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Articles by R Zhao
Total Records ( 11 ) for R Zhao
  H Zhao , Y Wang , Y Wu , X Li , G Yang , X Ma , R Zhao and H. Liu
 

Hyperlipidemia is regarded as an independent risk factor in the development of ischemic heart disease, and it can increase the myocardial susceptibility to ischemia/reperfusion (I/R) injury. Ischemic postconditioning (Postcon) has been demonstrated to attenuate the myocardial injury induced by I/R in normal conditions. But the effect of ischemic Postcon on hyperlipidemic animals is unknown. Hypoxia inducible factor-1 (HIF-1) has been demonstrated to play a central role in the cardioprotection by preconditioning, which is one of the protective strategies except for Postcon. The aim of this study was to determine whether Postcon could reduce myocardial injury in hyperlipidemic animals and to assess whether HIF-1 was involved in Postcon mechanisms. Male Wistar rats underwent the left anterior descending coronary occlusion for 30 min followed by 180 min of reperfusion with or without Postcon after fed with high fat diet or normal diet for 8 weeks. The detrimental indices induced by the I/R insult included infarct size, plasma creatine kinase activity and caspase-3 activity. Results showed that hyperlipidemia remarkably enhanced the myocardial injury induced by I/R, while Postcon significantly decreased the myocardial injury in both normolipidemic and hyperlipidemic rats. Moreover, both hyperlipidemia and I/R promoted the HIF-1 expression. Most importantly, we have for the first time demonstrated that Postcon further induced a significant increase in HIF-1 protein level not only in normolipidemic but also in hyperlipidemic conditions. Thus, Postcon reduces the myocardial injury induced by I/R in normal and hyperlipidemic animals, and HIF-1 upregulation may involve in the Postcon-mediated cardioprotective mechanisms.

  C. Y. Y Yip , J. H Chen , R Zhao and C. A. Simmons
 

Objective— Extensive remodeling of the valve ECM in calcific aortic valve sclerosis alters its mechanical properties, but little is known about the impact of matrix mechanics on the cells within the valve interstitium. In this study, the influence of matrix stiffness in modulating calcification by valve interstitial cells (VICs), and their differentiation to pathological phenotypes was assessed.

Methods and Results— Primary porcine aortic VICs were cultured in standard media or calcifying media on constrained type I fibrillar collagen gels. Matrix stiffness was altered by changing only the thickness of the gels. Calcification did not occur in standard media, regardless of matrix stiffness. However, when VICs were grown in calcifying media on relatively compliant matrices with stiffness similar to that of normal tissue, they readily formed calcified aggregates of viable cells that expressed osteoblast-related transcripts and proteins. In contrast, VICs cultured in calcifying media on stiffer matrices (similar to stenotic tissue) differentiated to myofibroblasts and formed calcified aggregates that contained apoptotic cells. Actin depolymerization reduced aggregation on stiff, but not compliant, matrices. TGF-β1 potentiated aggregate formation on stiff matrices by enhancing -smooth muscle actin expression and cellular contractility, but not on compliant matrices attributable to downregulation of TGF-β receptor I. Cell contraction by VICs inhibited Akt activation and enhanced apoptosis-dependent calcification on stiff matrices.

Conclusions— Differentiation of VICs to pathological phenotypes in response to biochemical cues is modulated by matrix stiffness. Although osteogenic or myofibrogenic differentiation of VICs can result in calcification, the processes are distinct.

  R Zhao , J. F DeCoteau , C.R Geyer , M Gao , H Cui and A. G. Casson
 

To evaluate loss of imprinting (LOI) and expression of the IGF2 gene in matched esophageal normal and adenocarcinoma tissues, we studied a prospective cohort of 77 patients who underwent esophageal resection between 1998 and 2003. IGF2 imprinting status was determined by reverse transcription–polymerase chain reaction (PCR) following ApaI digestion, and quantitative PCR was used to evaluate IGF2 expression, which was correlated with clinicopathologic findings, disease-free and overall survival. In total, 32% (14/44) of informative tissues showed loss of IGF2 imprinting, with a strong correlation between the tumor and normal esophageal epithelia (Kappa = 0.89, P < 0.01). Normal epithelia with LOI had increased expression of IGF2 [median: 2.91, 95% confidence interval (CI): 0.93–5.06] compared with imprinted normal epithelia (median: 1.13, 95% CI: 0.85–1.39) (P = 0.03). In contrast, tumors with LOI had significantly reduced IGF2 expression (median: 1.87, 95% CI: 0.53–5.21) compared with normally imprinted tumors (median: 6.79, 95% CI: 3.39–15.89) (P = 0.016). Patients below the age of 65 years with normally imprinted tumors had significantly reduced 5 year disease-free survival (DFS) (24%) compared with patients whose tumors had LOI for IGF2 (55%) (P = 0.03). Cox regression analysis showed that IGF2 overexpression was associated with significantly reduced disease-free survival (P = 0.04). We conclude that in a subgroup of younger patients, loss of IGF2 imprinting was associated with improved outcome following esophageal resection. Expression of IGF2 in esophageal adenocarcinoma and normal esophageal epithelia depended on imprinting status and tissue type, suggesting novel molecular regulatory mechanisms in esophageal tumorigenesis.

  R Zhao , T. J Raub , G. A Sawada , S. C Kasper , J. A Bacon , A. S Bridges and G. M. Pollack
 

Expression of breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) has been revealed recently. To investigate comprehensively the potential role of Bcrp at the murine BBB, a chemically diverse set of model compounds (cimetidine, alfuzosin, dipyridamole, and LY2228820) was evaluated using a multiexperimental design. Bcrp1 stably transfected MDCKII cell monolayer transport studies demonstrated that each compound had affinity for Bcrp and that polarized transport by Bcrp was abolished completely by the Bcrp inhibitor chrysin. However, none of the compounds differed in brain uptake between Bcrp wild-type and knockout mice under either an in situ brain perfusion or a 24-h subcutaneous osmotic minipump continuous infusion experimental paradigm. In addition, alfuzosin and dipyridamole were shown to undergo transport by P-glycoprotein (P-gp) in an MDCKII-MDR1 cell monolayer model. Alfuzosin brain uptake was 4-fold higher in mdr1a(–/–) mice than in mdr1a(+/+) mice in in situ and in vivo studies, demonstrating for the first time that it undergoes P-gp-mediated efflux at the BBB. In contrast, P-gp had no effect on dipyridamole brain penetration in situ or in vivo. In fact, in situ BBB permeability of these solutes appeared to be primarily dependent on their lipophilicity in the absence of efflux transport, and in situ brain uptake clearance correlated with the intrinsic transcellular passive permeability from in vitro transport and cellular accumulation studies. In summary, Bcrp mediates in vitro transport of various compounds, but seems to play a minimal role at the BBB in vivo.

  R Zhao , T. J Raub , G. A Sawada , S. C Kasper , J. A Bacon , A. S Bridges and G. M. Pollack
 

Expression of breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) has been revealed recently. To investigate comprehensively the potential role of Bcrp at the murine BBB, a chemically diverse set of model compounds (cimetidine, alfuzosin, dipyridamole, and LY2228820) was evaluated using a multiexperimental design. Bcrp1 stably transfected MDCKII cell monolayer transport studies demonstrated that each compound had affinity for Bcrp and that polarized transport by Bcrp was abolished completely by the Bcrp inhibitor chrysin. However, none of the compounds differed in brain uptake between Bcrp wild-type and knockout mice under either an in situ brain perfusion or a 24-h subcutaneous osmotic minipump continuous infusion experimental paradigm. In addition, alfuzosin and dipyridamole were shown to undergo transport by P-glycoprotein (P-gp) in an MDCKII-MDR1 cell monolayer model. Alfuzosin brain uptake was 4-fold higher in mdr1a(–/–) mice than in mdr1a(+/+) mice in in situ and in vivo studies, demonstrating for the first time that it undergoes P-gp-mediated efflux at the BBB. In contrast, P-gp had no effect on dipyridamole brain penetration in situ or in vivo. In fact, in situ BBB permeability of these solutes appeared to be primarily dependent on their lipophilicity in the absence of efflux transport, and in situ brain uptake clearance correlated with the intrinsic transcellular passive permeability from in vitro transport and cellular accumulation studies. In summary, Bcrp mediates in vitro transport of various compounds, but seems to play a minimal role at the BBB in vivo.

  R Zhao , J Zhu , X Ji , J Cai , F Wan , Q Li , B Zhong , S Tucker and D. Wang
  Objective

To assess the resectability rate of patients with initially unresectable liver-only metastases from colorectal cancer (CRC) after treatment with irinotecan/capecitabine.

Methods

Patients received irinotecan (240 mg/m2) as a 30 min intravenous infusion on day 1 and capecitabine (1000 mg/m2) orally bid for 14 days beginning on day 2. Treatment was repeated every 3 weeks. The protocol encouraged two to four cycles of irinotecan/capecitabine after recovery from surgery.

Results

Between May 2004 and February 2007, 48 patients entered in the study. Forty-seven (97.9%) of the 48 patients were assessable for response. The overall response rate before surgery was 56.3% (95% CI, 42.3–70.3%) in the treated population, including 2 non-confirmed complete response (CR), 18 partial responses (PR) and 7 non-confirmed PR. Twenty-three (47.9%) of 29 patients with tumor shrinkage proceeded to surgical intervention. Twenty of the 23 patients had a complete resection (S-CR). With a median follow-up time of 32 months (range, 24–38 months), the overall median time to progression and overall survival for all patients were 16.7 months (95% CI, 10.0–23.4 months) and 27.5 months (95% CI, 23.6–31.4 months) for all patients. The 1- 2- and 3-year overall survival estimates were 79.2% (95% CI, 67.7–90.7%), 60.4% (95% CI, 46.6–74.3%) and 29.2% (95% CI, 16.3–42.0%), respectively. Grade 3 diarrhea occurred in eight (17.0%) patients. The most common Grade 3/4 hematological adverse event was neutropenia in 8.5% of the patients. There were no treatment-related deaths during this study.

Conclusions

Irinotecan/capecitabine appears to be a safe and very effective regimen in selected patients with unresectable liver metastases from CRC, but who are treated with a curative intent.

  E. S Unal , R Zhao and I. D. Goldman
 

The proton-coupled folate transporter (PCFT) SLC46A1 mediates uphill folate transport into enterocytes in proximal small intestine coupled to the inwardly directed proton gradient. Hereditary folate malabsorption is due to loss-of-function mutations in the PCFT gene. This study addresses the functional role of conserved charged amino acid residues within PCFT transmembrane domains with a detailed analysis of the PCFT E185 residue. D156A-, E185A-, E232A-, R148A-, and R376A-PCFT mutants lost function at pH 5.5, as assessed by transient transfection in folate transport-deficient HeLa cells. At pH 7.4, function was preserved only for E185A-PCFT. Loss of function for E185A-PCFT at pH 5.5 was due to an eightfold decrease in the [3H]methotrexate (MTX) influx Vmax; the MTX influx Kt was identical to that of wild-type (WT)-PCFT (1.5 µM). Consistent with the intrinsic functionality of E185A-PCFT, [3H]MTX influx at pH 5.5 or 7.4 was trans-stimulated in cells preloaded with nonlabeled MTX or 5-formyltetrahydrofolate. Replacement of E185 with Leu, Cys, His, or Gln resulted in a phenotype similar to E185A-PCFT. However, there was greater preservation of activity (~38% of WT) for the similarly charged E185D-PCFT at pH 5.5. All E185 substitution mutants were biotin accessible at the plasma membrane at a level comparable to WT-PCFT. These observations suggest that the E185 residue plays an important role in the coupled flows of protons and folate mediated by PCFT. Coupling appears to have a profound effect on the maximum rate of transport, consistent with augmentation of a rate-limiting step in the PCFT transport cycle.

  K Mahadeo , N Diop Bove , D Shin , E. S Unal , J Teo , R Zhao , M. H Chang , A Fulterer , M. F Romero and I. D. Goldman
 

The proton-coupled folate transporter (PCFT-SLC46A1) is required for intestinal folate absorption and is mutated in the autosomal recessive disorder, hereditary folate malabsorption (HFM). This report characterizes properties and requirements of the R376 residue in PCFT function, including a R376Q mutant associated with HFM. Gln, Cys, and Ala substitutions resulted in markedly impaired transport of 5-formyltetrahydrofolate (5-FTHF) and 5-methyltetrahydrofolate (5-MTHF) due to an increase in Km and decrease in Vmax in HeLa R1–11 transfectants lacking endogenous folate transport function. In contrast, although the influx Km for pemetrexed was increased, transport was fully preserved at saturating concentrations and enhanced for the like-charged R376K- and R376H-PCFT. Pemetrexed and 5-FTHF influx mediated by R376Q-PCFT was markedly decreased at pH 5.5 compared with wild-type PCFT. However, while pemetrexed transport was substantially preserved at low pH (4.5–5.0), 5-FTHF transport remained very low. Electrophysiological studies in Xenopus oocytes demonstrated that 1) the R376Q mutant, like wild-type PCFT, transports protons in the absence of folate substrate, and in this respect has channel-like properties; and 2) the influx Km mediated by R376Q-PCFT is increased for 5-MTHF, 5-FTHF, and pemetrexed. The data suggest that mutation of the R376 residue to Gln impairs proton binding which, in turn, modulates the folate-binding pocket and depresses the rate of conformational alteration of the carrier, a change that appears to be, in part, substrate dependent.

  E. S Unal , R Zhao , M. H Chang , A Fiser , M. F Romero and I. D. Goldman
 

This report addresses the functional role of His residues in the proton-coupled folate transporter (PCFT; SLC46A1), which mediates intestinal folate absorption. Of ten His residues, only H247A and H281A mutations altered function. The folic acid influx Kt at pH 5.5 for H247A was 8.4-fold. Although wild type (WT)-PCFT Ki values varied among the folates, Ki values were much lower and comparable for H247-A, -R, -Q, or -E mutants. Homology modeling localized His247 to the large loop separating transmembrane domains 6 and 7 at the cytoplasmic entrance of the translocation pathway in hydrogen-bond distance to Ser172. The folic acid influx Kt for S172A-PCFT was decreased similar to H247A. His281 faces the extracellular region in the seventh transmembrane domain. H281A-PCFT results in loss-of-function due to ~12-fold in the folic acid influx Kt. When the pH was decreased from 5.5 to 4.5, the WT-PCFT folic acid influx Kt was unchanged, but the Kt decreased 4-fold for H281A. In electrophysiological studies in Xenopus oocytes, both WT-PCFT- and H281A-PCFT-mediated folic acid uptake produced current and acidification, and both exhibited a low level of folate-independent proton transport (slippage). Slippage was markedly increased for the H247A-PCFT mutant. The data suggest that disruption of the His247 to Ser172 interaction results in a PCFT conformational alteration causing a loss of selectivity, increased substrate access to a high affinity binding pocket, and proton transport in the absence of a folate gradient. The His281 residue is not essential for proton coupling but plays an important role in PCFT protonation, which, in turn, augments folate binding to the carrier.

  J. F Heneghan , T Mitra Ganguli , L. F Stanish , L Liu , R Zhao and A. R. Rittenhouse
 

In superior cervical ganglion (SCG) neurons, stimulation of M1 receptors (M1Rs) produces a distinct pattern of modulation of N-type calcium (N-) channel activity, enhancing currents elicited with negative test potentials and inhibiting currents elicited with positive test potentials. Exogenously applied arachidonic acid (AA) reproduces this profile of modulation, suggesting AA functions as a downstream messenger of M1Rs. In addition, techniques that diminish AA's concentration during M1R stimulation minimize N-current modulation. However, other studies suggest depletion of phosphatidylinositol-4,5-bisphosphate during M1R stimulation suffices to elicit modulation. In this study, we used an expression system to examine the physiological mechanisms regulating modulation. We found the β subunit (CaVβ) acts as a molecular switch regulating whether modulation results in enhancement or inhibition. In human embryonic kidney 293 cells, stimulation of M1Rs or neurokinin-1 receptors (NK-1Rs) inhibited activity of N channels formed by CaV2.2 and coexpressed with CaVβ1b, CaVβ3, or CaVβ4 but enhanced activity of N channels containing CaVβ2a. Exogenously applied AA produced the same pattern of modulation. Coexpression of CaVβ2a, CaVβ3, and CaVβ4 recapitulated the modulatory response previously seen in SCG neurons, implying heterogeneous association of CaVβ with CaV2.2. Further experiments with mutated, chimeric CaVβ subunits and free palmitic acid revealed that palmitoylation of CaVβ2a is essential for loss of inhibition. The data presented here fit a model in which CaVβ2a blocks inhibition, thus unmasking enhancement. Our discovery that the presence or absence of palmitoylated CaVβ2a toggles M1R- or NK-1R–mediated modulation of N current between enhancement and inhibition identifies a novel role for palmitoylation. Moreover, these findings predict that at synapses, modulation of N-channel activity by M1Rs or NK-1Rs will fluctuate between enhancement and inhibition based on the presence of palmitoylated CaVβ2a.

 
 
 
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