Tanshinone IIA inhibits hypoxia/reoxygenation-induced cardiomyocyte apoptosis and autophagy by regulating ABCE1 / 中华危重病急救医学

OBJECTIVE@#To investigate the effects of tanshinone IIA on apoptosis and autophagy induced by hypoxia/reoxygenation in H9C2 cardiomyocytes and its mechanism.@*METHODS@#H9C2 cardiomyocytes in logarithmic growth phase were divided into control group, hypoxia/reoxygenation model group and tanshinone IIA low-dose, medium-dose and high-dose groups (50, 100, 200 mg/L tanshinone IIA were treated after hypoxia/reoxygenation respectively). The dose with good therapeutic effect was selected for follow-up study. The cells were divided into control group, hypoxia/reoxygenation model group, tanshinone IIA+pcDNA3.1-NC group and tanshinone IIA+pcDNA3.1-ABCE1 group. The cells were transfected with the overexpressed plasmids pcDNA3.1-ABCE1 and pcDNA3.1-NC and then treated accordingly. Cell counting kit-8 (CCK-8) was used to detect H9C2 cell activity in each group. The apoptosis rate of cardiomyocytes was detected by flow cytometry. The ATP-binding cassette transporter E1 (ABCE1), apoptosis-related proteins Bcl-2 and Bax, caspase-3, autophagy-related proteins Beclin-1, microtubule-associated protein 1 light chain 3 (LC3II/I) and p62 mRNA expression level of H9C2 cells in each group were detected by real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-qPCR). The protein expression levels of the above indexes in H9C2 cells were detected by Western blotting.@*RESULTS@#(1) Cell activity and ABCE1 expression: tanshinone IIA inhibited the activity of H9C2 cells induced by hypoxia/reoxygenation, and the effect was significant at medium-dose [(0.95±0.05)% vs. (0.37±0.10)%, P < 0.01], mRNA and protein expression of ABCE1 were significantly reduced [ABCE1 mRNA (2-ΔΔCt): 2.02±0.13 vs. 3.74±0.17, ABCE1 protein (ABCE1/GAPDH): 0.46±0.04 vs. 0.68±0.07, both P < 0.05]. (2) Expression of apoptosis-related proteins: medium-dose of tanshinone IIA inhibited the apoptosis of H9C2 cells induced by hypoxia/reoxygenation [apoptosis rate: (28.26±2.52)% vs. (45.27±3.07)%, P < 0.05]. Compared with the hypoxia/reoxygenation model group, medium-dose of tanshinone IIA significantly down-regulated the protein expression of Bax and caspase-3 in H9C2 cells induced by hypoxia/reoxygenation, and significantly up-regulated the protein expression of Bcl-2 [Bax (Bax/GAPDH): 0.28±0.03 vs. 0.47±0.03, caspase-3 (caspase-3/GAPDH): 0.31±0.02 vs. 0.44±0.03, Bcl-2 (Bcl-2/GAPDH): 0.53±0.02 vs. 0.37±0.05, all P < 0.05]. (3) Expression of autophagy-related proteins: compared with the control group, the positive rate of LC3 in the hypoxia/reoxygenation model group was significantly increased, while the positive rate of LC3 in the medium-dose of tanshinone IIA group was significantly decreased [(20.67±3.09)% vs. (42.67±3.86)%, P < 0.01]. Compared with hypoxia/reoxygenation model group, medium-dose of tanshinone IIA significantly down-regulated Beclin-1, LC3II/I and p62 protein expressions [Beclin-1 (Beclin-1/GAPDH): 0.27±0.05 vs. 0.47±0.03, LC3II/I ratio: 0.24±0.05 vs. 0.47±0.04, p62 (p62/GAPDH): 0.21±0.03 vs. 0.48±0.02, all P < 0.05]. (4) Expression of apoptosis and autophagy related proteins after transfection with overexpressed ABCE1 plasmid: compared with tanshinone IIA+pcDNA3.1-NC group, the protein expression levels of Bax, caspase-3, Beclin-1, LC3II/I and p62 in tanshinone IIA+pcDNA3.1-ABCE1 group were significantly up-regulated, while the protein expression level of Bcl-2 was significantly down-regulated.@*CONCLUSIONS@#100 mg/L tanshinone IIA could inhibit autophagy and apoptosis of cardiomyocytes by regulating the expression level of ABCE1. So, it protects H9C2 cardiomyocytes injury induced by hypoxia/reoxygenation.

Cryo-EM structures for the Mycobacterium tuberculosis iron-loaded siderophore transporter IrtAB

The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter, IrtAB, plays a vital role in the replication and viability of Mycobacterium tuberculosis (Mtb), where its function is to import iron-loaded siderophores. Unusually, it adopts the canonical type IV exporter fold. Herein, we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP, ADP, or ATP analogue (AMP-PNP) at resolutions ranging from 2.8 to 3.5 Å. The structure of IrtAB bound ATP-Mg2+ shows a "head-to-tail" dimer of nucleotide-binding domains (NBDs), a closed amphipathic cavity within the transmembrane domains (TMDs), and a metal ion liganded to three histidine residues of IrtA in the cavity. Cryo-electron microscopy (Cryo-EM) structures and ATP hydrolysis assays show that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with IrtB. Moreover, the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport cycle. This study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.

Advances in bacterial adsorption and transport of aromatic compounds / 生物工程学报

Aromatic compounds are a class of organic compounds with benzene ring(s). Aromatic compounds are hardly decomposed due to its stable structure and can be accumulated in the food cycle, posing a great threat to the ecological environment and human health. Bacteria have a strong catabolic ability to degrade various refractory organic contaminants (e.g., polycyclic aromatic hydrocarbons, PAHs). The adsorption and transportation are prerequisites for the catabolism of aromatic compounds by bacteria. While remarkable progress has been made in understanding the metabolism of aromatic compounds in bacterial degraders, the systems responsible for the uptake and transport of aromatic compounds are poorly understood. Here we summarize the effect of cell-surface hydrophobicity, biofilm formation, and bacterial chemotaxis on the bacterial adsorption of aromatic compounds. Besides, the effects of outer membrane transport systems (such as FadL family, TonB-dependent receptors, and OmpW family), and inner membrane transport systems (such as major facilitator superfamily (MFS) transporter and ATP-binding cassette (ABC) transporter) involved in the membrane transport of these compounds are summarized. Moreover, the mechanism of transmembrane transport is also discussed. This review may serve as a reference for the prevention and remediation of aromatic pollutants.

Sterol transport proteins in yeast: a review / 生物工程学报

Sterols are a class of cyclopentano-perhydrophenanthrene derivatives widely present in living organisms. Sterols are important components of cell membranes. In addition, they also have important physiological and pharmacological activities. With the development of synthetic biology and metabolic engineering technology, yeast cells are increasingly used for the heterologous synthesis of sterols in recent years. Nevertheless, since sterols are hydrophobic macromolecules, they tend to accumulate in the membrane fraction of yeast cells and consequently trigger cytotoxicity, which hampers the further improvement of sterols yield. Therefore, revealing the mechanism of sterol transport in yeast, especially understanding the working principle of sterol transporters, is vital for designing strategies to relieve the toxicity of sterol accumulation and increasing sterol yield in yeast cell factories. In yeast, sterols are mainly transported through protein-mediated non-vesicular transport mechanisms. This review summarizes five types of sterol transport-related proteins that have been reported in yeast, namely OSBP/ORPs family proteins, LAM family proteins, ABC transport family proteins, CAP superfamily proteins, and NPC-like sterol transport proteins. These transporters play important roles in intracellular sterol gradient distribution and homeostasis maintenance. In addition, we also review the current status of practical applications of sterol transport proteins in yeast cell factories.

Disfunción del transportador del surfactante pulmonar ABCA3: reporte de un caso peruano / Surfactant ABCA3 transporter dysfunction: a case report from Peru

Resumen Introducción: Los trastornos genéticos que afectan la homeostasis del surfactante pulmonar son una causa importante del síndrome de dificultad respiratoria en el recién nacido a término y de enfermedad pulmonar intersticial difusa en niños. El transportador ABCA3 (ATP binding cassette A3) interviene en la producción normal del surfactante que recubre el interior de las paredes alveolares y funciona como agente tensioactivo. Caso clínico: Recién nacido a término que presentó dificultad respiratoria a los 3 días de vida y requirió ventilación mecánica. Los estudios para determinar otras causas de enfermedad pulmonar fueron negativos. Se realizó una biopsia de pulmón para realizar estudios de microscopía óptica y microscopía electrónica. Esta última mostró pequeños cuerpos lamelares anómalos, además de condensaciones electrodensas periféricas, características de las mutaciones del transportador ABCA3. Se inició tratamiento con pulsos de metilprednisolona, hidroxicloroquina, azitromicina y corticoides inhalados a dosis altas, y la respuesta clínica y radiológica fue favorable durante el seguimiento. Conclusiones: La correlación de las características clínicas y de las imágenes (tomografía y microscopía electrónica) puede ser útil para el diagnóstico de la disfunción del surfactante pulmonar, especialmente en los países de bajos y medianos recursos que no disponen de estudios genéticos para determinar las diferentes mutaciones del transportador ABCA3. Este es uno de los primeros casos reportados en Perú con respuesta adecuada al tratamiento y evolución favorable durante el seguimiento.

Abstract Background: Genetic disorders affecting pulmonary surfactant homeostasis are a major cause of respiratory distress syndrome in full-term newborn and childhood interstitial lung disease. The ABCA3 transporter (ATP binding cassette A3) intervenes in the normal production of surfactant that covers the interior of alveolar walls and plays a fundamental role as a surfactant. Case report: Male term newborn who presented respiratory distress 3 days after birth and required mechanical ventilation. Studies to determine other causes of lung disease were negative. Lung biopsy was performed for the study with light microscopy and electron microscopy. Electron microscopy showed small abnormal lamellar bodies in addition to peripheral electrodense condensations characteristic of ABCA3 transporter mutation. Treatment was started with pulses of methylprednisolone, hydroxychloroquine, azithromycin, and high-dose inhaled corticosteroids, finding a favorable clinical and radiological response to follow-up. Conclusions: Correlation of clinical characteristics and images (tomography and electron microscopy) can be useful for the diagnosis of lung surfactant dysfunction, especially in low and medium-income countries where genetic studies to determine the different ABCA3 transporter mutations are not available. This is one of the first cases reported in Peru with an adequate response to treatment and favorable evolution to follow-up.

Progress of studies on ATP-binding cassette transporters and transportation of secondary metabolites in medicinal plants / 中国中药杂志

ATP-binding cassette(ABC) transporters are one of the largest protein families in organisms, with important effects in regulating plant growth and development, root morphology, transportation of secondary metabolites and resistance of stress. Environmental stress promotes the biosynthesis and accumulation of secondary metabolites, which determines the quality of medicinal plants. Therefore, how to improve the accumulation of secondary metabolites has been a hotspot in studying medicinal plants. Many studies have showed that ABC transporters are extremely related to the transportation and accumulation of secondary metabolites in plants. Recently, with the great development of genomics and transcriptomic sequencing technology, the regulatory mechanisms of ABC transporters on secondary metabolites have attached great attentions in medicinal plants. This paper reviewed the mechanisms of different groups of ABC transporters in transporting secondary metabolites through cell membranes. This paper provided key theoretical basis and technical supports in studying the mechanisms of ABC transporters in medicinal plant, and promoting the accumulation of secondary metabolites, in order to improve the quality of medicinal plants.

El intersticio pulmonar y sus enfermedades en la infancia. Deficiencia de ABCA3. Seguimiento durante doce años. Perspectivas ¿Un nuevo paradigma genético? / The pulmonary interstitium and its diseases in childhood. ABCA3 deficiency. Follow-up for 12 years. Perspectives. A new genetic paradigm?

Introducción. Sobre la base de un caso clínico, se presenta la descripción del cuadro intersticial por deficiencia de ABCA3, de una paciente de catorce años de edad, en seguimiento durante doce años. Método. Evaluación clínica con extensos estudios para descartar otras patologías semejantes. El diagnóstico definitivo fue determinado por el estudio genético para deficiencias de ABCA3 y otros defectos genéticos realizados por el Dr. Larry Nogee, Hospital Johns Hopkins, EE. UU. Objetivos. Describir detalladamente la evolución de la paciente durante doce años, con énfasis en los estudios anteriormente mencionados. Sugerir la presencia de un cambio de paradigma pronóstico en lo que se conocía sobre la evolución de esta enfermedad intersticial pulmonar grave, tratar de mejorar la calidad de vida y posiblemente el pronóstico. Presentar los hallazgos de genética, anatomía patológica y radiología en consultas y evaluaciones por centros de referencia. Resultados. Realizado su diagnóstico de deficiencia genética de ABCA3, presentamos su seguimiento actualizado hasta el año 2020. Esta debe ser sospechada en niños pequeños desde el nacimiento y durante los primeros años ante la persistencia de cuadros pulmonares crónicos con desaturación de oxígeno e imágenes tomográficas que sugieren cuadro intersticial. Se decidió tratar el cuadro en los años 2019-2020, durante seis meses, según bibliografía y consultas con centros de referencia en los Estados Unidos, con la finalidad de determinar la posible mejoría de su patología y decidir la continuación o suspensión de la medicación. Se usaron pulsos con metilprednisolona- hidroxicloroquina y azitromicina. Se logró mantener estable su función pulmonar y mejorar notablemente su calidad de vida. (AU)

Introduction. A clinical case diagnosed with ABCA3 deficiency is described. Patient is now fourteen years old. She´s being followed up since she was two years old. Methodology. clinical follow ­ up with extensive studies to rule out other similar pathologies. Final diagnosis was done through genetic studies done at Johns Hopkins Hospital by Nogee LM. Objective. To present a detailed evolution description of twelve years' follow-up with the support of the aforementioned studies, to suggest a change in diagnostic ­ prognostic paradigm on what was known of mortality in this severe pulmonary interstitial pathology to improve life quality and possibly prognosis. Present the findings of genetics, pathological anatomy and radiology in consultations and evaluations by reference centers. Results. Having made her diagnosis of genetic ABCA3 deficiency, we present her up dated follow-up until 2020. This should be suspected in young children from birth and during the first years due to the persistence of chronic pulmonary symptoms with oxygen desaturation and tomographic images that suggest interstitial symptoms. It was decided to treat the condition in the years 2019-2020, for six months, according to the bibliography and consultations with reference centers in the United States, in order to determine the possible improvement of her pathology and decide to continue or suspend the medication. Pulses with methylprednisolone hydroxychloroquine and azithromycin were used. Her lung function was stable and her quality of life significantly improved. (AU)

MiR-124-3p Enhances the Sansitivity of Chronic Myelogenous Leukemia Cell K562-R to Imatinib by Targeting ABCA2 / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect and mechanism of miR-124-3p-targeing regulating ABCA2 on chronic myelogenous leukemia cell K562-R.@*METHODS@#CML cells with miR-124-3p-overexpression and ABCA2-over-expression as well as subcutaneoustrans planted tumor nude mice were used as study objects. And the CML cells were divided into four groups: K562-R blank control, miR-124-3p mimic control, ABCA2-overexpression and mimic+PC ABCA2. The effects of miR-124-3p and ABCA2 on CML cells were analyzed. The levels of proliferation-, apoptosis- and autophagy- related protein were determined by Western blot. qRT-PCR was employed to detect the levels of miR-124-3p and ABCA2 in K562-R cells. The relationship between miR-124-3p and ABCA2 was validated by luciferase reporter system assays and bioinformatics. Hoechst/immunohistochemical staining and CCK-8 assay were performed to investigate the function involved.@*RESULTS@#miR-124-3p highly expressed in K562-S cells and lowly expressed in K562-R cells, however, ABCA2 lowly expressed in K562-S cells and highly expressed in K562-R cells. Over-expression of miR-124-3p significantly decreased ABCA2 level and cell growth, but increased autophagy and apoptosis in K562-R cells (P＜0.01). When ABCA2 was over-expressed, the K562-R cell growth was promoted and autophagy and apoptosis were inhibited (P＜0.01). The miR-124-3p promoted cell autophagy and apoptosis but inhibited cell growth in nude mice transplant tumor model (P＜0.01).@*CONCLUSION@#miR-124-3p can target ABCA2 to inhibit the growth of CML cells and promote the cell autophagy and apoptosis of CML cells.

Genetic analysis and prenatal diagnosis of a fetus with harlequin ichthyosis / 中华医学遗传学杂志

OBJECTIVE@#To carry out variant analysis for a fetus suspected with harlequin ichthyosis (HI).@*METHODS@#Whole exome sequencing (WES) was employed to detect potential variant in the fetus. Suspected variant was validated by Sanger sequencing.@*RESULTS@#A homozygous missense variant c.6858delT (p.F2286fs) was detected in the fetus, for which both parents were heterozygous carriers. Pathological analysis confirmed the diagnosis of HI.@*CONCLUSION@#The c.6858delT variant of the ABCA12 gene probably underlies the disease in the fetus.

Two natural molecules preferentially inhibit azole-resistant Candida albicans with MDR1 hyperactivation / 中国天然药物

Antifungal drug resistance is a significant clinical problem, and antifungal agents that can evade resistance are urgently needed. In infective niches, resistant organisms often co-existed with sensitive ones, or a subpopulation of antibiotic-susceptible organisms may evolve into resistant ones during antibiotic treatment and eventually dominate the whole population. In this study, we established a co-culture assay in which an azole-resistant Candida albicans strain was mixed with a susceptible strain labeled with green fluorescent protein to mimic in vivo conditions and screen for antifungal drugs. Fluconazole was used as a positive control to verify the validity of this co-culture assay. Five natural molecules exhibited antifungal activity against both susceptible and resistant C. albicans. Two of these compounds, retigeric acid B (RAB) and riccardin D (RD), preferentially inhibited C. albicans strains in which the efflux pump MDR1 was activated. This selectivity was attributed to greater intracellular accumulation of the drugs in the resistant strains. Changes in sterol and lipid compositions were observed in the resistant strains compared to the susceptible strain, and might increase cell permeability to RAB and RD. In addition, RAB and RD interfered with the sterol pathway, further aggregating the decrease in ergosterol in the sterol synthesis pathway in the MDR1-activated strains. Our findings here provide an alternative for combating resistant pathogenic fungi.

Phenotype and genetic analysis of a pedigree affected with progressive familial intrahepatic cholestasis / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology for a pedigree affected with progressive familial intrahepatic cholestasis (PFIC).@*METHODS@#Target sequence capture and next generation sequencing (NGS) were applied for the proband. PCR and Sanger sequencing were used to verify the suspected mutation in his sister with similar symptoms and his parents.@*RESULTS@#The proband and his sister manifested after birth with symptoms including jaundice, pruritus and developmental retardation. NGS has identified compound heterozygous mutations of ABCB11 gene, which encodes bile salt export pump protein (BSEP), namely c.2494C>T (p.Arg832Cys) and c.3223C>T (p.Gln1075*), in the proband, which were inherited from his father and mother respectively. His sister carried the same compound mutations.@*CONCLUSION@#Based on the phenotype and genetic testing, the patients were diagnosed as PFIC2 caused by mutation of the ABCB11 gene. The c.3223C>T is a novel nonsense mutation which may cause premature termination of translation. Above results have enriched the spectrum of ABCB11 mutations and provided new evidence for the molecular basis of PFIC, which also facilitated genetic counseling for this pedigree.

ABCB1 and BMI1 mRNA expression in patients with chronic myeloid leukemia: impact on imatinib efficacy

BACKGROUND: ATP-binding cassette transporters are important in the mechanism of multidrug resistance. ABCB1 displays a high affinity for imatinib. BMI1 is a polycomb group protein thought to be overexpressed in leukemic cells. METHODS: This study was conducted to investigate the prognostic value of ABCB1 and BMI1 expressions in chronic myeloid leukemia (CML). Expression levels were measured in 81 patients newly diagnosed with CML and 20 healthy controls by real time reverse transcription- PCR. RESULTS: The ABCB1 expression levels did not differ between patients with CML and controls. Low ABCB1 mRNA levels were observed in patients who achieved an optimal response compared to suboptimal and resistant cases (P=0.005). Non-responders showed the highest ABCB1 levels. ABCB1 expression did not affect the progression-free survival (PFS) of patients. BMI1 expression was higher in patients than that in controls (P=0.001). Patients in advanced phases expressed higher levels of BMI1 than those in the chronic phase (P=0.004). High BMI1 expression was associated with a shorter PFS. CONCLUSION: ABCB1 mRNA expression may serve as a predictor of the optimal response to imatinib treatment in patients with CML. BMI1 expression was higher in the accelerated and blastic crisis phases of CML and associated with a shorter PFS.

Correlation between estrogen receptor β and ABCC11 gene single nucleotide polymorphisms and axillary osmidrosis / 中南大学学报(医学版)

To explore the correlation between single nucleotide polymorphisms (SNPs) of hormone receptor gene or other related genes and axillary osmidrosis (AO).
 Methods: Whole blood samples of 219 patients with AO and 159 normal people were collected, and their genomic DNA was extracted. SNPs of 49 selected gene loci were detected and analyzed by using matrix-assisted laser analysis and ionization time of flight mass spectrometry and other related technologies.
 Results: There were significant differences in SNPs at rs1256061 of estrogen receptor β gene and rs17822931, rs16945916 and rs62058521 in ABCC11 gene between the AO patients and normal people (all P<0.01). 81.1% of patients with AO carried G allele at rs1256061, while only 63.2% of normal people carried G allele; 96.3% of patients with AO carried G allele at rs17822931, while only 4.4% of the normal people carried G allele; 28.6% of the patients with armpit odor carried the G allele of rs16945916, while only 0.6% of the normal people carried G allele; 28.0% of patients with AO carried G allele at rs62058521, while only 0.6% of the normal people carried G allele.
 Conclusion: SNPs of rs1256061 at the locus of estrogen receptor gene are correlated with the pathogenesis of AO, while SNPs at multiple loci (rs16945916, rs62058521 and rs17822931) in ABCC11 gene are correlated with the pathogenesis of AO.

All-trans-retinoic acid generation is an antidotal clearance pathway for all-trans-retinal in the retina / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

The present study was designed to analyze the metabolites of all-trans-retinal (atRal) and compare the cytotoxicity of atRal versus its derivative all-trans-retinoic acid (atRA) in human retinal pigment epithelial (RPE) cells. We confirmed that atRA was produced in normal pig neural retina and RPE. The amount of all-trans-retinol (atROL) converted from atRal was about 2.7 times that of atRal-derived atRA after incubating RPE cells with 10 μmol/L atRal for 24 h, whereas atRA in medium supernatant is more plentiful (91 vs. 29 pmol/mL), suggesting that atRA conversion facilitates elimination of excess atRal in the retina. Moreover, we found that mRNA expression of retinoic acid-specific hydroxylase CYP26b1 was dose-dependently up-regulated by atRal exposure in RPE cells, indicating that atRA inactivation may be also initiated in atRal-accumulated RPE cells. Our data show that atRA-caused viability inhibition was evidently reduced compared with the equal concentration of its precursor atRal. Excess accumulation of atRal provoked intracellular reactive oxygen species (ROS) overproduction, heme oxygenase-1 (HO-1) expression, and increased cleaved poly(ADP-ribose) polymerase 1 (PARP1) expression in RPE cells. In contrast, comparable dosage of atRA-induced oxidative stress was much weaker, and it could not activate apoptosis in RPE cells. These results suggest that atRA generation is an antidotal metabolism pathway for atRal in the retina. Moreover, we found that in the eyes of ABCA4-/-RDH8-/- mice, a mouse model with atRal accumulation in the retina, the atRA content was almost the same as that in the wild type. It is possible that atRal accumulation simultaneously and equally promotes atRA synthesis and clearance in eyes of ABCA4-/-RDH8-/- mice, thus inhibiting the further increase of atRA in the retina. Our present study provides further insights into atRal clearance in the retina.

Pharmacokinetics mechanism of ABC efflux proteins-mediated seven features of compatibility / 中国中药杂志

ABC efflux proteins are a kind of transporters mediating diversified endogenous and exogenous efflux protein substrates across the plasma membrane by depending on the chemical energy released by ATP hydrolysis. As a vitally important functional membrane, it is widely found in various tissues and organs. The drug changes the expressions and/or functions of the transport proteins, which will affect the disposal process of substrate drugs corresponding to transporters , and finally lead to the pharmacokinetic interactions. The efflux proteins take part in the absorption, distribution, metabolism and excretion of drugs, and mainly consist of P-glycoprotein(P-gp), multidrug resistance associated protein(MRP) and breast cancer resistance protein(BCRP). The induction effect or inhibition effect of drugs on efflux protein plays a greatly significant role in the drug interaction produced by the compatibility of traditional Chinese medicine, which may be one of the important mechanisms of the theory of seven features of compatibility. In this article, the effects of seven features of compatibility on the ABC efflux transporters were reviewed, in order to reveal the roles of efflux protein in the herb-pairs compatibility, and provide new ideas for the mechanism and rationality of herb compatibility.

Absorption mechanism of three curcumin constituents through in situ intestinal perfusion method

This study aimed to investigate the absorption mechanism of three curcumin constituents in rat small intestines. Self-emulsification was used to solubilize the three curcumin constituents, and the rat in situ intestinal perfusion method was used to study factors on drug absorption, including drug mass concentration, absorption site, and the different types and concentrations of absorption inhibitors. Within the scope of experimental concentrations, three curcumin constituents were absorbed in rat small intestines through the active transport mechanism.

The effect of smoking on myeloid-related protein-8 and myeloid-related protein-14

Abstract The aim of this study was to determine the myeloid-related protein-8 and myeloid-related protein-14 levels in the gingival crevicular fluid of smoker patients with generalized aggressive periodontitis (SAgP), smoker patients with chronic periodontitis (SCP), smoker patients with gingivitis (SG-smoker control), non-smoker patients with generalized aggressive periodontitis (AgP), non-smoker patients with chronic periodontitis (CP), and non-smoker patients with gingivitis (G-non-smoker control). The periodontal statuses of the patients were determined by periodontal clinical measurements and radiographical evaluations. The levels of myeloid-related protein-8 and myeloid-related protein-14 in the gingival crevicular fluid were assessed using enzyme-linked immuno sorbent assay. The myeloid-related protein-8 and myeloid-related protein-14 levels in the gingival crevicular fluid of patients with generalized aggressive periodontitis (non-smoker and smoker) were found to be statistically higher than patients with chronic periodontitis (non-smoker and smoker) and patients with gingivitis (non-smoker and smoker). Myeloid-related protein-8 and myeloid-related protein-14 levels of non-smokers were significantly higher than smokers in all types of periodontitis and gingivitis. The decreased myeloid-related protein-8 and myeloid-related protein-14 level could have prevented the haemostasis of calcium which plays a significant role in the migration of neutrophiles. Smoking affects myeloid-related protein-8 and myeloid-related protein-14 levels and may inhibit the antimicrobial efficiency against microorganisms. Due to these reasons smoker generalized aggressive periodontitis patients need to be treated in detail and their maintenance durations should be shortened.

Pulmonary surfactant homeostasis associated genetic abnormalities and lung diseases / 中华医学遗传学杂志

Pulmonary surfactant (PS) is synthesized and secreted by alveolar epithelial type II (AEII) cells, which is a complex compound formed by proteins and lipids. Surfactant participates in a range of physiological processes such as reducing the surface tension, keeping the balance of alveolar fluid, maintaining normal alveolar morphology and conducting host defense. Genetic disorders of the surfactant homeostasis genes may result in lack of surfactant or cytotoxicity, and lead to multiple lung diseases in neonates, children and adults, including neonatal respiratory distress syndrome, interstitial pneumonia, pulmonary alveolar proteinosis, and pulmonary fibrosis. This paper has provided a review for the functions and processes of pulmonary surfactant metabolism, as well as the connection between disorders of surfactant homeostasis genes and lung diseases.

Thermodynamics of ABC transporters

ABC transporters form the largest of all transporter families, and their structural study has made tremendous progress over recent years. However, despite such advances, the precise mechanisms that determine the energy-coupling between ATP hydrolysis and the conformational changes following substrate binding remain to be elucidated. Here, we present our thermodynamic analysis for both ABC importers and exporters, and introduce the two new concepts of differential-binding energy and elastic conformational energy into the discussion. We hope that the structural analysis of ABC transporters will henceforth take thermodynamic aspects of transport mechanisms into account as well.

c-Myc regulation of ATP-binding cassette transporter reverses chemoresistance in CD133(+) colon cancer stem cells / 生理学报

The present study was aimed to explore the role of c-Myc gene regulation in maintaining the self-renewal and drug-resistant properties of colon cancer stem cells (CSCs) and the underlying mechanism. CD133(+) cells were isolated by flow cytometry cell sorting from human HT29 cancer cells. A small interfering RNA (siRNA) against c-Myc was used, and the mRNA and protein expressions of c-Myc were investigated by real-time PCR and Western blotting, respectively. To evaluate the effect of c-Myc on the drug resistance of colon CSCs, CD133(+) cells transfected with c-Myc-siRNA were exposed to 5-FU, oxaliplatin, or their combination. The expressions of ATP-binding cassette (ABC) transporters, including ABCG2, ABCB5 and MDR-1, were detected by Western blotting. The results showed that c-Myc was highly expressed in CD133(+) colon CSCs, and the protein and mRNA expressions of c-Myc were effectively blocked by c-Myc siRNA. Furthermore, CD133(+) cells showed significantly increased survival rate in chemotherapy treatment, compared with CD133(-) cells. c-Myc silencing sensitized CD133(+) cells to chemotherapy-induced cytotoxicity and down-regulated the protein expression levels of ABCG2, MDR-1 and ABCB5. These results suggest c-Myc silencing may regulate the expressions of ABC transporters in colon CSCs, and enhance the sensitivity of CSCs to the chemotherapy.