cell repertoire in intestinal mucosa and the tumor-infiltrating lymphocytes in colorectal cancer (CRC) remain poorly understood. In this study, we developed an unbiased method to amplify the IgH repertoire, as well as a bioinformatic pipeline to process these high-throughput sequencing data. With biopsies from seven intestinal mucosal segments, we uncovered their strong spatial homogeneity among the large intestine, where the clone overlap rate was up to 62.21%. The heterogeneity between terminal ileum and large intestine was also observed, including discrepant isotype distribution and low clone overlap rate. With tumor and adjacent normal mucosal tissues from CRC and colorectal advanced adenoma (AD) patients, we observed a similar IgH profile between tumor and adjacent normal mucosal tissues in AD, as well as a slight difference in CRC. Interestingly, we found distinct repertoire properties in the CRC tumor from AD and normal mucosa. Finally, we identified 1445 public clones for the normal mucosa, and 22 public clones for the CRC tumor with characteristic features. These data may be of potential use in clinical prognosis, diagnosis, and treatment of CRC.