Biomedical subjects

Hongyu Liu

Publications and source records attributed to Hongyu Liu.

At least 19 recordsLinked to original sources

PubMed2026

Multi-omics characterization of flavor profile differences in the Longissimus thoracis between Angus and Hereford cattle.

BACKGROUND: Angus and Hereford cattle are premier breeds widely used in genetic improvement and crossbreeding programs to enhance meat quality, yet the flavor differences between them remain poorly understood. RESULTS: In this study, we performed an integrated analysis using headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME-GC-MS)-based volatile metabolomics, lipidomics, and untargeted metabolomics to characterize the flavor profiles of the Longissimus thoracis (LT) muscle from both breeds and to identify potential precursor substances underlying flavor formation. In total, we identified 76 differential volatile organic compounds (VOCs) among the 493 candidate VOCs. By combing relative odor activity value (ROAV) and sensory attribute annotation, 2,3-butanedione which may contribute to the creamy aroma was revealed as the core differential VOC between the two breeds. This finding was robustly validated across SHAP (Shapley additive explanations) analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment, and flavor annotation. Lipidomic analysis revealed 689 differential lipids primarily belonging to classes such as phosphatidylcholine, triglycerides, and phosphatidylethanolamine. Correlation analysis further linked these lipid profiles to flavor, showing that fatty acids (FAs) including FA(19:0), FA(18:2 + O), FA(14:1), FA(16:1), and FA(14:0) were significantly correlated with 2,3-butanedione. Notably, the unsaturated fatty acids (UFAs) in the Longissimus thoracis (LT) of Hereford cattle exhibited higher double bond content compared to Angus cattle, suggesting a greater potential for rich flavor development. Untargeted metabolomics revealed that nine of the 9474 metabolites were significantly correlated with both 2,3-butanedione and FAs, including norepinephrine, l-beta-aspartyl-l-leucine, and artemetin. CONCLUSIONS: Overall, our research has identified differential flavor compounds and potential precursor substances between Angus cattle and Hereford cattle, providing targeted guidance for breed improvement. © 2026 Society of Chemical Industry.

2,3‐butanedione↗

PubMed2025

Identification of a prognostic signature consisting of three macrophage-related genes for glioblastoma based on bulk and single-cell transcriptomes analyses.

BACKGROUND: Tumor-associated macrophages have been implicated in the progression and treatment resistance of glioblastoma (GBM). This study aimed to identify macrophage-related genes associated with prognosis and therapeutic response in GBM. MATERIALS AND METHODS: Bulk RNA-seq data from 533 patients with GBM were downloaded from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Bioinformatic tools were used to detect the co-expression gene modules associated with the infiltration of immune cells, identify a prognostic macrophage-related gene signature, and explore their association with sensitivity to chemotherapeutic drugs and immune checkpoint blockade. Single-cell RNA-seq data and multiplexed immunofluorescence were used to validate ISG20 expression (a member of the identified gene signature) in macrophages. RESULTS: We detected gene modules associated with macrophages and identified a signature consisting of three macrophage-related genes (ISG20, PARP12 and IFIT5) in the discovery set (TCGA-GBM, n = 159), and validated its prognostic value in the validation set (CGGA-GBM, n = 374). This gene signature demonstrated favorable accuracy in predicting prognosis and resistance of immuno- and chemo-therapy. The co-expression of ISG20 and PD-1 in macrophages was verified by single-cell RNA-seq data and multiplex immunofluorescence. CONCLUSIONS: This study presents a macrophage-related gene signature to predict prognosis and therapeutic response in GBM. ISG20, PARP12 and IFIT5 are interferon-stimulated genes, and further investigations may provide new insights into the interplay between macrophages and interferon signaling in GBM.

Humans↗

PubMed2024

L3MBTL1, a polycomb protein, promotes Osimertinib acquired resistance through epigenetic regulation of DNA damage response in lung adenocarcinoma.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) approved for patients with EGFR T790M resistance mutations as first- or second-line treatment of EGFR-positive patients. Resistance to Osimertinib will inevitably develop, and the underlying mechanisms are largely unknown. In this study, we discovered that acquired resistance to Osimertinib is associated with abnormal DNA damage response (DDR) in lung adenocarcinoma cells. We discovered that the polycomb protein Lethal(3) Malignant Brain Tumor-Like Protein 1 (L3MBTL1) regulates chromatin structure, thereby contributing to DDR and Osimertinib resistance. EGFR oncogene inhibition reduced L3MBTL1 ubiquitination while stabilizing its expression in Osimertinib-resistant cells. L3MBTL1 reduction and treatment with Osimertinib significantly inhibited DDR and proliferation of Osimertinib-resistant lung cancer cells in vitro and in vivo. L3MBTL1 binds throughout the genome and plays an important role in EGFR-TKI resistance. It also competes with 53BP1 for H4K20Me2 and inhibits the development of drug resistance in Osimertinib-resistant lung cancer cells in vitro and in vivo. Our findings suggest that L3MBTL1 inhibition is a novel approach to overcoming EGFR-TKI-acquired resistance.

Humans↗

PubMed2006

Dual PPARalpha/gamma ligand TZD18 either alone or in combination with imatinib inhibits proliferation and induces apoptosis of human CML cell lines.

Despite progress in the treatment of early-stage chronic myeloid leukemia (CML), the accelerated and blastic phases of CML still remain a therapeutic challenge. Persistence of BCR-ABL-positive (bcr-abl(+)) cells or secondary resistance during imatinib therapy frequently occurs. In this study, we investigated the activity of a novel dual ligand specific for peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) against CML blast crisis cell lines. Exposure of these cell lines (K562, KU812 and KCL22) to TZD18 resulted in a growth inhibition in a dose- and time-dependent manner. This effect may not be mediated through PPARgamma and PPARalpha activation, since antagonists of PPARgamma and/or PPARalpha could not reverse this inhibition. Western blotting analysis showed that expression of the cyclin dependent kinase inhibitor (CDKI) p27(kip1) was enhanced, whereas levels of cyclin E, cyclin D2 and cyclin dependent kinase 2 (CDK-2) were decreased when these cells were treated with TZD18. Most interestingly, TZD18 synergistically enhanced the antiproliferative and pro-apoptotic effect of imatinib. Overall, our findings strongly suggest that either TZD18, either alone or in combination with imatinib may be beneficial for the treatment of CML in myeloid blast crisis.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPARalpha/gamma ligand TZD18.

Treatment of adult Philadelphia chromosome-positive lymphocytic leukemia is rarely successful. We report here the effects of TZD18, a novel dual ligand specific for peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) on Ph(+) lymphocytic leukemia cell lines BV173, SD1, and SupB-15. Exposure of these cells to TZD18 resulted in growth inhibition in a dose- and time-dependent manner that was associated with G(1) cell cycle arrest. This effect was much stronger than that mediated by the PPARgamma ligand pioglitazone (PGZ), which also belongs to the thiazolidinediones (TZD) class of ligands. However, it may not be mediated through PPARgamma or PPARalpha activation because antagonists of PPARgamma and PPARalpha cannot reverse it. Study of the key regulators of cell cycle progression by Western blot analysis showed that the expression of the cyclin-dependent kinase inhibitor (CDKI) p27(kip1), but not that of p21(cip1), was enhanced, whereas that of c-Myc, cyclin E, cyclin D2, and cyclin-dependent kinases 2 and 4 (CDK-2 and CDK-4) was decreased when these cells were treated with TZD18 (10 or 20 microM). Therefore, the up-regulation of p27(kip1) and the down-regulation of CDK-2 and CDK-4 may, at least in part, account for the G(1) cell cycle arrest. Furthermore, a remarkable induction of apoptosis was observed in the cells treated with this dual ligand. No obvious alteration of bcl-2 protein level occurred, but bax was up-regulated in these TZD18-treated cells. Activation of caspase 8 and caspase 9 by TZD18 was also observed. Importantly, NF-kappaB DNA-binding activity was markedly decreased by the TZD18 treatment. In addition, TZD18 enhanced the growth inhibitory effect of imatinib, a specific tyrosine kinase inhibitor therapeutically used in the treatment of Ph(+) leukemia. Overall, our findings strongly suggest that TZD18 may offer a new therapeutic approach to aid in the treatment of Ph(+) lymphocytic leukemia.

Apoptosis↗

PubMed2006

On-line identification of the constituents of Buyang Huanwu decoction in pig serum using combined HPLC-DAD-MS techniques.

Buyang Huanwu decoction (BYHWD) is a widely used Chinese traditional compound medicine that has proved effective in treating cerebrovascular illnesses; however, its active substances have remained unknown. In this paper, serum chemistry and combined high-performance liquid chromatography (HPLC), photodiode-array detection and mass-spectrometry techniques were used to study the constituents of BYHWD from pig serum after oral administration. A total of 45 characteristic HPLC peaks were detected from serum containing drug. The chemical structures of nine of the peaks were tentatively elucidated as 7,3'-dihydroxy-4'-methoxyisoflavone-7-O-glucuronide (P1), 7-hydroxy-4'-methoxyisoflavone-7-O-glucuronide (P2), 7,2',4'-trihydroxy-3'-methoxyisoflavane-7-O-sulphate (P3), 3-hydroxy-9,10-dimethoxypterocarpan-3-O-glucuronide (P4), 7,2'-dihydroxy-3',4'-dimethoxyisoflavane-7-O-glucuronide (P5), 3-hydroxy-9,10-dimethoxypterocarpane-3-O-sulphate (P6), 4(1H)-quinolinone (P7 or P8), 4-hydroxyquinoline (P8 or P7) and oleic acid (P9). All of the identified peaks, with the exception of P9, were metabolites of the constituents of BYHWD in vivo.

Animals↗

PubMed2006

Analysis of placental growth factor in placentas of normal pregnant women and women with hypertensive disorders of pregnancy.

To investigate the expressions of placental growth factor (PLGF) in placenta with hypertensive disorders of pregnancy (HDP), 45 women with HDP and 20 normally pregnant women were studied. Among 45 women with HDP, there were 23 cases of severe preeclampsia and one case of eclampsia. The location and level of PLGF proteins was determined by immunohistochemistry and Western blot. The expression of PLGF mRNA in placenta was assessed by reverse transcriptional-polymerase chain reaction (RT-PCR). The results showed that: (1) The distribution of PLGF in placenta with HDP was similar to normal one, which was mainly in the cytoplasm of villous syncytiotrophoblast and villous stroma; (2) The expression of PLGF protein was significantly decreased in placentas with mild and severe preeclampsia compared to the normal ones (0.3 +/- 0.4 vs 0.6 +/- 0.4, 0.2 +/- 0.5 vs 0.6 +/- 0.4, P < 0.01). There were no differences between the gestational hypertension placenta and normal one (0.5 +/- 0.6 vs 0.6 +/- 0.4, P > 0.05); (3) The transcription levels of the PLGF mRNA in placentas with preeclampsia were significantly lower than in normal groups (3.33 +/- 0.39 vs 4.87 +/- 0.60, 1.97 +/- 0.29 vs 4.87 +/- 0.60, P < 0.01), and no differences were found between the gestational hypertension placenta and normal groups. These findings suggest that the abnormal expression of PLGF in placentas is related to the pathogenesis of HDP.

Adult↗

PubMed2006

Keeping the heart empty and beating improves preservation of hypertrophied hearts for valve surgery.

OBJECTIVE: This study was designed to determine whether keeping the heart empty and beating improved myocardial fluid homeostasis and energy metabolism of hypertrophied pig hearts in comparison with cardioplegic arrest. METHODS: Twenty piglets underwent a 8-weeks (corrected) ascending aortic banding to induce left ventricular hypertrophy. Isolated hypertrophied hearts were divided into 4 groups (n = 5 in each group). Two groups underwent normothermic normokalemic simultaneous perfusion. The other 2 groups were subjected to normothermic hyperkalemic simultaneous perfusion and used as controls. Intramyocardial hydrostatic pressure was monitored with a microtip pressure transducer. Volumes of intracellular and extracellular compartments and myocardial energy metabolism were monitored by using phosphorus 31 magnetic resonance spectroscopy. RESULTS: Normothermic normokalemic simultaneous perfusion (NNSP) maintained intramyocardial hydrostatic pressure at a significantly lower level (13.0 +/- 0.6 mm Hg) compared with normothermic hyperkalemic simultaneous perfusion (NHSP) (23.3 +/- 1.2 mm Hg) during a 90-minute preservation. NNSP maintained the normal volume of the intracellular compartment throughout the preservation period, whereas NHSP caused significant enlargement (to 123% +/- 6% of its normal volume) of the intracellular compartment. Expansion of the extracellular compartment during preservation was significantly less in the NNSP group (124% +/- 6%) than in the NHSP group (152% +/- 7%). NNSP maintained normal levels of phosphocreatine and adenosine triphosphate until coronary perfusion flow was reduced to 50% of the initial control level. No decrease in energy metabolites was observed in the NHSP group even when coronary perfusion flow was reduced to 10% of the initial control level. CONCLUSIONS: Keeping the heart empty and beating improves myocardial fluid homeostasis for hypertrophied hearts relative to cardioplegic arrest. Its ability to maintain energy metabolism depends on the degree of coronary stenosis. This technique may be a promising protective strategy for hypertrophied hearts.

Animals↗

PubMed2005

Metal contamination of soils and crops affected by the Chenzhou lead/zinc mine spill (Hunan, China).

In 1985, the collapse of the tailing dam in Chenzhou lead/zinc mine (Hunan, southern China) led to the spread of mining waste spills on the farmland along the Dong River. After the accident, an urgent soil cleaning up was carried out in some places. Seventeen years later, cereal (rice, maize, and sorghum), pulses (soybean, Adzuki bean, mung bean and peanut), vegetables (ipomoea, capsicum, taro and string bean) and the rooted soils were sampled at four sites: (1) the mining area (SZY), (2) the area still covered with the mining tailing spills (GYB), (3) the cleaned area from mining tailing spills (JTC), and (4) a background site (REF). Metal concentrations in the crops and soils were analyzed to evaluate the long-term effects of the spilled waste on the soil and the potential human exposure through food chains. The results showed that the physical-chemical properties of the soils obviously changed due to the different farming styles used by each individual farmer. Leaching effects and plant extraction of metals from some soils were quite weak. Certain soils were still heavily polluted with As, Cd, Zn, Pb and Cu. The contamination levels were in the order of GYB>SZY>JTC showing that the clean-up treatment was effective. The maximum allowable concentration (MAC) levels for Chinese agricultural soils were still highly exceeded, particularly for As and Cd (followed by Zn, Pb and Cu), with mean concentrations of 709 and 7.6 mg kg(-1), respectively. These concentrations exceed the MAC levels by 24 times for As and 13 times for Cd at GYB. Generally, the edible leaves or stems of crops were more heavily contaminated than seeds or fruits. Ipomoea was the most severely contaminated crop. The concentrations of Cd and Pb were 3.30 and 76.9 mg kg(-1) in ipomoea leaves at GYB, which exceeded the maximum permit levels (0.5 mg kg(-1) for Cd and 9 mg kg(-1) for Pb) by 6.6 and 8.5 times, respectively. Taro (+skin) could accumulate high concentrations of Zn and Cd in the edible stem, and rice and capsicum had high Cd concentration in the edible parts. However, the toxic element concentrations in maize, sorghum, Adzuki bean, soybean and mung bean remained lower than the threshold levels. The bio-accumulation factors (BAFs) of crops were in the order: Cd>Zn>Cu>Pb>As. BAF was typically lower in the edible seeds or fruits than in stems and leaves. The accumulation effect strongly depends on the crop's physiological properties, the mobility, of the metals, and the availability of metals in soils but not entirely on the total element concentrations in the soils. Even so, the estimated daily intake amount of Cu, Zn, Cd, and Pb from the crops grown in the affected three sites and arsenic at SZY and GYB exceeded the RDA (Recommended dietary allowance) levels. Subsequently, the crops grown in Chenzhou Pb/Zn mine waste affected area might have a hazardous effect on the consumer's health. This area still needs effective measures to cure the As, Cd, Pb, Zn and Cu contamination.

Accidents, Occupational↗

PubMed2005

Tissue edema does not change gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced T1 relaxation times of viable myocardium.

PURPOSE: To determine whether tissue edema changes gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA)-enhanced T1 relaxation times of the viable myocardium. MATERIALS AND METHODS: A total of 16 isolated pig hearts were divided into four groups (N=4/group) and perfused in a Langendorff apparatus. Gd-DTPA was injected into the aortic perfusion line. Tissue edema was then induced by two hours of simultaneous arterial/venous perfusion (SAVP). Myocardial water content and T1 relaxation times were monitored throughout SAVP. The volumes of the extracellular and intracellular compartments were assessed using 31P MRS-detectable markers, phenylphosphonic acid (PPA) and dimethyl methylphosphonate (DMMP). RESULTS: Tissue water content in both viable and infarcted myocardium increased significantly during two-hour SAVP. However, Gd-DTPA-enhanced T1 relaxation times of the viable myocardium remained relatively unchanged. Infarcted myocardium, on the other hand, exhibited significant T1 shortening during SAVP. Furthermore, SAVP resulted in significant expansions of both extracellular and intracellular compartments, but the ratio of the volumes of the two compartments remained relatively constant. CONCLUSION: Tissue edema in the viable myocardium does not increase the relative distribution volume of the contrast agent. As a result, edema does not change Gd-DTPA-enhanced T1 relaxation times of the viable myocardium.

Analysis of Variance↗

PubMed2005

[Fragmentation process of wetland landscape in watersheds of Sanjiang Plain, China].

The Sanjiang Plain is the largest fresh water wetland distribution area in China and the center of waterfowls breeding and habitat area in Asia, but over the past 50 years, more than 73% of its wetland had lost because of agricultural development, and as a result, the wetland biodiversity declines dramatically, and the remnant wetlands are in a very fragment state. Based on historical maps, remote sensing data and GIS techniques, this paper selected two watersheds to analyze their wetland landscape fragmentation process during 1950-2000. It was indicated that land reclamation resulted in a decrease of 98% wetland corridors in Qixing River, 90% in Naoli River, 87% in the middle reach of Bielahong River, and 94% in the lower reach of Bielahong River; The amount of isolated wetlands in watershed increased dramatically; The maximum patch areas of wetland decreased by 92.6% in Naoli River watershed and 74.6% in Bielahong River watershed, and the mean wetland patch area in the two watersheds decreased by 99%. Before 1983, the wetland landscape was in an extensive area distribution state (the index of patch density was < 0.1), but after 1983, it fragmented dramatically, with the index of patch density larger than 1.5. The shape fragmentation indices of wetland decreased from 1950 to 2000, indicating a very big change in wetland patch shapes in the watersheds. The area fragmentation indices of wetland also increased from 1950 to 2000, especially after 1983, showing that the wetlands were in a serious fragmentation state. The wetland landscape fragmentation changed from a landmass and island model to a satellite model, and finally to a completely isolated model, which indicated the great changes in spatial structure of wetland in the Sanjiang Plain.

Agriculture↗

PubMed2004

Peroxisome proliferator-activated receptor gamma ligands induce growth inhibition and apoptosis of human B lymphocytic leukemia.

This study examined the expression and structural intactness of peroxisome proliferator-activated receptor gamma (PPARgamma) in human acute lymphocytic leukemia (ALL) cells and determined the effect of PPARgamma ligands on growth and apoptosis of these cells. We noted that all lymphocytic leukemia cell lines expressed PPARgamma and no PPARgamma mutations were found in these cell lines as indicated by SSCP analysis. Effect of the PPARgamma ligands on the proliferation, differentiation and apoptosis of B type ALL cells was further examined. Treatment of these cells with the PPARgamma ligands Pioglitazone (PGZ) and 15-deoxy-delta (12,14)-prostaglandin J2 (15d-PGJ2) resulted in growth inhibition in a dose-dependent manner which was associated with a G1 to S cell cycle arrest. However, this effect appeared to be PPARgamma-independent since several PPARgamma antagonists could not reverse this effect. No differentiation was induced by this treatment. Four out of five cell lines underwent apoptosis after culture with the PPARgamma ligands. This effect was partially caspase-dependent because a pan-caspase inhibitor partially reversed this effect. In conclusion, our results suggest that PPARgamma ligands may offer a new therapeutic approach to aid in the treatment of ALL.

Adolescent↗

PubMed2004

Mapping myocardial viability using interleaved T1-T2* weighted imaging.

The present study was to evaluate the efficacy of our interleaved T1-T2* weighted imaging for assessing myocardial viability. The left anterior descending coronary artery (LAD) of pig hearts (n = 7) were occluded for 2 h, followed by 1 h reperfusion. After removed from animals, the hearts were perfused in a Langendorff apparatus with a mixture of pig blood and crystalloid solution in 1:1 ratio. T1 relaxation times of the myocardium were measured with a TurboFLASH inversion-recovery sequence. Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) (0.05 mmol/kg body wt) was then injected as a bolus into the aortic perfusion line. The first pass of the contrast agent through the heart was followed using the interleaved T1-T2* imaging sequence. Once the concentration of the contrast agent was in an equilibrium state, T1 relaxation times were measured again. It was found that the percentage recovery of T2* intensity (PRT2*) at the maximum T1 intensity measured during the first pass of the contrast agent with the interleaved T1-T2* imaging was significantly higher in infarcted myocardium than in normal myocardium. Moreover, the regions showing a high T2* percentage recovery on PRT2* maps matched well with the infarcted myocardium demarcated with triphenyl tetrazolium chloride (TTC) staining. We therefore conclude that infarcted myocardium can be delineated using the interleaved T1-T2* imaging method.

Animals↗

PubMed2004

Impacts on wetlands of large-scale land-use changes by agricultural development: the Small Sanjiang Plain, China.

The Small Sanjiang Plain (SSP), was formerly the largest wetland complex in China, located in the Northeastern part of Heilongjiang Province, China. Home to vast numbers of waterfowls, fish, and plants, the SSP is globally significant for biodiversity conservation. The loss and fragmentation of wetlands as a result agricultural development over 50 years has impacted wetland communities and their biodiversity. We used GIS to inventory large-scale land-use changes from 1950 to 2000, together with other statistical data. We found that 73.6% of the wetlands were lost due to agricultural development. Consequences of these land-use changes included: i) a rapid decline in waterfowl and plant species with the loss and fragmentation of natural wetlands and wetland ecosystem degradation; ii) greater variation in wetland water levels as the result of land-use changes over the years; iii) disruption of the dynamic river-floodplain connection by construction of drainage ditches and levees; and iv) a decrease in floodplain area that caused increased flooding peak flows and runoff. Here we show how these changes affect wetland biodiversity and impact important wetland species.

Agriculture↗

PubMed2004

[Toxicity of surfactant, acid rain and Cd2+ combined pollution to the nucleus of Vicia faba root tip cells].

The toxicity of Cd2+ and its combination with surfactant or simulated acid rain to Vicia faba root tip cell was studied by using micro-nucleus technique. The results showed that the formation of micro-nucleus in Vicia faba root tip cell was strongly induced by Cd2+ in its concentration of 0-10.0 mg.L-1. The micro-nucleus rate was 13.85@1000 at 6.0 mg.L-1Cd2+, 4.53@1000 at 0 mg.L-1Cd2+, and the pollution index (PI) was 3.06. The micro-nucleus ratio and PI decreased when the accompanied surfactant LAS was also presented or the pH values decreased to 4.5 or 3.5. In the meantime, many deformed nuclei and grains were observed in the root tip cells. The growth of the Vicia faba roots was restrained, and the root cells were not easy to be scattered. Therefore, the toxicity of Cd2+ was increased by its combination with surfactant or acid rain. The Cd2+ toxicity to Vicia faba cells at pH3.5 was stronger than that at pH4.5. When the mutation effect of contaminant with high concentration or with strong toxicity to plant cell was tested, the contaminant should be diluted for at least three times, and hence, the highest micro-nucleus ratio and pollution index (PI) could be found.

Acid Rain↗

PubMed2003

Antisense BAG-1 sensitizes HeLa cells to apoptosis by multiple pathways.

To study the mechanism of action of BAG-1 in drug-induced apoptosis, we constructed an antisense BAG-1 vector and established a stably transfected cell line from BAG-1-over-expressing HeLa cells. Reduced BAG-1 protein was confirmed by Western blot. Treatment of the antisense BAG-1-transfected cells with the anti-cancer drugs staurosporine, paclitaxel, all-trans retinoic acid (ATRA), and N-(4-hydroxyphenyl) retinamide (4-HPR) resulted in significantly enhanced apoptosis and reduced cell viability relative to vector-transfected cells. While the expression of p53 was increased, the level of Bcl-2 and Bax was decreased. Cells underexpressing BAG-1 had reduced cytosolic cytochrome c level. Treatment with staurosporine and paclitaxel resulted in increased cytochrome c release from mitochondria, whereas there was no change induced by treatment with ATRA and 4-HPR. Our experiments suggest that BAG-1 inhibits anti-cancer drug-induced apoptosis through apoptosis regulation pathways that may involve the mitochondrial Bcl-2/Bax ratio, p53, and differential anti-cancer drug-mediated cytochrome c release.

Antineoplastic Agents↗

PubMed2003

Ligands for PPARgamma and RAR cause induction of growth inhibition and apoptosis in human glioblastomas.

High-grade gliomas are characterized by a rapid proliferation rate, invasiveness and angiogenesis. Our previous data indicated that the combination of ligands for peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoic acid receptor (RAR) induces apoptosis of breast cancer cells in vitro and in a murine model. In this study, we have shown that 11 glioblastoma cell lines and nine fresh glioblastoma tissue samples from patients expressed high-levels of PPARgamma. In contrast, glia from nine healthy human brains expressed very low levels of PPARgamma. No mutations or polymorphisms of the PPARgamma gene were observed in these cell lines. The effect of the PPARgamma ligand Pioglitazone (PGZ) either in the absence or in the presence of a RAR ligand [all-trans retinoic acid (ATRA)] on the proliferation and apoptosis of glioblastoma cells was examined using two glioblastoma cell lines (N39 and DBTRG05MG). PGZ and/or ATRA inhibited significantly the proliferation of both cell lines. Flow cytometry analysis showed that G1 cell cycle arrest was induced by these ligands. In addition, apoptosis occurred in both cell lines treated with either PGZ or ATRA, which was associated with a downregulation of bcl-2 and an upregulation of bax proteins. An enhanced effect was observed when PGZ and ATRA were combined. Furthermore, treatment of fresh glioblastoma tissue from patients with PGZ, either alone or in combination with ATRA, induced a significant level of tumor cell apoptosis together with a downregulation of bcl-2 protein level as compared with untreated control brain tissue. Taken together, our data demonstrated that PGZ, either alone or in combination with ATRA, induced apoptosis and inhibited proliferation of glioblastoma cells, and more interestingly, induced apoptosis of fresh glioblastoma cells from patients. Therefore, we conclude that these ligands may possess adjuvant therapeutic potential for patients with glioblastoma.

Antineoplastic Agents↗

PubMed2002

Distinct BAG-1 isoforms have different anti-apoptotic functions in BAG-1-transfected C33A human cervical carcinoma cell line.

BAG-1 protein can be expressed as four isoforms of 50, 46, 33 and 29 kDa with different subcellular localizations, which may have different functions in anti-apoptosis, but the exact mechanism remains unclear. We constructed BAG-1 full length and deletion mutated plasmids in a pCR3.1 vector and established stable transfections of BAG-1 isoforms in low BAG-1 expressing C33A cells. Treatment of the transfected cells with cisplatin, staurosporine, paclitaxel and doxorubicine showed that BAG-1 p50, p46 and p33 isoforms enhanced the resistance to apoptosis. BAG-1 p50, p46 and p33 exhibited different degrees of apoptosis inhibition in the transfected cells and BAG-1 p46 isoform had the most pronounced effect on anti-apoptosis. BAG-1 p29 failed to protect the transfected cells from apoptosis. Resistance to apoptosis by BAG-1 isoforms was correlated with decreased caspase-3 activation. We also detected the expression of Bax, Bak, p53, Bcl-2, Bcl-X(L), AIF and MRP1 by Western blots. Bcl-2 protein expression was significantly increased in p50, p46 and p33 transfected cells, while the expression of Bax, Bak, p53, Bcl-X(L) and MRP1 was essentially unchanged. These in vitro results suggest that distinct isoforms of BAG-1 have different anti-apoptotic functions and their functions may be correlated to increased Bcl-2 expression.

Apoptosis↗