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Articles by Y Lu
Total Records ( 21 ) for Y Lu
  Y Min , W Xu , D Liu , S Shen , Y Lu , L Zhang and H. Wang
 

Dendritic cells (DCs) are important for the initiation of the adaptive immune response against Mycobacterium tuberculosis. Autophagy is an innate and adaptive defense mechanism and important for the control of M. tuberculosis. However, the role of autophagy in the adaptive immune response against M. tuberculosis remains to be determined. In the present study, we studied the effects of autophagy on the maturation of DCs infected with Bacillus Calmette–Guérin (BCG). The phenotype and function of the DCs were assessed by measuring the expression of CD86 and HLA-DR and the secretion of IL-10 and IL-6. Autophagy was evaluated by the change in LC3II, a molecular marker for autophagy. Following stimulation of autophagy, DCs that were matured in the presence of BCG showed enhanced expression of CD86 and HLA-DR and increased IL-6 production. The expression of LC3II was increased after the stimulation of autophagy. These results demonstrated that autophagy might result in the increased maturation of BCG-infected DCs, suggesting that autophagy could contribute to an enhanced adaptive immune response against M. tuberculosis.

  A. N Van Hoek , R Bouley , Y Lu , C Silberstein , D Brown , M. B Wax and R. V. Patil
 

Aquaporin-4 (AQP4) is a basolateral water channel in collecting duct principal cells and assembles into orthogonal array particles (OAPs), the size of which appears to depend on relative expression levels of AQP4 splice variants. Because the higher-order organization of AQP4 was perturbed by vasopressin in Brattleboro rats and phosphorylation sites have been identified on AQP4, we investigated whether vasopressin and forskolin (Fk) affect AQP4 assembly and/or expression in LLC-PK1 cells stably transfected with the AQP4 splice variant M23, which is responsible for formation of OAPs, and/or the splice variant M1, which does not form OAPs. Our data show that [lys8]-vasopressin (LVP) and Fk treatment led to differential increases in expression levels of M23-AQP4 and M1-AQP4 that varied as a function of incubation time. At early time points (day 1) expression of M1 was significantly stimulated (4.5-fold), over that of M23 (1.6-fold), but after 3 days the expression of M23 became predominant (4.1-fold) over that of M1 (1.9-fold). This pattern of stimulation was dependent on an intact AQP4 residue serine 111 and required protein synthesis. In cells expressing both M1 and M23 (M1/M23 ~ 1), with small sized OAPs at the membrane, the LVP/Fk-induced stimulation of M23 was modified and mimicked that of M1 when expressed alone, suggesting a dominant role for M1. In Brattleboro kidney inner medulla, an 8-day chronic exposure to the vasopressin agonist (dDAVP) led to reduction in M1 and a significant increase in M23 immunoblot staining (M1/M23 = 2/3 -> 1/4). These results indicate that AQP4 organization and expression are regulated by vasopressin in vivo and in vitro and demonstrate that the dominant role for M1 is restricted to a one-to-one interaction between AQP4 splice variants that regulates the membrane expression of OAPs.

  Y Lu , L Jia , S He , M. C Hurley , M. J Leys , T Jayasundera and J. R. Heckenlively
 

Objectives  To study 11 patients with melanoma-associated retinopathy (MAR) to clarify the reliability of various methods of diagnostic testing, to determine the underlying antigenic retinal proteins, and to study the clinical histories and types of associated melanomas.

Methods  Clinical data were obtained from patients with melanoma who developed marked visual problems. Testing included electroretinography, kinetic visual fields, comparative studies of Western blots, and indirect immunohistologic examination to detect antiretinal antibodies, as well as proteomic studies to identify underlying antigenic retinal proteins.

Results  Patients with MAR typically have rapid onset of photopsias, scotomata, and loss of central or paracentral vision. Ophthalmoscopy seldom shows significant changes early, but electroretinograms are abnormal. Results of Western blots and immunohistologic examination can show antiretinal antibodies but not always. Most patients (9 of 11) had a strong family history of autoimmune disorders. Any type of melanoma (cutaneous, choroidal, ciliary body, or choroidal nevi) may be associated with this paraneoplastic autoimmune reactivity. MAR may precede or follow the diagnosis of melanoma. Patients with MAR have the same antigenic retinal proteins that have been associated with cancer-associated retinopathy. In addition, 2 new antigenic retinal proteins, aldolase A and aldolase C, were found.

Conclusions  There was a high prevalence of positive family histories of autoimmune disease in patients with MAR. To confirm the disorder, multiple clinical and serum diagnostic techniques (Western blot or indirect immunohistologic examination) are needed. Two newly observed antigenic retinal proteins, aldolase A and aldolase C, are associated with MAR.

  Y Lu , P Huggins and Z. Bar Joseph
 

Motivation: Many biological systems operate in a similar manner across a large number of species or conditions. Cross-species analysis of sequence and interaction data is often applied to determine the function of new genes. In contrast to these static measurements, microarrays measure the dynamic, condition-specific response of complex biological systems. The recent exponential growth in microarray expression datasets allows researchers to combine expression experiments from multiple species to identify genes that are not only conserved in sequence but also operated in a similar way in the different species studied.

Results: In this review we discuss the computational and technical challenges associated with these studies, the approaches that have been developed to address these challenges and the advantages of cross-species analysis of microarray data. We show how successful application of these methods lead to insights that cannot be obtained when analyzing data from a single species. We also highlight current open problems and discuss possible ways to address them.

Contact: zivbj@cs.cmu.edu

  J. Y Tang , M Aszterbaum , M Athar , F Barsanti , C Cappola , N Estevez , J Hebert , J Hwang , Y Khaimskiy , A Kim , Y Lu , P. L So , X Tang , M. A Kohn , C. E McCulloch , L Kopelovich , D. R Bickers and E. H. Epstein
 

In vitro and epidemiologic studies favor the efficacy of nonsteroidal anti-inflammatory drugs (NSAID) in preventing skin squamous photocarcinogenesis, but there has been relatively little study of their efficacy in preventing the more common skin basal cell carcinoma (BCC) carcinogenesis. We first compared the relative anti-BCC effects of genetic deletion and NSAID pharmacologic inhibition of cyclooxygenase (COX) enzymes in the skin of Ptch1+/– mice. We then assessed the effects of celecoxib on the development of BCCs in a 3-year, double-blinded, randomized clinical trial in 60 (PTCH1+/–) patients with the basal cell nevus syndrome. In Ptch1+/– mice, genetic deletion of COX1 or COX2 robustly decreased (75%; P < 0.05) microscopic BCC tumor burden, but pharmacologic inhibition with celecoxib reduced microscopic BCCs less efficaciously (35%; P < 0.05). In the human trial, we detected a trend for oral celecoxib reducing BCC burden in all subjects (P = 0.069). Considering only the 60% of patients with less severe disease (<15 BCCs at study entry), celecoxib significantly reduced BCC number and burden: subjects receiving placebo had a 50% increase in BCC burden per year, whereas subjects in the celecoxib group had a 20% increase (Pdifference = 0.024). Oral celecoxib treatment inhibited BCC carcinogenesis in PTCH1+/– mice and had a significant anti-BCC effect in humans with less severe disease. Cancer Prev Res; 3(1); OF1–11

  W Chen , Y Luo , L Liu , H Zhou , B Xu , X Han , T Shen , Z Liu , Y Lu and S. Huang
 

Cryptotanshinone (CPT), a natural compound isolated from the plant Salvia miltiorrhiza Bunge, is a potential anticancer agent. However, little is known about its anticancer mechanism. Here, we show that CPT inhibited cancer cell proliferation by arresting cells in G1-G0 phase of the cell cycle. This is associated with the inhibition of cyclin D1 expression and retinoblastoma (Rb) protein phosphorylation. Furthermore, we found that CPT inhibited the signaling pathway of the mammalian target of rapamycin (mTOR), a central regulator of cell proliferation. This is evidenced by the findings that CPT inhibited type I insulin-like growth factor I– or 10% fetal bovine serum–stimulated phosphorylation of mTOR, p70 S6 kinase 1, and eukaryotic initiation factor 4E binding protein 1 in a concentration- and time-dependent manner. Expression of constitutively active mTOR conferred resistance to CPT inhibition of cyclin D1 expression and Rb phosphorylation, as well as cell growth. The results suggest that CPT is a novel antiproliferative agent. Cancer Prev Res; 3(8); 1015–25. ©2010 AACR.

  Y Lu , Y Zhang , N Wang , Z Pan , X Gao , F Zhang , H Shan , X Luo , Y Bai , L Sun , W Song , C Xu , Z Wang and B. Yang
  Background—

A characteristic of both clinical and experimental atrial fibrillation (AF) is atrial electric remodeling associated with profound reduction of L-type Ca2+ current and shortening of the action potential duration. The possibility that microRNAs (miRNAs) may be involved in this process has not been tested. Accordingly, we assessed the potential role of miRNAs in regulating experimental AF.

Methods and Results—

The miRNA transcriptome was analyzed by microarray and verified by real-time reverse-transcription polymerase chain reaction with left atrial samples from dogs with AF established by right atrial tachypacing for 8 weeks and from human atrial samples from AF patients with rheumatic heart disease. miR-223, miR-328, and miR-664 were found to be upregulated by >2 fold, whereas miR-101, miR-320, and miR-499 were downregulated by at least 50%. In particular, miR-328 level was elevated by 3.9-fold in AF dogs and 3.5-fold in AF patients relative to non-AF subjects. Computational prediction identified CACNA1C and CACNB1, which encode cardiac L-type Ca2+ channel 1c- and β1 subunits, respectively, as potential targets for miR-328. Forced expression of miR-328 through adenovirus infection in canine atrium and transgenic approach in mice recapitulated the phenotypes of AF, exemplified by enhanced AF vulnerability, diminished L-type Ca2+ current, and shortened atrial action potential duration. Normalization of miR-328 level with antagomiR reversed the conditions, and genetic knockdown of endogenous miR-328 dampened AF vulnerability. CACNA1C and CACNB1 as the cognate target genes for miR-328 were confirmed by Western blot and luciferase activity assay showing the reciprocal relationship between the levels of miR-328 and L-type Ca2+ channel protein subunits.

Conclusions—

miR-328 contributes to the adverse atrial electric remodeling in AF through targeting L-type Ca2+ channel genes. The study therefore uncovered a novel molecular mechanism for AF and indicated miR-328 as a potential therapeutic target for AF.

  T Hattori , J Chen , A. M. S Harding , M. P Price , Y Lu , F. M Abboud and C. J. Benson
 

Rationale: Acid-sensing ion channels (ASICs) are Na+ channels that are activated by acidic pH. Their expression in cardiac afferents and remarkable sensitivity to small pH changes has made them leading candidates to sense cardiac ischemia.

Objective: Four genes encode six different ASIC subunits, however it is not yet clear which of the ASIC subunits contribute to the composition of ASICs in cardiac afferents.

Methods and Results: Here, we labeled cardiac afferents using a retrograde tracer dye in mice, which allowed for patch-clamp studies of murine cardiac afferents. We found that a higher percentage of cardiac sensory neurons from the dorsal root ganglia respond to acidic pH and generated larger currents compared to those from the nodose ganglia. The ASIC-like current properties of the cardiac dorsal root ganglia neurons from wild-type mice most closely matched the properties of ASIC2a/3 heteromeric channels. This was supported by studies in ASIC-null mice: acid-evoked currents from ASIC3–/– cardiac afferents matched the properties of ASIC2a channels, and currents from ASIC2–/– cardiac afferents matched the properties of ASIC3 channels.

Conclusions: We conclude that ASIC2a and -3 are the major ASIC subunits in cardiac dorsal root ganglia neurons and provide potential molecular targets to attenuate chest pain and deleterious reflexes associated with cardiac disease.

  Z. Y Tan , Y Lu , C. A Whiteis , A. E Simms , J. F.R Paton , M. W Chapleau and F. M. Abboud
 

Rationale: Increased sympathetic nerve activity has been linked to the pathogenesis of hypertension in humans and animal models. Enhanced peripheral chemoreceptor sensitivity which increases sympathetic nerve activity has been observed in established hypertension but has not been identified as a possible mechanism for initiating an increase in sympathetic nerve activity before the onset of hypertension.

Objective: We tested this hypothesis by measuring the pH sensitivity of isolated carotid body glomus cells from young spontaneously hypertensive rats (SHR) before the onset of hypertension and their control normotensive Wistar–Kyoto (WKY) rats.

Methods and Results: We found a significant increase in the depolarizing effect of low pH in SHR versus WKY glomus cells which was caused by overexpression of 2 acid-sensing non–voltage-gated channels. One is the amiloride-sensitive acid-sensing sodium channel (ASIC3), which is activated by low pH and the other is the 2-pore domain acid-sensing K+ channel (TASK1), which is inhibited by low pH and blocked by quinidine. Moreover, we found that the increase in sympathetic nerve activity in response to stimulation of chemoreceptors with sodium cyanide was markedly enhanced in the still normotensive young SHR compared to control WKY rats.

Conclusions: Our results establish a novel molecular basis for increased chemotransduction that contributes to excessive sympathetic activity before the onset of hypertension.

  D. x Bu , V Rai , X Shen , R Rosario , Y Lu , V D'Agati , S. F Yan , R. A Friedman , E Nuglozeh and A. M. Schmidt
 

Rationale: The multiligand RAGE (receptor for advanced glycation end products) contributes to atherosclerosis in apolipoprotein (Apo)E-null mice.

Objective: To delineate the specific mechanisms by which RAGE accelerated atherosclerosis, we performed Affymetrix gene expression arrays on aortas of nondiabetic and diabetic ApoE-null mice expressing RAGE or devoid of RAGE at nine weeks of age, as this reflected a time point at which frank atherosclerotic lesions were not yet present, but that we would be able to identify the genes likely involved in diabetes- and RAGE-dependent atherogenesis.

Methods and Results: We report that there is very little overlap of the genes that are differentially expressed both in the onset of diabetes in ApoE-null mice, and in the effect of RAGE deletion in diabetic ApoE-null mice. Pathway-Express analysis revealed that the transforming growth factor-β pathway and focal adhesion pathways might be expected to play a significant role in both the mechanism by which diabetes facilitates the formation of atherosclerotic plaques in ApoE-null mice, and the mechanism by which deletion of RAGE ameliorates this effect. Quantitative polymerase chain reaction studies, Western blotting, and confocal microscopy in aortic tissue and in primary cultures of murine aortic smooth muscle cells supported these findings.

Conclusions: Taken together, our work suggests that RAGE-dependent acceleration of atherosclerosis in ApoE-null mice is dependent, at least in part, on the action of the ROCK1 (rho-associated protein kinase 1) branch of the transforming growth factor-β pathway.

  M. E Putt , S Hannenhalli , Y Lu , P Haines , H. R Chandrupatla , E. E Morrisey , K. B Margulies and T. P. Cappola
 

Background— Pathological stresses induce heart failure in animal models through activation of multiple cardiac transcription factors (TFs) working cooperatively. However, interactions among TFs in human heart failure are less understood. Here, we use genomic data to examine the evidence that 5 candidate TF families coregulate gene expression in human heart failure.

Methods and Results— RNA isolates from failing (n=86) and nonfailing (n=16) human hearts were hybridized with Affymetrix HU133A arrays. For each gene on the array, we determined conserved MEF2, NFAT, NKX , GATA , and FOX binding motifs within the –1-kb promoter region using human-murine sequence alignments and the TRANSFAC database. Across 9076 genes expressed in the heart, TF-binding motifs tended to cluster together in nonrandom patterns within promoters of specific genes (P values ranging from 10–2 to 10–21), suggesting coregulation. We then modeled differential expression as a function of TF combinations present in promoter regions. Several combinations predicted increased odds of differential expression in the failing heart, with the highest odds ratios noted for genes containing both MEF2 and NFAT binding motifs together in the same promoter region (peak odds ratio, 3.47; P=0.005).

Conclusions— These findings provide genomic evidence for coregulation of myocardial gene expression by MEF2 and NFAT in human heart failure. In doing so, they extend the paradigm of combinatorial regulation of gene expression to the human heart and identify new target genes for mechanistic study. More broadly, we demonstrate how integrating diverse sources of genomic data yields novel insight into human cardiovascular disorders.

  L Pourcel , N. G Irani , Y Lu , K Riedl , S Schwartz and E. Grotewold
 

Anthocyanins are flavonoid pigments that accumulate in the large central vacuole of most plants. Inside the vacuole, anthocyanins can be found uniformly distributed or as part of sub-vacuolar pigment bodies, the Anthocyanic Vacuolar Inclusions (AVIs). Using Arabidopsis seedlings grown under anthocyanin-inductive conditions as a model to understand how AVIs are formed, we show here that the accumulation of AVIs strongly correlates with the formation of cyanidin 3-glucoside (C3G) and derivatives. Arabidopsis mutants that fail to glycosylate anthocyanidins at the 5-O position (5gt mutant) accumulate AVIs in almost every epidermal cell of the cotyledons, as compared to wild-type seedlings, where only a small fraction of the cells show AVIs. A similar phenomenon is observed when seedlings are treated with vanadate. Highlighting a role for autophagy in the formation of the AVIs, we show that various mutants that interfere with the autophagic process (atg mutants) display lower numbers of AVIs, in addition to a reduced accumulation of anthocyanins. Interestingly, vanadate increases the numbers of AVIs in the atg mutants, suggesting that several pathways might participate in AVI formation. Taken together, our results suggest novel mechanisms for the formation of sub-vacuolar compartments capable of accumulating anthocyanin pigments.

  Y Lu and K. Morimoto
 

Alcohol drinking-derived acetaldehyde is believed to cross-link DNA and induce sister chromatid exchanges in peripheral blood lymphocytes. However, little population data are available to illustrate effects of alcohol-derived acetaldehyde on DNA migration as assayed by the comet assay in peripheral lymphocytes. In the present study, we investigated lifestyle behaviours, including alcohol consumption, in 150 Japanese males by questionnaire, determined their aldehyde dehydrogenase 2 (ALDH2) family genotypes by polymerase chain reaction and measured the DNA migration in peripheral blood leukocytes by the alkaline comet assay. The results showed that habitual alcohol drinking is significantly negatively associated with DNA migration in peripheral blood leukocytes (r = –0.321, P = 0.005) of ALDH2-deficient, but not of ALDH2-proficient genotypes (r = 0.048, P = 0.683). The amount of pure alcohol consumed per time by the subjects showed a similar phenomenon (r = –0.257, P = 0.025 for the ALDH2-deficient, but r = –0.061, P = 0.606 for the ALDH2-proficient genotype). Further stepwise multiple regression analysis showed that alcohol drinking frequency was a significant predictor of DNA migration for subjects with ALDH2-deficient genotype, but not for subjects with ALDH2-proficient genotype. In summary, the present result suggests that frequent alcohol drinking is significantly associated with a reduced electrophoretic DNA migration in peripheral blood leukocytes from ALDH2-deficient male Japanese subjects.

  L. D Kaplan , Y Lu , J Snitzer , B Nemke , Z Hao , S Biro , W Albiero , H. F Stampfli , M Markel , C Popkin and S. Z. Baum
  Background

Partial-thickness articular cartilage lesions occur with knee trauma and may progress to osteoarthritis. This study evaluates the effectiveness of hyaluronic acid on cartilage healing after acute knee injury in sheep.

Hypothesis

Early administration of hyaluronic acid to an acute cartilage injury will prevent chondrocyte death and improve cartilage metabolism.

Study Design

Controlled laboratory study.

Methods

A 10 x 10 mm partial-thickness articular cartilage lesion was created on the medial condyle of 16 adult sheep stifles (hindlimbs). Eight sheep received intra-articular hyaluronic acid injections at days 0, 8, and 15, and 8 controls received saline. Contralateral stifles were nonoperated controls. All sheep were sacrificed at 12 weeks after surgery. Synovial fluid was drawn before surgery and after euthanasia for collagen II, nitric oxide, and interleukin-1 beta analysis. The medial condyle was analyzed by gross appearance, confocal laser microscopy for cell viability, histologic analysis for cartilage morphology, and dimethylmethylene blue assay for proteoglycan.

Results

At 12 weeks, histologic analysis revealed that the hyaluronic acid group had significantly better scores than the saline group (P = .001). The hyaluronic acid group had significantly greater glycosaminoglycan content than the saline group (P = .011), and showed a trend of reduced chondrocyte death compared with the saline group (P = .07). Synovial fluid showed no significant differences between the groups in collagen II, nitric oxide, and interleukin-1 beta levels.

Conclusion

The results demonstrated that early administration of hyaluronic acid shows a significant improvement in cartilage histologic analysis and increased glycosaminoglycan content after acute traumatic cartilage injury.

Clinical Relevance

Early hyaluronic acid treatment for acute partial-thickness articular cartilage lesions may decrease or delay articular degeneration.

  S. G Rolland , Y Lu , C. N David and B. Conradt
 

The mammalian dynamin-related guanosine triphosphatases Mfn1,2 and Opa1 are required for mitochondrial fusion. However, how their activities are controlled and coordinated is largely unknown. We present data that implicate the BCL-2–like protein CED-9 in the control of mitochondrial fusion in Caenorhabditis elegans. We demonstrate that CED-9 can promote complete mitochondrial fusion of both the outer and inner mitochondrial membrane. We also show that this fusion is dependent on the C. elegans Mfn1,2 homologue FZO-1 and the C. elegans Opa1 homologue EAT-3. Furthermore, we show that CED-9 physically interacts with FZO-1 in vivo and that the ability of CED-9 to interact with FZO-1 is important for its ability to cause mitochondrial fusion. CED-9–induced mitochondrial fusion is not required for the maintenance of mitochondrial morphology during embryogenesis or in muscle cells, at least under normal conditions and in the absence of stress. Therefore, we propose that the BCL-2–like CED-9 acts through FZO-1/Mfn1,2 and EAT-3/Opa1 to promote mitochondrial fusion in response to specific cellular signals.

 
 
 
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