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1.
J Affect Disord ; 361: 277-284, 2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38844166

ABSTRACT

BACKGROUND: The short-term adverse effects of ambient fine particulate matter (PM2.5) and ozone (O3) on anxiety disorders (ADs) remained inconclusive. METHODS: We applied an individual-level time-stratified case-crossover study, which including 126,112 outpatient visits for ADs during 2019-2021 in Guangdong province, China, to investigate the association of short-term exposure to PM2.5 and O3 with outpatient visits for ADs, and estimate excess outpatient visits in South China. Daily residential air pollutant exposure assessments were performed by extracting grid data (spatial resolution: 1 km × 1 km) from validated datasets. We employed the conditional logistic regression model to quantify the associations and excess outpatient visits. RESULTS: The results of the single-pollutant models showed that each 10 µg/m3 increase of PM2.5 and O3 exposures was significantly associated with a 3.14 % (95 % confidence interval: 2.47 %, 3.81 %) and 0.88 % (0.49 %, 1.26 %) increase in odds of outpatient visits for ADs, respectively. These associations remained robust in 2-pollutant models. The proportion of outpatient visits attributable to PM2.5 and O3 exposures was up to 7.20 % and 8.93 %, respectively. Older adults appeared to be more susceptible to PM2.5 exposure, especially in cool season, and subjects with recurrent outpatient visits were more susceptible to O3 exposure. LIMITATION: As our study subjects were from one single hospital in China, it should be cautious when generalizing our findings to other regions. CONCLUSION: Short-term exposure to ambient PM2.5 and O3 was significantly associated with a higher odds of outpatient visits for ADs, which can contribute to considerable excess outpatient visits.

2.
Ying Yong Sheng Tai Xue Bao ; 35(2): 339-346, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38523090

ABSTRACT

Forest type and stand age are important biological factors affecting soil enzyme activities. However, the changes in soil enzyme activities across stand ages and underlying mechanisms under the two forest restoration strate-gies of plantations and natural secondary forests remain elusive. In this study, we investigated the variations of four soil enzyme activities including cello-biohydrolase (CBH), ß-1,4-glucosidase (ßG), acid phosphatase (AP) and ß-1,4-N-acetylglucosaminidase (NAG), which were closely associated with soil carbon, nitrogen, and phosphorus cycling, across Cunninghamia lanceolata plantations and natural secondary forests (5, 8, 21, 27 and 40 years old). The results showed that soil enzyme activities showed different patterns across different forest types. The acti-vities of AP, ßG and CBH in the C. lanceolata plantations were significantly higher than those in the natural secon-dary forests, and there was no significant difference in the NAG activity. In the plantations, AP activity showed a decreasing tendency with the increasing stand ages, with the AP activity in the 5-year-old plantations significantly higher than other stand ages by more than 62.3%. The activities of NAG and CBH decreased first and then increased, and ßG enzyme activity fluctuated with the increasing stand age. In the natural secondary forests, NAG enzyme activity fluctuated with the increasing stand age, with that in the 8-year-old and 27-year-old stand ages being significantly higher than the other stand ages by more than 14.9%. ßG and CBH enzyme activities increased first and then decreased, and no significant difference was observed in the AP activity. Results of the stepwise regression analyses showed that soil predictors explained more than 34% of the variation in the best-fitting models predicting soil enzyme activities in the C. lanceolata plantations and natural secondary forests. In conclusion, there would be a risk of soil fertility degradation C. lanceolata plantations with the increasing stand age, while natural secondary forests were more conducive to maintaining soil fertility.


Subject(s)
Cunninghamia , Humans , Adult , Child, Preschool , Child , Soil , Forests , Nitrogen/analysis , Phosphorus/analysis , Carbon/analysis , Soil Microbiology , China
3.
Am J Cardiol ; 211: 239-244, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-37979640

ABSTRACT

Excessive calcium-phosphorus product (Ca-P product) in patients with chronic kidney disease (CKD) is associated with coronary artery calcification and coronary artery disease, but the relation between Ca-P product and coronary artery disease in non-CKD populations has rarely been reported. Therefore, we designed a cross-sectional study to investigate the role of Ca-P product in total coronary artery occlusion (TCAO) in a non-CKD population. We reviewed 983 patients who underwent coronary angiography at Guangyuan Central Hospital from February 2018 to January 2020. Ca-P product (mg2/dl2) was calculated as Ca (mmol/L) × 4 × P (mmol/L) × 3.1 and was analyzed as a continuous and tertiary variable. TCAO was defined as complete occlusion of any coronary artery by coronary angiography (thrombolysis in myocardial infarction flow grade 0). Statistical analysis was performed using univariate and multivariate logistic regression models and restricted cubic splines. Univariate logistic regression analysis showed a statistically significant association between Ca-P product and TCAO (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.95 to 0.99, p <0.001). After stepwise adjustment for covariates, the risk of TCAO was reduced by 40% in the high versus low Ca-P group (OR 0.6, 95% CI 0.38 to 0.95, p = 0.031), and the risk of TCAO was predicted to decrease by 4% (OR 0.96, 95% CI 0.94 to 0.99, p = 0.006) for each unit increase in Ca-P product. Restricted cubic splines showed a nonlinear relation between Ca-P product and TCAO, with a significant decrease in the risk of TCAO after reaching 27.46 (nonlinear p = 0.047). In conclusion, in non-CKD populations, a higher Ca-P product (≥27.46 mg2/dl2) may help avoid TCAO.


Subject(s)
Coronary Artery Disease , Coronary Occlusion , Renal Insufficiency, Chronic , Humans , Calcium , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/epidemiology , Coronary Artery Disease/complications , Coronary Occlusion/complications , Coronary Occlusion/diagnosis , Coronary Occlusion/epidemiology , Cross-Sectional Studies , Phosphorus , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/epidemiology , Risk Factors
4.
Environ Sci Technol ; 58(1): 171-181, 2024 Jan 09.
Article in English | MEDLINE | ID: mdl-38100468

ABSTRACT

A case-crossover study among 511,767 cardiovascular disease (CVD) deaths in Jiangsu province, China, during 2015-2021 was conducted to assess the association of exposure to ambient ozone (O3) and heat wave with CVD mortality and explore their possible interactions. Heat wave was defined as extreme high temperature for at least two consecutive days. Grid-level heat waves were defined by multiple combinations of apparent temperature thresholds and durations. Residential O3 and heat wave exposures were assessed using grid data sets (spatial resolution: 1 km × 1 km for O3; 0.0625° × 0.0625° for heat wave). Conditional logistic regression models were applied for exposure-response analyses and evaluation of additive interactions. Under different heat wave definitions, the odds ratios (ORs) of CVD mortality associated with medium-level and high-level O3 exposures ranged from 1.029 to 1.107 compared with low-level O3, while the ORs for heat wave exposure ranged from 1.14 to 1.65. Significant synergistic effects on CVD mortality were observed for the O3 and heat wave exposures, which were generally greater with higher levels of the O3 exposure, higher temperature thresholds, and longer durations of heat wave exposure. Up to 5.8% of the CVD deaths were attributable to O3 and heat wave. Women and older adults were more vulnerable to the exposure to O3 and heat wave exposure. Exposure to both O3 and heat wave was significantly associated with an increased odds of CVD mortality, and O3 and heat wave can interact synergistically to trigger CVD deaths.


Subject(s)
Air Pollutants , Air Pollution , Cardiovascular Diseases , Ozone , Humans , Female , Aged , Ozone/analysis , Cardiovascular Diseases/epidemiology , Air Pollutants/analysis , Cross-Over Studies , Hot Temperature , China/epidemiology , Air Pollution/analysis , Environmental Exposure/analysis , Particulate Matter/analysis
5.
Ying Yong Sheng Tai Xue Bao ; 34(11): 2898-2906, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37997400

ABSTRACT

Soil respiration is a key process in forest biogeochemical cycling. Exploring the relationship between plant functional traits and soil respiration can help understand the effects of tree species conversion on soil carbon cycling. In this study, we selected 15 common subtropical tree species planted in the logging site of second-generation Chinese fir forest to measure soil CO2 emission fluxes, soil physicochemical properties, leaf and root functional traits of each species, and explored the effects of plant functional traits on soil respiration. The results showed that the annual flux of soil CO2 emissions varied from 7.93 to 22.52 Mg CO2·hm-2, with the highest value under Castanopsis carlesii (22.52 Mg CO2·hm-2) and the lowest value under Taxus wallichiana (7.93 Mg CO2·hm-2). Results of stepwise regression analysis showed that the annual flux of soil CO2 emission decreased with the increases of leaf nitrogen content and fine root diameter, and increased with increasing leaf non-structural carbohydrate. In the structural equation model, leaf non-structural carbohydrate had a direct and significant positive effect on soil CO2 emission fluxes, while leaf nitrogen content and fine root diameter had a direct negative effect by decreasing soil pH and soluble organic nitrogen content. Plantations of different tree species would affect soil CO2 emission directly by changing functional traits related to water and nutrient acquisition or indirectly through soil properties. When creating plantations, we should select tree species based on the relationship between plant functional traits and ecosystem functions, with a view to improving forest productivity and soil carbon sequestration potential.


Subject(s)
Ecosystem , Soil , Soil/chemistry , Carbon Dioxide/analysis , Forests , Trees , Nitrogen/analysis , Carbohydrates
6.
Sci Rep ; 13(1): 16805, 2023 10 05.
Article in English | MEDLINE | ID: mdl-37798470

ABSTRACT

In terrestrial ecosystems, leaf litter is the main source of nutrients returning to the soil. Understanding how litter decomposition responds to stand age is critical for improving predictions of the effects of forest age structure on nutrient availability and cycling in ecosystems. However, the changes in this critical process with stand age remain poorly understood due to the complexity and diversity of litter decomposition patterns and drivers among different stand ages. In this study, we examined the effects of stand age on litter decomposition with two well-replicated age sequences of naturally occurring secondary forests and Chinese fir (Cunninghamia lanceolata) plantations in southern China. Our results showed that the litter decomposition rates in the secondary forests were significantly higher than those in the Chinese fir plantations of the same age, except for 40-year-old forests. The litter decomposition rate of the Chinese fir initially increased and then decreased with stand age, while that of secondary forests gradually decreased. The results of a structural equation model indicated that stand age, litter quality and microbial community were the primary factors driving nutrient litter loss. Overall, these findings are helpful for understanding the effects of stand age on the litter decomposition process and nutrient cycling in plantation and secondary forest ecosystems.


Subject(s)
Cunninghamia , Microbiota , Ecosystem , Forests , Soil/chemistry , Nutrients , Plant Leaves/chemistry
7.
Ying Yong Sheng Tai Xue Bao ; 31(11): 3597-3604, 2020 Nov.
Article in Chinese | MEDLINE | ID: mdl-33300708

ABSTRACT

We investigated soil C:N:P stoichiometry and nutrient dynamics of Cunninghamia lanceolata plantations at different stand ages (5, 8, 21, 27 and 40 years old) in Fujian Baisha Fores-try Farm. We measured the concentrations of soil total carbon (TC), total nitrogen (TN), total phosphorus (TP), total potassium (TK), total calcium (Ca), total magnesium (Mg), and soil C:N:P stoichiometry at 0-10, 10-20, and 20-40 cm soil layers during different growth stages. The results showed that soil TC and TN concentrations and C:N remained unchanged during stand development. Soil TP content showed an increase-decrease-increase trend with increasing stand ages. Soil TP content was lowest, whereas C:P and N:P were highest at the mature stage of C. lanceolate plantation in the 0-10 and 10-20 cm soil layers. However, soil TP content showed no significant differences in all stand ages at the 20-40 cm soil layer. The contents of Ca and Mg were lowest at the mature stage of C. lanceolata stand. The TC was positively correlated with soil C:N, C:P and N:P. The TP was significantly and negatively correlated with soil C:P and N:P. Soil TP was a key factor regulating soil C:P and N:P stoichiometry. The development of mature plantation was mainly limited by soil P availability. To sustain the development of C. lanceolata plantations and improve nutrient cycling, phosphorus fertilizer could be applied during the rapid growth period of C. lanceolata. In addition, an appropriate extension of the rotation period of C. lanceolata plantation could facilitate soil nutrient restoration.


Subject(s)
Cunninghamia , Nitrogen/analysis , Nutrients , Phosphorus , Soil
8.
Ying Yong Sheng Tai Xue Bao ; 31(11): 3851-3858, 2020 Nov.
Article in Chinese | MEDLINE | ID: mdl-33300736

ABSTRACT

Investigating the response of soil microbial biomass and ecological stoichiometry to tree species transition is of great significance for understanding soil nutrient cycling and availability in forest ecosystems. We measured soil microbial biomass carbon (MBC), nitrogen (MBN), phosphorus (MBP) and their stoichiometry across 0-40 cm soil depth between Mytilaria laosensis and Cunninghamia lanceolata plantations by the chloroform fumigation extraction method, which were replanted after the harvest of C. lanceolata plantation. The results showed that soil MBC in the 0-10 cm layer and soil MBN and MBP in the 0-20 cm layer under the M. laosensis were significantly higher than those under the C. lanceolata. The MBC/MBP in the 0-20 cm layer and MBN/MBP in the 10-20 cm layer were significantly lower under the M. laosensis plantation. The MBC/MBN showed no significant differences between the two forests. Soil moisture, organic carbon, total nitrogen, total phosphorus, available phosphorus were positively correlated with MBC, MBN and MBP, but negatively correlated with MBC/MBP and MBN/MBP. Results of stepwise linear regression analysis showed that MBN and MBP were mainly affected by soil total nitrogen and available phosphorus, while MBC/MBP and MBN/MBP were mainly driven by available phosphorus and organic carbon, respectively. Our results indicated that tree species transition from C. lanceolata to M. laosensis could increase soil microbial biomass in the surface layers, accelerate soil nutrients turnover and enhance soil nutrient supply. The increases of MBP under M. laosensis indicate alleviation of soil phosphorus limitation for tree growth.


Subject(s)
Cunninghamia , Ecosystem , Soil , Soil Microbiology , Trees
9.
Ying Yong Sheng Tai Xue Bao ; 31(4): 1088-1096, 2020 Apr.
Article in Chinese | MEDLINE | ID: mdl-32530182

ABSTRACT

Phosphorus (P) limitation is one of the major issues for the management of subtropical plantations. Understanding the effects of tree species transition from conifer to broadleaved trees on soil P fraction and availability in different soil layers are of great significance for the sustainable development of subtropical forests. We compared changes in soil chemical properties, P fraction and availability across 0-100 cm soil profile between Mytilaria laosensis and Cunninghamia lanceolata plantations, which were initially reforested from C. lanceolata plantation in the spring of 1993. The results showed that soil organic P content in both plantations decreased significantly with soil depth. Compared with C. lanceolata, the M. laosensis plantation significantly increased soil available P content by 35.7% and 86.2% in the 0-10 and 10-20 cm, respectively. The contents of soil labile P and moderately labile P decreased significantly with soil depth in both plantations. The contents of labile P and moderately labile P were significantly higher in the surface soil (0-20 cm), while the non-labile P in the 80-100 cm was increased by 13.6%, and the free iron content in the 20-80 cm significantly decreased. Results of redundancy analysis showed that dissolved organic carbon and free iron were the most important factors influencing P fraction in those plantations. Tree species transition from C. lanceolata to M. laosensis could change the pattern of soil P fraction in soil profile, and greatly enhance soil P availability.


Subject(s)
Cunninghamia , Carbon , China , Forests , Nitrogen , Phosphorus , Soil , Trees
10.
Appl Opt ; 57(5): 1241-1246, 2018 Feb 10.
Article in English | MEDLINE | ID: mdl-29469870

ABSTRACT

Beads trapped in optical tweezers are aligned along the optical propagation direction, which makes it difficult to determine the number of beads with bright-field microscopy. This problem also dramatically influences the measurement of the optical trapping based single-molecule force spectroscopy. Here, we propose a video processing approach to count the number of trapped micro-objects in real time. The approach uses a normalized cross-correlation algorithm and image enhancement techniques to amplify a slight change of the image induced by the entry of an exotic object. As tested, this method introduces a ∼10% change per bead to the image similarity, and up to four beads, one-by-one falling into the trap, are identified. Moreover, the feasibility of the above analysis in a moving trap is investigated. A movement of the trap leads to a fluctuation of less than 2% for the similarity signal and can be ignored in most cases. The experimental results prove that image similarity measurement is a sensitive way to monitor the interruption, which is very useful, especially during experiments. In addition, the approach is easy to apply to an existing optical tweezers system.

11.
Ther Apher Dial ; 17(4): 454-61, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23931889

ABSTRACT

The aim of this study was to investigate the effect of neutral microporous resin hemoperfusion on oxygenation improvement, removal of inflammatory cytokines in plasma and bronchoalveolar lavage, and mortality in acute lung injury induced by extrapulmonary sepsis. Forty-six patients with acute lung injury induced by extrapulmonary sepsis were randomized to HA type hemoperfusion treatment (N=25) or standard therapy (N=21). Those undergoing hemoperfusion treatment received HA330 hemoperfusion. We measured the plasma and bronchoalveolar lavage concentrations of TNF-α and IL-1, and the following parameters were compared between the control group and the hemoperfusion group on days 0, 3 and 7: lung injury measurements (arterial oxygen tension/fractional inspired oxygen ratio, lung injury score, chest X-ray score); interstitial edema of lung (extravascular lung water). Duration of mechanical ventilation, hospital, 28-day, and intensive care unit mortality were also observed. Patients treated with HA hemoperfusion showed a significant removal of plasma and bronchoalveolar lavage TNF-α and IL-1 over time while in the study. Patients in the HA group also demonstrated not only significant improvement of PaO2 /FiO2 , but also decreased Lung Injury Score and chest X-ray score at days 3 and 7. Furthermore, the measurements of the arterial oxygen tension/fractional inspired oxygen ratio, lung injury score and extravascular lung water (EVLWI) significantly correlated with and the concentration of cytokines in the plasma (all P<0.05). The HA hemoperfusion treatment group had a significant reduction in duration of mechanical ventilation, length of intensive care unit stay, and intensive care unit mortality. Significant removal of inflammatory cytokines from circulation and lung by hemoperfusion treatment using the HA type cartridge may contribute to the improvement of lung injury and intensive care unit outcome in extrapulmonary septic patients.


Subject(s)
Acute Lung Injury/therapy , Hemoperfusion/methods , Sepsis/complications , Acute Lung Injury/etiology , Aged , Bronchoalveolar Lavage Fluid/chemistry , Female , Humans , Inflammation Mediators/metabolism , Intensive Care Units , Interleukin-1/metabolism , Length of Stay , Male , Middle Aged , Respiration, Artificial/methods , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/metabolism
12.
Ther Apher Dial ; 14(6): 596-602, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21118369

ABSTRACT

The aim of this study is to evaluate the impact of neutral microporous resin hemoperfusion on hemodynamic improvement, removal of inflammatory cytokines, and mortality in critical care patients with severe sepsis. Forty-four patients with severe sepsis or septic shock were randomized to HA type hemoperfusion treatment (N=24) or standard therapy (N=20). Those undergoing hemoperfusion treatment received HA330 hemoperfusion. We measured the plasma concentrations of IL-6 and IL-8 at the start of every hemoperfusion treatment, and the following parameters were compared between the control group and the hemoperfusion group on days 3, 7, and 14: hemodynamics (cardiac index, systemic vascular resistance index, heart rate, and mean arterial pressure); change of hematology and coagulation function; organ function; and the sequential organ failure assessment (SOFA) score. Hospital, 28-day, and ICU mortality were also observed. Patients treated with HA hemoperfusion showed a significant removal of plasma IL-6 and IL-8 over time while in the study. Patients in the HA group also demonstrated significant increases in cardiac index, systemic vascular resistant index, fast withdrawal of vasoactive agents and decreases in heart rate compared with the controls at days 3 and 7. Although there was no significant difference between the groups in organ dysfunction as assessed by SOFA scores from day 0 (baseline) to day 7, significant improvement can be demonstrated in the hemoperfusion group at day 14. There was no significant difference between the groups in 28-day mortality, hospital mortality, or length of hospital stay, but ICU mortality and the length of ICU stay in the HA group were markedly reduced. Hemoperfusion treatment using the HA type cartridge in sepsis is safe and it may improve organ dysfunction, ICU mortality, and shorten the length of ICU stay. Clinical significant removal of inflammatory cytokines such as IL-6 and IL-8 from circulation by hemoperfusion may contribute to improving a patient's outcome in an ICU.


Subject(s)
Hemoperfusion/methods , Sepsis/therapy , Shock, Septic/therapy , Aged , Aged, 80 and over , Blood Pressure , Female , Heart Rate , Hemoperfusion/adverse effects , Hospital Mortality , Humans , Intensive Care Units , Interleukin-6/blood , Interleukin-8/blood , Length of Stay , Male , Middle Aged , Multiple Organ Failure/diagnosis , Multiple Organ Failure/etiology , Severity of Illness Index , Survival , Time Factors
13.
Biochem Pharmacol ; 78(2): 153-61, 2009 Jul 15.
Article in English | MEDLINE | ID: mdl-19427995

ABSTRACT

Nilotinib, a BCR-Abl tyrosine kinase inhibitor (TKI), was developed to surmount resistance or intolerance to imatinib in patients with Philadelphia positive chronic myelogenous leukemia. Recently, it was shown that several human multidrug resistance (MDR) ATP-binding cassette (ABC) proteins could be modulated by specific TKIs. MDR can produce cancer chemotherapy failure, typically due to overexpression of ABC transporters, which are involved in the extrusion of therapeutic drugs. Here, we report for the first time that nilotinib potentiates the cytotoxicity of widely used therapeutic substrates of ABCG2, such as mitoxantrone, doxorubicin, and ABCB1 substrates including colchicine, vincristine, and paclitaxel. Nilotinib also significantly enhances the accumulation of paclitaxel in cell lines overexpressing ABCB1. Similarly, nilotinib significantly increases the intracellular accumulation of mitoxantrone in cells transfected with ABCG2. Furthermore, nilotinib produces a concentration-dependent inhibition of the ABCG2-mediated transport of methotrexate (MTX), as well as E(2)17betaG a physiological substrate of ABCG2. Uptake studies in membrane vesicles overexpressing ABCG2 have indicated that nilotinib inhibits ABCG2 similar to other established TKIs as well as fumitremorgin C. Nilotinib is a potent competitive inhibitor of MTX transport by ABCG2 with a K(i) value of 0.69+/-0.083 microM as demonstrated by kinetic analysis of nilotinib. Overall, our results indicate that nilotinib could reverse ABCB1- and ABCG2-mediated MDR by blocking the efflux function of these transporters. These findings may be used to guide the design of present and future clinical trials with nilotinib, elucidating potential pharmacokinetic interactions. Also, these findings may be useful in clinical practice for cancer combination therapy with nilotinib.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP-Binding Cassette Transporters/antagonists & inhibitors , Drug Resistance, Multiple/physiology , Neoplasm Proteins/antagonists & inhibitors , Pyrimidines/pharmacology , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/metabolism , Cell Line , Cell Survival/drug effects , Cell Survival/physiology , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/physiology , Humans , KB Cells , Neoplasm Proteins/metabolism
14.
Cancer Res ; 68(19): 7905-14, 2008 Oct 01.
Article in English | MEDLINE | ID: mdl-18829547

ABSTRACT

Lapatinib is active at the ATP-binding site of tyrosine kinases that are associated with the human epidermal growth factor receptor (Her-1 or ErbB1) and Her-2. It is conceivable that lapatinib may inhibit the function of ATP-binding cassette (ABC) transporters by binding to their ATP-binding sites. The aim of this study was to investigate the ability of lapatinib to reverse tumor multidrug resistance (MDR) due to overexpression of ABC subfamily B member 1 (ABCB1) and ABC subfamily G member 2 (ABCG2) transporters. Our results showed that lapatinib significantly enhanced the sensitivity to ABCB1 or ABCG2 substrates in cells expressing these transporters, although a small synergetic effect was observed in combining lapatinib and conventional chemotherapeutic agents in parental sensitive MCF-7 or S1 cells. Lapatinib alone, however, did not significantly alter the sensitivity of non-ABCB1 or non-ABCG2 substrates in sensitive and resistant cells. Additionally, lapatinib significantly increased the accumulation of doxorubicin or mitoxantrone in ABCB1- or ABCG2-overexpressing cells and inhibited the transport of methotrexate and E(2)17betaG by ABCG2. Furthermore, lapatinib stimulated the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner. However, lapatinib did not affect the expression of these transporters at mRNA or protein levels. Importantly, lapatinib also strongly enhanced the effect of paclitaxel on the inhibition of growth of the ABCB1-overexpressing KBv200 cell xenografts in nude mice. Overall, we conclude that lapatinib reverses ABCB1- and ABCG2-mediated MDR by directly inhibiting their transport function. These findings may be useful for cancer combinational therapy with lapatinib in the clinic.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP-Binding Cassette Transporters/antagonists & inhibitors , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Neoplasm Proteins/antagonists & inhibitors , Neoplasms/pathology , Quinazolines/pharmacology , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Adenosine Triphosphatases/drug effects , Adenosine Triphosphatases/metabolism , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cells, Cultured , Dose-Response Relationship, Drug , Drug Resistance, Multiple/genetics , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Lapatinib , Mice , Mice, Nude , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolism , Paclitaxel/administration & dosage , Paclitaxel/pharmacokinetics , Quinazolines/administration & dosage , Quinazolines/pharmacokinetics , Transfection , Tumor Burden/drug effects , Up-Regulation/drug effects , Up-Regulation/physiology , Xenograft Model Antitumor Assays
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