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1.
Heterodimerization of the Sialidase NEU1 with the Chaperone Protective Protein/Cathepsin A Prevents Its Premature Oligomerization 总被引:1,自引:0,他引:1
Erik J. Bonten Yvan Campos Viateslav Zaitsev Amanda Nourse Brett Waddell William Lewis Garry Taylor Alessandra d'Azzo 《The Journal of biological chemistry》2009,284(41):28430-28441
Lysosomal neuraminidase-1 (NEU1) forms a multienzyme complex with β-galactosidase and protective protein/cathepsin A (PPCA). Because of its association with PPCA, which acts as a molecular chaperone, NEU1 is transported to the lysosomal compartment, catalytically activated, and stabilized. However, the mode(s) of association between these two proteins both en route to the lysosome and in the multienzyme complex has remained elusive. Here, we have analyzed the hydrodynamic properties of PPCA, NEU1, and a complex of the two proteins and identified multiple binding sites on both proteins. One of these sites on NEU1 that is involved in binding to PPCA can also bind to other NEU1 molecules, albeit with lower affinity. Therefore, in the absence of PPCA, as in the lysosomal storage disease galactosialidosis, NEU1 self-associates into chain-like oligomers. Binding of PPCA can reverse self-association of NEU1 by causing the disassembly of NEU1-oligomers and the formation of a PPCA-NEU1 heterodimeric complex. The identification of binding sites between the two proteins allowed us to create innovative structural models of the NEU1 oligomer and the PPCA-NEU1 heterodimeric complex. The proposed mechanism of interaction between NEU1 and its accessory protein PPCA provides a rationale for the secondary deficiency of NEU1 in galactosialidosis.Mammalian neuraminidases have been classified as lysosomal (NEU1),4 cytosolic (NEU2), plasma membrane (NEU3), and mitochondria/lysosomal (NEU4) based on their subcellular distributions, pH optimum, kinetic properties, responses to ions and detergents, and substrate specificities (1–3). Of the four sialidases, only NEU1 is ubiquitously expressed at different levels in various tissues and cell types (4–7). The importance of these proteins in normal cellular physiology is illustrated by the numerous metabolic processes that they control, including cell proliferation and differentiation, cell adhesion, membrane fusion and fluidity, immunocyte function, and receptor modification (8–21).NEU1 initiates the intralysosomal hydrolysis of sialo-oligosaccharides, -glycolipids, and -glycoproteins by removing their terminal sialic acid residues. In human and murine tissues, NEU1 forms a complex with at least two other proteins, β-galactosidase and the protective protein/cathepsin A (PPCA) (22). By virtue of their association with PPCA, NEU1 and β-galactosidase acquire their active and stable conformation in lysosomes. However, PPCA appears to function as a crucial chaperone/transport protein for NEU1. Because NEU1 is poorly mannose 6-phosphorylated, it depends on PPCA for correct compartmentalization and catalytic activation in lysosomes (23–25). Only a small amount of PPCA and β-galactosidase activities is found in the NEU1-PPCA-β-galactosidase complex, which instead contains all of the NEU1 catalytic activity (24–27). By understanding how and when NEU1 and PPCA interact, how they regulate each other in different cell types, and what determinants control their association, we may gain important insight into their significance in physiologic and pathologic conditions.The absence of NEU1 is associated with two neurodegenerative diseases that involve glycoprotein metabolism; sialidosis, which is caused by structural lesions in the lysosomal NEU1 locus (28), and galactosialidosis (GS), a combined deficiency of NEU1 and β-galactosidase which is caused by the absence of PPCA (22). Patients with sialidosis and those with GS have similar clinical and biochemical features, and both diseases are characterized by multiple phenotypes that are classified according to the age of onset and severity of the symptoms.Previously, we generated two animal models of primary or secondary NEU1 deficiency, Neu1−/− mice and Ppca−/− mice. Both mouse models have a profound loss of Neu1 activity in multiple tissues and develop clinical, biochemical, and pathologic manifestations resembling those seen in patients with severe sialidosis and GS (29–31). Neu1−/− mice are phenotypically similar but not identical to Ppca−/− mice and, like children with the disease, exhibit a time-dependent splenomegaly associated with extramedullary hematopoiesis (30, 31). We found that the cause of these phenotypic abnormalities is the gradual loss of retention of hematopoietic progenitors within the bone niche due to exacerbated lysosomal exocytosis of bone marrow cells. The latter process is negatively regulated by NEU1 activity (31).The mode of interaction between PPCA and NEU1 and the mechanism of catalytic activation are not well understood. Here we present biochemical, analytical, and structural analyses of NEU1, PPCA, and the PPCA-NEU1 complex by using purified baculovirus (BV)-expressed wild-type and mutagenized recombinant enzymes and synthetic peptides. 相似文献
2.
Giuseppina Andreotti Valentina Citro Antonella Correra Maria Vittoria Cubellis 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
The majority of the disease-causing mutations affect protein stability, but not functional sites and are amenable, in principle, to be treated with pharmacological chaperones. These drugs enhance the thermodynamic stability of their targets. Fabry disease, a disorder caused by mutations in the gene encoding lysosomal alpha-galactosidase, represents an excellent model system to develop experimental protocols to test the efficiency of such drugs.Methods
The stability of lysosomal alpha-galactosidase under different conditions was studied by urea-induced unfolding followed by limited proteolysis and Western blotting.Results
We measured the concentration of urea needed to obtain half-maximal unfolding because this parameter represents an objective indicator of protein stability.Conclusions
Urea-induced unfolding is a versatile technique that can be adapted to cell extracts containing tiny amounts of wild-type or mutant proteins. It allows testing of protein stability as a function of pH, in the presence or in the absence of drugs. Results are not influenced by the method used to express the protein in transfected cells.General significance
Scarce and dispersed populations pose a problem for the clinical trial of drugs for rare diseases. This is particularly true for pharmacological chaperones that must be tested on each mutation associated with a given disease. Diverse in vitro tests are needed. We used a method based on chemically induced unfolding as a tool to assess whether a particular Fabry mutation is responsive to pharmacological chaperones, but, by no means is our protocol limited to this disease. 相似文献3.
Wenbing Yang Haitao Shen Guodong Fang Hui Li Lan Li Fang Deng Wei Gu Kangsheng Li Lian Ma Jiang Gu Yongyu Wang 《Life sciences》2014
Aims
Surfactant protein A (SP-A) plays critical roles in the innate immune system and surfactant homeostasis of the lung. Mutations in SP-A2 of the carbohydrate recognition domain (CRD) impair its glycosylation and are associated with pulmonary fibrosis in humans. We aim to examine how mutations in SP-A that impair its glycosylation affect its biological properties and lead to disease.Main methods
We generated rat SP-A constructs with two types of mutations that impair its glycosylation: N-glycosylation site mutations (N21T, N207S and N21T/N207S) and disease-associated CRD mutations (G231V, F198S). We transfected these constructs into Chinese hamster ovary (CHO)-K1 cells and assessed biochemical differences in cellular and secreted wild-type and mutant SP-As by western blot, immunofluorescence, and sensitivity to enzymatic digestion.Key findings
Mutations of the CRD completely impaired SP-A secretion, whereas mutations of N-glycosylation sites had little effect. Both types of mutations formed nonidet p-40 (NP-40) insoluble aggregates, but the aggregates only from CRD mutations could be partially rescued by a chemical chaperone, 4-phenylbutyrate acid (4-PBA). The majority of CRD mutant SP-A was retained in the endoplasmic reticulum. Moreover, both types of mutations reduced SP-A stability, with CRD mutant SP-A being more sensitive to chymotrypsin digestion. Both types of soluble mutant SP-A could be degraded by the proteasome pathway, while insoluble aggregates could be additionally degraded by the lysosomal pathway.Significance
Our data provide evidence that the differential glycosylation of SP-A may play distinct roles in SP-A secretion, aggregation and degradation which may contribute to familial pulmonary fibrosis caused by SP-A2 mutations. 相似文献4.
5.
Keisuke Ito Taishi Sugawara Ayako Koizumi Ken-ichiro Nakajima Akiko Shimizu-Ibuka Mitsunori Shiroishi Hidetsugu Asada Takami Yurugi-Kobayashi Tatsuro Shimamura Tomiko Asakura Katsuyoshi Masuda Masaji Ishiguro Takumi Misaka So Iwata Takuya Kobayashi Keiko Abe 《Biochimica et Biophysica Acta (BBA)/General Subjects》2010
Background
Miraculin (MCL) is a taste-modifying protein that converts sourness into sweetness. The molecular mechanism underlying the taste-modifying action of MCL is unknown.Methods
Here, a yeast expression system for MCL was constructed to accelerate analysis of its structure–function relationships. The Saccharomyces cerevisiae expression system has advantages as a high-throughput analysis system, but compared to other hosts it is characterized by a relatively low level of recombinant protein expression. To alleviate this weakness, in this study we optimized the codon usage and signal-sequence as the first step. Recombinant MCL (rMCL) was expressed and purified, and the sensory taste was analyzed.Results
As a result, a 2 mg/l yield of rMCL was successfully obtained. Although sensory taste evaluation showed that rMCL was flat in taste under all the pH conditions employed, taste-modifying activity similar to that of native MCL was recovered after deglycosylation. Mutagenetic analysis revealed that the N-glycan attached to Asn42 was bulky in rMCL.Conclusions
The high-mannose-type N-glycan attached in yeast blocks the taste-modifying activity of rMCL.General significance
The bulky N-glycan attached to Asn42 may cause steric hindrance in the interaction between active residues and the sweet taste receptor hT1R2/hT1R3. 相似文献6.
Hazuki E. Miwa Thomas A. Gerken Tru D. Huynh Lori R. Duesler Meghan Cotter Thomas M. Hering 《Biochimica et Biophysica Acta (BBA)/General Subjects》2009
Background
Cleavage of aggrecan by ADAMTS proteinases at specific sites within highly conserved regions may be important to normal physiological enzyme functions, as well as pathological degradation.Methods
To examine ADAMTS selectivity, we assayed ADAMTS-4 and -5 cleavage of recombinant bovine aggrecan mutated at amino acids N-terminal or C-terminal to the interglobular domain cleavage site.Results
Mutations of conserved amino acids from P18 to P12 to increase hydrophilicity resulted in ADAMTS-4 cleavage inhibition. Mutation of Thr, but not Asn within the conserved N-glycosylation motif Asn-Ile-Thr from P6 to P4 enhanced cleavage. Mutation of conserved Thr residues from P22 to P17 to increase hydrophobicity enhanced ADAMTS-4 cleavage. A P4′ Ser377Gln mutant inhibited cleavage by ADAMTS-4 and -5, while a neutral Ser377Ala mutant and species mimicking mutants Ser377Thr, Ser377Asn, and Arg375Leu were cleaved normally by ADAMTS-4. The Ser377Thr mutant, however, was resistant to cleavage by ADAMTS-5.Conclusion
We have identified multiple conserved amino acids within regions N- and C-terminal to the site of scission that may influence enzyme–substrate recognition, and may interact with exosites on ADAMTS-4 and ADAMTS-5.General significance
Inhibition of the binding of ADAMTS-4 and ADAMTS-5 exosites to aggrecan should be explored as a therapeutic intervention for osteoarthritis. 相似文献7.
8.
Keisuke Kaneko Yasunori Sugiyama Yusuke Yamada Noriyuki Sueyoshi Akira Watanabe Yasuhiko Asada Atsuhiko Ishida Isamu Kameshita 《Biochimica et Biophysica Acta (BBA)/General Subjects》2011
Background
In a previous study, we conducted an expression cloning screen of a cDNA library prepared from Coprinopsis cinerea mycelia using Multi-PK antibodies and detected a wide variety of Ser/Thr protein kinases. One of the isolated clones, CMZ032, was found to encode a putative Ser/Thr protein kinase designated CoPK32. In the present study, we investigated the biochemical properties and physiological significance of CoPK32.Methods
CoPK32 was expressed in Escherichia coli, and its biochemical properties were examined. The effects of high osmotic stresses on the growth of C. cinerea and on the endogenous CoPK32 activity in mycelia were also examined.Results
CoPK32 showed autophosphorylation activity and effectively phosphorylated exogenous protein substrates. CoPK32S, a splice variant that was 18 amino acids shorter than CoPK32, showed much lower protein kinase activity than CoPK32. The catalytic properties of CoPK32 deletion mutants suggested that the C-terminal region of CoPK32 was important for the kinase activity and recognition of substrates. CoPK32 was highly expressed in the actively growing region of the mycelial colony. When mycelia were stimulated by high osmotic stresses, endogenous CoPK32 was markedly activated and the mycelial growth was severely inhibited. The activation of CoPK32 activity by high osmotic stresses was abrogated by SB202190 or SB239063 as well-known inhibitors of p38 mitogen-activated protein kinase.Conclusions
CoPK32 is involved in the stress response pathway in mycelia of C. cinerea in response to environmental stresses.General significance
In C. cinerea, protein kinases such as CoPK32 play important roles in signal transduction pathways involved in stress responses. 相似文献9.
Sander S. van Leeuwen Ruud J.W. Schoemaker Christel J.A.M. Timmer Johannis P. Kamerling Lubbert Dijkhuizen 《Biochimica et Biophysica Acta (BBA)/General Subjects》2012
Background
Over the years, the N-glycosylation of both human and bovine lactoferrin (LF) has been studied extensively, however not all aspects have been studied in as much detail. Typically, the bovine LF complex-type N-glycans include certain epitopes, not found in human LF N-glycans, i.e. Gal(α1-3)Gal(β1-4)GlcNAc (αGal), GalNAc(β1-4)GlcNAc (LacdiNAc), and N-glycolylneuraminic acid (Neu5Gc). The combined presence of complex-type N-glycans, with αGal, LacdiNAc, LacNAc [Gal(β1-4)GlcNAc], Neu5Ac (N-acetylneuraminic acid), and Neu5Gc epitopes, and oligomannose-type N-glycans complicates the high-throughput analysis of such N-glycoprofiles highly.Methods
For the structural analysis of enzymatically released N-glycan pools, containing both LacNAc and LacdiNAc epitopes, a prefractionation protocol based on Wisteria floribunda agglutinin affinity chromatography was developed. The sub pools were analysed by MALDI-TOF-MS and HPLC-FD profiling, including sequential exoglycosidase treatments.Results
This protocol separates the N-glycan pool into three sub pools, with (1) free of LacdiNAc epitopes, (2) containing LacdiNAc epitopes, partially shielded by sialic acid, and (3) containing LacdiNAc epitopes, without shielding by sialic acid. Structural analysis by MALDI-TOF-MS and HPLC-FD showed a complex pattern of oligomannose-, hybrid-, and complex-type di-antennary structures, both with, and without LacdiNAc, αGal and sialic acid.Conclusions
Applying the approach to bovine LF has led to a more detailed N-glycome pattern, including LacdiNAc, αGal, and Neu5Gc epitopes, than was shown in previous studies.General significance
Bovine milk proteins contain glycosylation patterns that are absent in human milk proteins; particularly, the LacdiNAc epitope is abundant. Analysis of bovine milk serum proteins is therefore excessively complicated. The presented sub fractionation protocol allows a thorough analysis of the full scope of bovine milk protein glycosylation. This article is part of a Special Issue entitled Glycoproteomics. 相似文献10.
Shivani Kanodia Gautam Kumar Luca Rizzi Alessandro Pedretti Anthony N. Hodder Sergio Romeo Pawan Malhotra 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Plasmodium falciparum serine repeat antigen 5 (PfSERA5) is an abundant blood stage protein that plays an essential role in merozoite egress and invasion. The native protein undergoes extensive proteolytic cleavage that appears to be tightly regulated. PfSERA5 N-terminal fragment is being developed as vaccine candidate antigen. Although PfSERA5 belongs to papain-like cysteine protease family, its catalytic domain has a serine in place of cysteine at the active site.Methods
In the present study, we synthesized a number of peptides from the N- and C-terminal regions of PfSERA5 active domain and evaluated their inhibitory potential.Results
The final proteolytic step of PfSERA5 involves removal of a C-terminal ~ 6 kDa fragment that results in the generation of a catalytically active ~ 50 kDa enzyme. In the present study, we demonstrate that two of the peptides derived from the C-terminal ~ 6 kDa region inhibit the parasite growth and also cause a delay in the parasite development. These peptides reduced the enzyme activity of the recombinant protein and co-localized with the PfSERA5 protein within the parasite, thereby indicating the specific inhibition of PfSERA5 activity. Molecular docking studies revealed that the inhibitory peptides interact with the active site of the protein. Interestingly, the peptides did not have an effect on the processing of PfSERA5.Conclusions
Our observations indicate the temporal regulation of the final proteolytic cleavage step that occurs just prior to egress.General significance
These results reinforce the role of PfSERA5 for the intra-erythrocytic development of malaria parasite and show the role of carboxy terminal ~ 6 kDa fragments in the regulation of PfSERA5 activity. The results also suggest that final cleavage step of PfSERA5 can be targeted for the development of new anti-malarials. 相似文献11.
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13.
Paola Marcolongo Rosella Fulceri Alessandra Gamberucci Ibolya Czegle Gabor Banhegyi Angelo Benedetti 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
The endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate. The enzyme is a part of a multicomponent system that includes several integral membrane proteins; the catalytic subunit (G6PC) and transporters for glucose-6-phosphate, inorganic phosphate and glucose. The G6PC gene family presently includes three members, termed as G6PC, G6PC2, and G6PC3. Although the three isoforms show a moderate amino acid sequence homology, their membrane topology and catalytic site are very similar. The isoforms are expressed differently in various tissues. Mutations in all three genes have been reported to be associated with human diseases.Scope of review
The present review outlines the biochemical features of the G6PC gene family products, the regulation of their expression, their role in the human pathology and the possibilities for pharmacological interventions.Major conclusions
G6PCs emerge as integrators of extra- and intracellular glucose homeostasis. Beside the well known key role in blood glucose homeostasis, the members of the G6PC family seem to play a role as sensors of intracellular glucose and of intraluminal glucose/glucose-6-phosphate in the endoplasmic reticulum.General significance
Since mutations in the three G6PC genes can be linked to human pathophysiological conditions, the better understanding of their functioning in connection with genetic alterations, altered expression and tissue distribution has an eminent importance. 相似文献14.
Clara Pereira L. Miguel Martins Lucília Saraiva 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Mutations in LRRK2 are the most common genetic cause of Parkinson's disease (PD). Studies in the yeast Saccharomyces cerevisiae have provided valuable insights into the mechanisms of cellular dysfunction associated with the expression of faulty PD genes.Methods
We developed a yeast model for full-length LRRK2 studies. We expressed wild-type (wt) LRRK2 and mutations and evaluated their role during oxidative stress conditions. The involvement of mitochondria was assessed by using rho-zero mutants and by evaluating reactive oxygen species (ROS) production and mitochondrial membrane potential by flow cytometry. The involvement of endocytosis was also studied by testing several endocytic mutants and by following the vacuolar delivery of the probe FM4-64.Results
Expression of LRRK2 in yeast was associated to increased hydrogen peroxide resistance. This phenotype, which was dependent on mitochondrial function, was not observed for PD-mutants G2019S and R1441C or in the absence of the kinase activity and the WD40 repeat domain. Expression of the pathogenic mutants stimulated ROS production and increased mitochondrial membrane potential. For the PD-mutants, but not for wild-type LRRK2, endocytic defects were also observed. Additionally, several endocytic proteins were required for LRRK2-mediated protection against hydrogen peroxide.Conclusions
Our results indicate that LRRK2 confers cellular protection during oxidative stress depending on mitochondrial function and endocytosis.General significance
Both the loss of capacity of LRRK2 pathogenic mutants to protect against oxidative stress and their enhancement of dysfunction may be important for the development of PD during the aging process. 相似文献15.
16.
Background
Mucolipidosis type III gamma (MLIII gamma) is an autosomal recessive disease caused by a mutation in the GNPTG gene, which encodes the γ subunit of the N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase). This protein plays a key role in the transport of lysosomal hydrolases to the lysosome.Methods
Three Chinese children with typical skeletal abnormalities of MLIII were identified, who were from unrelated consanguineous families. After obtaining informed consent, genomic DNA was isolated from the patients and their parents. Direct sequencing of the GNPTG and GNPTAB genes was performed using standard PCR reactions.Results
The three probands showed clinical features typical of MLIII gamma, such as joint stiffness and vertebral scoliosis without coarsened facial features. Mutation analysis of the GNPTG gene showed that three novel mutations were identified, two in exon seven [c.425G>A (p.Cys142Val)] and [c.515dupC (p.His172Profs27X)], and one in exon eight [c.609+1G>C]. Their parents were determined to be heterozygous carriers when compared to the reference sequence in GenBank on NCBI.Conclusions
Mutation of the GNPTG gene is the cause of MLIII gamma in our patients. Our findings expand the mutation spectrum of the GNPTG gene and extend the knowledge of the phenotype–genotype correlation of the disease. 相似文献17.
Sylvain Hanein Mathilde Garcia Lucas Fares-Taie Valérie Serre Yves De Keyzer Thierry Delaveau Isabelle Perrault Nathalie Delphin Sylvie Gerber Alain Schmitt Jean-Marc Masse Arnold Munnich Josseline Kaplan Frédéric Devaux Jean-Michel Rozet 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Hereditary optic neuropathies (HONs) are a heterogeneous group of disorders that affect retinal ganglion cells (RGCs) and axons that form the optic nerve. Leber's Hereditary Optic Neuropathy and the autosomal dominant optic atrophy related to OPA1 mutations are the most common forms. Nonsyndromic autosomal recessive optic neuropathies are rare and their existence has been long debated. We recently identified the first gene responsible for these conditions, TMEM126A. This gene is highly expressed in retinal cellular compartments enriched in mitochondria and supposed to encode a mitochondrial transmembrane protein of unknown function.Methods
A specific polyclonal antibody targeting the TMEM126A protein has been generated. Quantitative fluorescent in situ hybridization, cellular fractionation, mitochondrial membrane association study, mitochondrial sub compartmentalization analysis by both proteolysis assays and transmission electron microscopy, and expression analysis of truncated TMEM126A constructs by immunofluorescence confocal microscopy were carried out.Results
TMEM126A mRNAs are strongly enriched in the vicinity of mitochondria and encode an inner mitochondrial membrane associated cristae protein. Moreover, the second transmembrane domain of TMEM126A is required for its mitochondrial localization.Conclusions
TMEM126A is a mitochondrial located mRNA (MLR) that may be translated in the mitochondrial surface and the protein is subsequently imported to the inner membrane. These data constitute the first step toward a better understanding of the mechanism of action of TMEM126A in RGCs and support the importance of mitochondrial dysfunction in the pathogenesis of HON.General significance
Local translation of nuclearly encoded mitochondrial mRNAs might be a mechanism for rapid onsite supply of mitochondrial membrane proteins. 相似文献18.
19.
Background
Orlistat, a fatty acid synthase (FASN) inhibitor, has been demonstrated to inhibit tumor cell survival. However, the mechanism(s) of its tumor growth retarding action against malignancies of hematological origin remains unclear. It is also not understood if the antitumor action of orlistat implicates modulated susceptibility of tumor cell to anticancer drugs. Therefore, the present investigation focuses to study the antitumor and chemosensitizing action of orlistat in a murine host bearing a progressively growing T cell lymphoma.Methods
Tumor-bearing mice were administered with vehicle alone or containing orlistat followed by administration of PBS with or without cisplatin. Tumor progression and survival of tumor-bearing host were monitored along with analysis of tumor cell survival and apoptosis. Tumor ascitic fluid was examined for pH, NO and cytokines. Expression of genes and proteins was investigated by RT-PCR and western blot respectively. ROS was analyzed by DCFDA staining and FASN activity by spectrophotometry.Results
Orlistat administration to tumor-bearing mice resulted in tumor growth retardation, prolonged life span, declined tumor cell survival and chemosensitization to cisplatin. It was accompanied by increased osmotic fragility, modulated acidosis, expression of ROS, NO, cytokines, MCT-1 and VH+ ATPase, Bcl2, Caspase-3, P53, inhibited FASN activity and declined expression of MDR and MRP-1 proteins.Conclusion
Orlistat manifests antitumor and chemosensitizing action implicating modulated regulation of cell survival, reconstituted-tumor microenvironment and altered MDR phenotype.General significance
These observations indicate that orlistat could be utilized as an adjunct regimen for improving antitumor efficacy of cisplatin. 相似文献20.
Babu Sudhamalla Mahesh Kumar Karnati R. Roy R. Sunil Kumar Abani K. Bhuyan 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013