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1
Hopkins, Michael, John J. Tyson, and Béla Novák. "Cell-cycle transitions: a common role for stoichiometric inhibitors." Molecular Biology of the Cell 28, no. 23 (November 7, 2017): 3437–46. http://dx.doi.org/10.1091/mbc.e17-06-0349.
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The cell division cycle is the process by which eukaryotic cells replicate their chromosomes and partition them to two daughter cells. To maintain the integrity of the genome, proliferating cells must be able to block progression through the division cycle at key transition points (called “checkpoints”) if there have been problems in the replication of the chromosomes or their biorientation on the mitotic spindle. These checkpoints are governed by protein-interaction networks, composed of phase-specific cell-cycle activators and inhibitors. Examples include Cdk1:Clb5 and its inhibitor Sic1 at the G1/S checkpoint in budding yeast, APC:Cdc20 and its inhibitor MCC at the mitotic checkpoint, and PP2A:B55 and its inhibitor, alpha-endosulfine, at the mitotic-exit checkpoint. Each of these inhibitors is a substrate as well as a stoichiometric inhibitor of the cell-cycle activator. Because the production of each inhibitor is promoted by a regulatory protein that is itself inhibited by the cell-cycle activator, their interaction network presents a regulatory motif characteristic of a “feedback-amplified domineering substrate” (FADS). We describe how the FADS motif responds to signals in the manner of a bistable toggle switch, and then we discuss how this toggle switch accounts for the abrupt and irreversible nature of three specific cell-cycle checkpoints.
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Silva, Maria Cristina Mattar da, Luciane Vieira Mello, Marise Ventura Coutinho, Daniel John Rigden, Goran Neshich, Maarten John Chrispeels, and Maria Fátima Grossi-de-Sá. "Mutants of common bean alpha-amylase inhibitor-2 as an approach to investigate binding specificity to alpha-amylases." Pesquisa Agropecuária Brasileira 39, no. 3 (March 2004): 201–8. http://dx.doi.org/10.1590/s0100-204x2004000300001.
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Despite the presence of a family of defense proteins, Phaseolus vulgaris can be attacked by bruchid insects resulting in serious damage to stored grains. The two distinct active forms of a-amylase inhibitors, a-AI1 and a-AI2, in P. vulgaris show different specificity toward a-amylases. Zabrotes subfasciatus a-amylase is inhibited by a-AI2 but not by a-AI1. In contrast, porcine a-amylase is inhibited by a-AI1 but not by a-AI2. The objective of this work was to understand the molecular basis of the specificity of two inhibitors in P. vulgaris (a-AI1 and a-AI2) in relation to a-amylases. Mutants of a-AI2 were made and expressed in tobacco plants. The results showed that all the a-AI2 mutant inhibitors lost their activity against the insect a-amylases but none exhibited activity toward the mammalian a-amylase. The replacement of His33 of a-AI2 with the a-AI1-like sequence Ser-Tyr-Asn abolished inhibition of Z. subfasciatus a-amylase. From structural modeling, the conclusion is that the size and complexity of the amylase-inhibitor interface explain why mutation of the N-terminal loop and resultant abolition of Z. subfasciatus a-amylase inhibition are not accompanied by gain of inhibitory activity against porcine a-amylase.
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Arita, Minetaro, Takaji Wakita, and Hiroyuki Shimizu. "Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime." Journal of General Virology 90, no. 8 (August 1, 2009): 1869–79. http://dx.doi.org/10.1099/vir.0.012096-0.
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Previously, we identified a cellular kinase inhibitor, GW5074, that inhibits poliovirus (PV) and enterovirus 71 replication strongly, although its target has remained unknown. To identify the target of GW5074, we searched for cellular kinase inhibitors that have anti-enterovirus activity similar or related to that of GW5074. With this aim, we performed screenings to identify cellular kinase inhibitors that could inhibit PV replication cooperatively with GW5074 or synthetically in the absence of GW5074. We identified MEK1/2 inhibitors (SL327 and U0126), an EGFR inhibitor (AG1478) and a phosphatidylinositol 3-kinase inhibitor (wortmannin) as compounds with a cooperative inhibitory effect with GW5074, and an Akt1/2 inhibitor (Akt inhibitor VIII) as a compound with a synthetic inhibitory effect with MEK1/2 inhibitors and AG1478. Individual treatment with the identified kinase inhibitors did not affect PV replication significantly, but combined treatment with MEK1/2 inhibitor, AG1478 and Akt1/2 inhibitor suppressed the replication synthetically. The effect of AG1478 in this synthetic inhibition was compensated by other receptor tyrosine kinase inhibitors (IGF-1R inhibitor II and Flt3 inhibitor II). We isolated mutants resistant to Flt3 inhibitor II and GW5074 and found that these mutants had cross-resistance to each treatment. These mutants had a common mutation in viral protein 3A that results in an amino acid change at position 70 (Ala to Thr), a mutation that was previously identified in mutants resistant to a potent anti-enterovirus compound, enviroxime. These results suggest that cellular kinase inhibitors and enviroxime have a conserved target in viral protein 3A to suppress enterovirus replication.
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Scandella, D., GE Gilbert, M. Shima, H. Nakai, C. Eagleson, M. Felch, R. Prescott, KJ Rajalakshmi, LW Hoyer, and E. Saenko. "Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site." Blood 86, no. 5 (September 1, 1995): 1811–19. http://dx.doi.org/10.1182/blood.v86.5.1811.bloodjournal8651811.
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The finding that human factor VIII (fVIII) inhibitor antibodies with C2 domain epitopes interfere with the binding of fVIII to phosphatidylserine (PS) suggested that this is the mechanism by which they inactivate fVIII. We constructed a recombinant C2 domain polypeptide and demonstrated that it bound to all six human inhibitors with fVIII light chain specificity. Thus, some antibodies within the polyclonal anti-light chain population require only amino acids within C2 for binding. Recombinant C2 also partially or completely neutralized the inhibitor titer of these plasmas, demonstrating that anti-C2 antibodies inhibit fVIII activity. Immunoblotting of a series of C2 deletion polypeptides, expressed in Escherichia coli, with inhibitor plasmas showed that the epitopes for human inhibitors consist of a common core of amino acid residues 2248 through 2312 with differing extensions for individual inhibitors. The epitope of inhibitory monoclonal antibody (MoAb) ESH8 was localized to residues 2248 through 2285. Three human antibodies and anti-C2 MoAb NMC-VIII/5 bound to a synthetic peptide consisting of amino acids 2303 through 2332, a PS- binding site, but MoAb ESH8 did not. These antibodies also inhibited the binding of fVIII to synthetic phospholipid membranes of PS and phosphatidylcholine, confirming that the blocked epitopes contribute to membrane binding as well as binding to PS. In contrast, MoAb ESH8 did not inhibit binding. As the maximal function of activated fVIII in the intrinsic factor Xase complex requires its binding to a phospholipid membrane, we propose that fVIII inhibition by anti-C2 antibodies is related to the overlap of their epitopes with the PS-binding site. MoAb ESH8 did not inhibit fVIII binding to PS-containing membranes, suggesting the existence of a second mechanism of fVIII inhibition by anti-C2 antibodies.
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Watson, R. J., and B. Blackwell. "Purification and characterization of a common soil component which inhibits the polymerase chain reaction." Canadian Journal of Microbiology 46, no. 7 (July 1, 2000): 633–42. http://dx.doi.org/10.1139/w00-043.
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DNA prepared from soil usually contains a brown-tinted inhibitor of the polymerase chain reaction (PCR) which limits the sensitivity of this technique for specific detection of microorganisms. To localize the inhibitor, soil fractions were tested for their inhibitory effect on the PCR reaction. A highly inhibitory activity, sufficient to account for the inhibition typically exhibited by soil DNA, was found to be tightly associated with the soil microorganism fraction. After cell breakage, the inhibitory material became soluble, and was not separable from DNA by standard purification procedures. A method was derived by which most of the inhibitory material could be selectively solubilized from the microorganism fraction without cell breakage, using successive washes with buffers differing in EDTA concentration. This technique was used to isolate a substance with characteristics suggesting that it is the major PCR inhibitor contaminating DNA purified from soil. It was found to be an organic, water-soluble compound of high molecular weight, and was present in a variety of soil types from different locations. It was found to be distinctly different in its solubility properties from humic and fulvic acids, and also in its FT-IR and NMR spectra. It forms a complex with protein and may inhibit the PCR reaction by an interaction with Taq DNA polymerase.Key words: fulvic acid, humic acid, PCR inhibitor, soil DNA, soil microorganisms.
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E, Jingwen, Ye Liu, Shanshan Guan, Zhijian Luo, Fei Han, Weiwei Han, Song Wang, and Hao Zhang. "How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFRL858R/T790M/C797S Inhibitors: A Molecular Dynamics Simulation Study." Molecules 25, no. 4 (February 18, 2020): 895. http://dx.doi.org/10.3390/molecules25040895.
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Lung cancer is the most frequent cause of cancer-related deaths worldwide, and mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are a common cause of non-small-cell lung cancers, which is a major subtype of lung cancers. Recently, a series of 5-methylpyrimidine-pyridinone derivatives have been designed and synthesized as novel selective inhibitors of EGFR and EGFR mutants. However, the binding-based inhibition mechanism has not yet been determined. In this study, we carried out molecular dynamic simulations and free-energy calculations for EGFR derivatives to fill this gap. Based on the investigation, the three factors that influence the inhibitory effect of inhibitors are as follows: (1) The substitution site of the Cl atom is the main factor influencing the activity through steric effect; (2) The secondary factors are repulsion between the F atom (present in the inhibitor) and Glu762, and the blocking effect of Lys745 on the phenyl ring of the inhibitor. (3) The two factors function synergistically to influence the inhibitory capacity of the inhibitor. The theoretical results of this study can provide further insights that will aid the design of oncogenic EGFR inhibitors with high selectivity.
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Meeks, Shannon L., John F. Healey, Ernest T. Parker, Rachel T. Barrow, and Pete Lollar. "Nonclassical anti-C2 domain antibodies are present in patients with factor VIII inhibitors." Blood 112, no. 4 (August 15, 2008): 1151–53. http://dx.doi.org/10.1182/blood-2008-01-132639.
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Abstract The antihuman factor VIII (fVIII) C2 domain immune response in hemophilia A mice consists of antibodies that can be divided into 5 groups of structural epitopes and 2 groups of functional epitopes. Groups A, AB, and B consist of classical C2 antibodies that inhibit the binding of fVIII to phospholipid and von Willebrand factor. Groups BC and C contain nonclassical C2 antibodies that block the activation of fVIII by thrombin or factor Xa. Group BC antibodies are the most common and display high specific inhibitory activity and type II kinetics. The C2 epitope groups recognized by 26 polyclonal human anti-fVIII inhibitor plasmas were identified by a novel competition enzyme-linked immunosorbent assay using group-specific murine monoclonal antibodies. Most of the anti-C2 inhibitor plasmas inhibited the binding of both classical and nonclassical antibodies. These results suggest that nonclassical anti-C2 antibodies contribute significantly to the pathogenicity of fVIII inhibitors.
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Yee, Kevin W. H., Marcus Schittenhelm, Anne-Marie O'Farrell, Ajia R. Town, Laura McGreevey, Troy Bainbridge, Julie M. Cherrington, and Michael C. Heinrich. "Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD–positive leukemic cells." Blood 104, no. 13 (December 15, 2004): 4202–9. http://dx.doi.org/10.1182/blood-2003-10-3381.
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Abstract Fetal liver tyrosine kinase 3 internal tandem duplication (FLT3 ITD) mutations are the most common molecular abnormality associated with adult acute myeloid leukemia (AML). To exploit this molecular target, a number of potent and specific FLT3 kinase inhibitors have been developed and are currently being tested in early phase clinical trials of patients with refractory AML. To explore the efficacy of combining a FLT3 inhibitor with standard AML chemotherapy drugs, we tested the effect of combining the FLT3 inhibitor SU11248 with cytarabine or daunorubicin on the proliferation and survival of cell lines expressing either mutant (FLT3 ITD or FLT3 D835V) or wild-type (WT) FLT3. SU11248 had additive-to-synergistic inhibitory effects on FLT3-dependent leukemic cell proliferation when combined with cytarabine or daunorubicin. The synergistic interaction of SU11248 and the traditional antileukemic agents was more pronounced for induction of apoptosis. SU11248 inhibited the proliferation of primary AML myeloblasts expressing mutant FLT3 ITD but not WT FLT3 protein. Combining SU11248 and cytarabine synergistically inhibited the proliferation of primary AML myeloblasts expressing FLT3 ITD but not WT FLT3 protein. These data suggest that the addition of potent FLT3 inhibitors such as SU11248 to AML chemotherapy regimens could result in improved treatment results.
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Chen, Shanshan, Yutong Xue, Liping Peng, Haobo Li, Yabo Lei, Zhixiang Huang, and Jian Jiao. "Research Progress on Types and Mechanism of Common Organic Corrosion Inhibitors." International Journal of Energy 2, no. 3 (May 25, 2023): 9–12. http://dx.doi.org/10.54097/ije.v2i3.8739.
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In this paper, several kinds of common organic corrosion inhibitors, such as heterocyclic, aldehydes and ketones, organic phosphonic acid, are introduced. The development prospects and application limitations of some corrosion inhibitors are discussed and pointed out. There are also studies have shown that usually two or more corrosion inhibitors are combined or better than a single corrosion inhibitor. Taking the effect as the introduction point, the mechanism of action of organic corrosion inhibitors is generally recognized. Finally, the future research direction of organic corrosion inhibitors is prospected.
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Korsten, Sandra G. P. J., Laura Peracic, Luka M. B. van Groeningen, Mara A. P. Diks, Herman Vromans, Johan Garssen, and Linette E. M. Willemsen. "Butyrate Prevents Induction of CXCL10 and Non-Canonical IRF9 Expression by Activated Human Intestinal Epithelial Cells via HDAC Inhibition." International Journal of Molecular Sciences 23, no. 7 (April 2, 2022): 3980. http://dx.doi.org/10.3390/ijms23073980.
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Non-communicable diseases are increasing and have an underlying low-grade inflammation in common, which may affect gut health. To maintain intestinal homeostasis, unwanted epithelial activation needs to be avoided. This study compared the efficacy of butyrate, propionate and acetate to suppress IFN-γ+/−TNF-α induced intestinal epithelial activation in association with their HDAC inhibitory capacity, while studying the canonical and non-canonical STAT1 pathway. HT-29 were activated with IFN-γ+/−TNF-α and treated with short chain fatty acids (SCFAs) or histone deacetylase (HDAC) inhibitors. CXCL10 release and protein and mRNA expression of proteins involved in the STAT1 pathway were determined. All SCFAs dose-dependently inhibited CXCL10 release of the cells after activation with IFN-γ or IFN-γ+TNF-α. Butyrate was the most effective, completely preventing CXCL10 induction. Butyrate did not affect phosphorylated STAT1, nor phosphorylated NFκB p65, but inhibited IRF9 and phosphorylated JAK2 protein expression in activated cells. Additionally, butyrate inhibited CXCL10, SOCS1, JAK2 and IRF9 mRNA in activated cells. The effect of butyrate was mimicked by class I HDAC inhibitors and a general HDAC inhibitor Trichostatin A. Butyrate is the most potent inhibitor of CXCL10 release compared to other SCFAs and acts via HDAC inhibition. This causes downregulation of CXCL10, JAK2 and IRF9 genes, resulting in a decreased IRF9 protein expression which inhibits the non-canonical pathway and CXCL10 transcription.
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El-latif, Ashraf Oukasha Abd. "Protease purification and characterization of a serine protease inhibitor from Egyptian varieties of soybean seeds and its efficacy against Spodoptera littoralis." Journal of Plant Protection Research 55, no. 1 (January 1, 2015): 16–25. http://dx.doi.org/10.1515/jppr-2015-0003.
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Abstract Serine inhibitors have been described in many plant species and are universal throughout the plant kingdom. Trypsin inhibitors are the most common type. In the present study, trypsin and chymotrypsin inhibitory activity was detected in the seed flour extracts of four Egyptian varieties of soybean (Glycine max). The soybean variety, Giza 22, was found to have higher trypsin and chymotrypsin inhibitory potential compared to other tested soybean varieties. For this reason, Giza 22 was selected for further purification studies which used ammonium sulphate fractionation and DEAE-Sephadex A-25 column. Soybean purified proteins showed a single band on SDS-PAGE corresponding to a molecular mass of 17.9 kDa. The purified inhibitor was stable at temperatures below 60°C and was active at a wide range of pH, from 2 to 12 pH. The kinetic analysis revealed a non-competitive type of inhibition against trypsin and chymotrypsin enzymes. The inhibitor constant (Ki) values suggested that the inhibitor has higher affinity toward a trypsin enzyme than to a chymotrypsin enzyme. Purified inhibitor was found to have deep and negative effects on the mean larval weight, larval mortality, pupation, and mean pupal weight of Spodoptera littoralis. It may be concluded, that soybean protease inhibitor gene(s) could be potential targets for those future studies which are concerned with developing insect resistant transgenic plants
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Königs, Christoph, Christoph Kessel, Susanne Stumpf, Janti Roland, Thomas Klingebiel, and Wolfhart Kreuz. "Inhibitor Epitopes Identified from Inhibitor Positive Plasma of a Hemophilia B Patient Change during ITT." Blood 106, no. 11 (November 16, 2005): 3201. http://dx.doi.org/10.1182/blood.v106.11.3201.3201.
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Abstract Hemophilia B is an X-linked bleeding disorder. Substitution of recombinant (rFIX) or plasma derived (pdFIX) FIX preparations are required to restore coagulation. A rare but severe complication is the development of FIX inhibitors that are often accompanied by allergic reactions. Immune tolerance therapies (ITTs) for inhibitor elimination are difficult and can induce further allergic reactions. ITTs for FIX inhibitors are less established and less successful than for FVIII inhibitors. In this study, three phage displayed random peptide libraries were screened by biopanning to isolate small peptides that mimic the epitope of FIX inhibitors. In the patient, the inhibitor was eliminated by ITT but reappeared again. Plasma samples before ITT and at reappearance of inhibitor were used to isolate inhibitor specific phage clones. Phage clones showing specific reactivity with inhibitor positive plasma compared to control plasma by ELISA were amplified and DNA was sequenced to determine the peptide sequence displayed on the phage. Before ITT, 31 isolated phage clones specific for FIX inhibitors have been sequenced so far. 10/31 contain a common motif. After ITT, 24 clones specific for patient plasma have been sequenced. 10/24 contain a different common motif. Synthetic peptides have been generated according to the phage displayed sequence to demonstrate binding of inhibitors and test for cross reactivity. The surface of the model of FIX was screened for these motifs with a novel software tool. Different conformational epitopes could be identified on the surface of the molecule before and after ITT. Small peptides (mimotopes) have been identified that mimic epitopes for FIX inhibitors in a hemophilia B patient. The sequences can be aligned to different conformational epitopes on FIX. It appears that the epitope has changed in the course of the ITT. The mimotopes can also be used to target inhibitor specific B cells for a novel approach in inhibitor elimination in hemophilia B.
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&NA;. "Lipodystrophy syndrome common during protease inhibitor therapy." Reactions Weekly &NA;, no. 757 (June 1999): 5. http://dx.doi.org/10.2165/00128415-199907570-00013.
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Paul, Sudipta, Dola Mukherjee, Kousik Pramanick, Sourav Kundu, S. P. Bhattacharyya, Priyanka De, and Dilip Mukherjee. "Stimulation of salmon calcitonin on secretion of 17β-estradiol by the ovarian follicles of common carp, Cyprinus carpio." Journal of Endocrinology 196, no. 2 (November 23, 2007): 413–24. http://dx.doi.org/10.1677/joe-07-0188.
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The effects of salmon calcitonin (sCT) on the secretion of 17β-estradiol (E2) were examined in female common carp, Cyprinus carpio. Vitellogenic stage fish adapted to high-Ca water were i.p. injected with vehicle, sCT, human chorionic gonadotropin (hCG), or hCG plus sCT. To determine whether ovarian follicles are equipped with CT receptors, a CT binding assay was conducted. In the in vitro experiments, vitellogenic follicles were incubated with stimulators and inhibitors. Administration of sCT increased the basal and hCG-stimulated E2 release in vivo and in vitro. Binding characteristics of [125I]sCT to plasma membrane preparation of carp ovarian follicles showed saturability with high-affinity (Kd=48.48 pmol/l and Bmax=1.2 pmol/mg protein). To clarify the mechanism of E2 production by sCT, in vitro effect of sCT and hCG on aromatase activity (conversion of testosterone to E2) and cytochrome P450 aromatase (P450arom) gene expression in carp ovarian follicles were investigated. Salmon CT-stimulated both aromatase activity and P450arom gene expression in ovarian follicles of carp. sCT-stimulated E2 release by the ovarian follicles in vitro was augmented in the presence of dibutyryl cAMP. Inhibitor of protein kinase A (PKA), SQ 22536 inhibited sCT-stimulated steroid production in a dose-dependent manner. Specific inhibitor of protein kinase C (PKC), NPC-15437 dihydrochloride had no inhibitory effects on sCT-induced E2 release. The present study indicates that sCT binds specifically to carp ovary and stimulates E2 production by increasing the activity of cytochrome P450 aromatase and P450arom gene expression. The results further suggest that stimulatory action of sCT on E2 production is mediated through cAMP pathway.
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Gao, Xuejun, Dandan Xue, Jingjing Cheng, Xin Zhang, and Xia Cai. "Inhibition of Axl Promotes the Therapeutic Effect of Targeted Inhibition of the PI3K/Akt Pathway in NRAS Mutant Melanoma Cells." Journal of Oncology 2022 (March 11, 2022): 1–9. http://dx.doi.org/10.1155/2022/2946929.
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Melanoma is a malignant tumor produced by highly aggressive and metastatic melanocytes. NRAS mutation is a relatively common mutation in melanoma cells. Mitogen-activated protein kinase (MAPK) signaling pathway and the PI3K/Akt pathway in melanoma cells are relatively common signaling pathways. In this study, we investigated the effect of inhibition of Axl expression on the targeted inhibition of the PI3K/Akt pathway in NRAS-mutant melanoma cells. In this study, immunohistochemistry and western blot methods were used to detect the expression of Axl and Akt proteins in melanoma cells. Axl inhibitor was added, and it detected the inhibitory efficiency of Akt inhibitor in melanoma cells. Finally, a melanoma mouse model was established, and it detected the proliferation and apoptosis of mouse tumor cells induced by Axl inhibitor and Akt inhibitor. The results showed that Axl and Akt were highly expressed in NRAS-mutant melanoma cells, and stimulation of Axl expression could reduce the inhibitory effect of Akt inhibitor on melanoma cells. The addition of Axl inhibitor can synergistically promote the effect of Akt inhibitor, slow down the proliferation of tumor cells, and induce cell apoptosis. According to the experiment in this study, Axl inhibitor combined with Akt inhibitor has a stronger therapeutic effect on melanoma than Akt inhibitor alone.
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Wei, Jia, Ling Ma, Chenglong Li, Christopher R. Pierson, Jonathan L. Finlay, and Jiayuh Lin. "Targeting Upstream Kinases of STAT3 in Human Medulloblastoma Cells." Current Cancer Drug Targets 19, no. 7 (August 2, 2019): 571–82. http://dx.doi.org/10.2174/1568009618666181016165604.
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Background:Medulloblastoma is the most common malignant brain tumor in children. Despite improvement in overall survival rate, it still lacks an effective targeted treatment strategy. The Janus family of cytoplasmic tyrosine kinases (JAKs) and Src kinases, upstream protein kinases of signal transducer and activator of transcription 3 (STAT3), play important roles in medulloblastoma pathogenesis and therefore represent potential therapeutic targets.Methods:In this report, we examined the inhibitory efficacy of the JAK1/2 inhibitor, ruxolitinib, the JAK3 inhibitor, tofacitinib and two Src inhibitors, KX2-391 and dasatinib.Results:These small molecule drugs significantly reduce cell viability and inhibit cell migration and colony formation in human medulloblastoma cells in vitro. Src inhibitors have more potent efficacy than JAK inhibitors in inhibiting medulloblastoma cell migration ability. The Src inhibitors can inhibit both phosphorylation of STAT3 and Src while JAK inhibitors reduce JAK/STAT3 phosphorylation. We also investigated the combined effect of the Src inhibitor, dasatinib with cisplatin. The results show that dasatinib exerts synergistic effects with cisplatin in human medulloblastoma cells through the inhibition of STAT3 and Src.Conclusion:Our results suggest that the small molecule inhibitors of STAT3 upstream kinases, ruxolitinib, tofacitinib, KX2-391, and dasatinib could be novel and attractive candidate drugs for the treatment of human medulloblastoma.
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Juhász, Szilvia, Rebecca Smith, Tamás Schauer, Dóra Spekhardt, Hasan Mamar, Siham Zentout, Catherine Chapuis, Sébastien Huet, and Gyula Timinszky. "The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment." Science Advances 6, no. 51 (December 2020): eabb8626. http://dx.doi.org/10.1126/sciadv.abb8626.
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Poly(ADP-ribose) polymerase (PARP) inhibitors are used in the treatment of BRCA-deficient cancers, with treatments currently extending toward other homologous recombination defective tumors. In a genome-wide CRISPR knockout screen with olaparib, we identify ALC1 (Amplified in Liver Cancer 1)—a cancer-relevant poly(ADP-ribose)-regulated chromatin remodeling enzyme—as a key modulator of sensitivity to PARP inhibitor. We found that ALC1 can remove inactive PARP1 indirectly through binding to PARylated chromatin. Consequently, ALC1 deficiency enhances trapping of inhibited PARP1, which then impairs the binding of both nonhomologous end-joining and homologous recombination repair factors to DNA lesions. We also establish that ALC1 overexpression, a common feature in multiple tumor types, reduces the sensitivity of BRCA-deficient cells to PARP inhibitors. Together, we conclude that ALC1-dependent PARP1 mobilization is a key step underlying PARP inhibitor resistance.
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Shi, Yun Feng, Li Li Zhang, Mu Qiu Zhao, and Gang Wang. "Inhibitory Effects of Aqueous Extracts from Leaves of Common Tropical Green Plants on Urea Hydrolysis in Soils." Advanced Materials Research 1010-1012 (August 2014): 614–17. http://dx.doi.org/10.4028/www.scientific.net/amr.1010-1012.614.
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Tropical plants contain a variety of secondary metabolites, and plant aqueous extracts can be used as urease inhibitors to improve nitrogen use efficiency and reduce the negative environmental effects. An incubation experiment was carried out to investigate the effects of aqueous extracts of 32 common tropical green plant species from 24 families on urea hydrolysis. The results indicated that the aqueous extracts from 3 of the common tropical green plants (Pterocarpus indicus, Callistemon rigidus, Terminalia mantaly) belonging to Leguminosae, Myrtaceae and Combretaceae respectively showed better inhibitory effects on urease than hydroquinone as a chemical inhibitor, and had more obvious potential applications. The inhibitory effects of active substances in plants were affected by extract temperature causing by solubility and thermal stability of active substances. T. mantaly had the most potential for development in this study as a fertilizer additive. The inhibitory effects of aqueous extracts of T. mantaly leaves on urea hydrolysis increased with increasing concentration of aqueous extracts, the strongest inhibitory effect on urease occurred after 2-3 d of incubation.
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Ahmed, Maryam Usman, Martha Ignatus, Benjamin Yakubu, Isaac John Umaru, Zuhairah Ismail Muhammad, Bilyaminu Habibu, Chikodiri Emmanuel Okoli, and Dawoye Yusufu. "Alpha amylase and angiotensin converting enzyme inhibitory potential of aqueous extract of Azanza garckeana fruit." Journal of Applied and Natural Science 14, no. 2 (June 18, 2022): 283–88. http://dx.doi.org/10.31018/jans.v14i2.3305.
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Diabetes mellitus and hypertension are common diseases affecting a lot of people. Alpha amylase and angiotensin-converting enzyme (ACE) inhibitors are used to treat type II diabetes and hypertension respectively. This study investigated the alpha amylase and ACE inhibitory potential of Azanza garckeana fruits. Phytochemical screening, α-amylase and ACE inhibitory potential of the aqueous extract of A. garckeana fruit was determined using standard procedures. The mode of inhibition of α-amylase by A. garckeana fruit was determined from the Lineweaver-Burk plot. Alkaloids, flavonoids, anthraquinones, steroids, tannins, phenols and terpenoids were present in the aqueous extract of A. garkeana fruit. The percent inhibition of α-amylase was greater than 50%. The IC50 values were 2.6 ± 0.02 and 0.04 ± 0.09 for the extract and acarbose (standard drug) respectively. The Lineweaver-Burk plot showed that extract Vmax did not change when compared to the no inhibitor (no extract) but the km increased. The percent inhibition of ACE by A. garckeana was also greater than 50%. Its IC50 was 0.625 ± 0.03 while that of the standard drug (captopril) was 0.875 ± 0.07. Thus A. garckeana inhibited α-amylase and ACE and can be used to treat type II diabetes and hypertension. It is a competitive inhibitor of α-amylase.
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Scandella, Dorothea. "Epitope Specificity of Factor VIII Inhibitor Antibodies." Hämostaseologie 18, no. 03 (May 1998): 121–28. http://dx.doi.org/10.1055/s-0038-1655342.
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SummaryAntibodies that inactivate factor VIII develop most frequently in patients with severe hemophilia A, and they present a serious complication in the therapy of such individuals. Most patients with inhibitors have two or more different antibodies capable of factor VIII inactivation in their plasma, as shown by assays in which several factor VIII domain fragments are tested for neutralization of the inhibitor activity. Such neutralization assays of 23 patient plasmas suggest that there are three common epitopes. These epitopes have been localized by several methods to the A2, A3, and C2 factor VIII domains. Less common inhibitor epitopes lie within the heavy chain acidic region residues 336-372 and in a second region of the C2 domain. The light chain acidic region, residues 1649-1689, may also contain an inhibitor epitope, but this remains to be confirmed. The inhibitor epitopes of autoantibody patients are more restricted as half of them have anti-C2 domain antibodies that make up 95% of the inhibitor activity. The remainder have several inhibitors similar to those of the hemophiliacs. The predominant C2 domain epitope specificity was also seen in rare cases of inhibitor development due to two heat pasteurized factor VIII concentrates in previously treated patients without inhibitors. Inhibitors in mild hemophiliacs are rare as these individuals are usually tolerant to factor VIII. When tolerance is overcome in such patients, the immune responses characterized were diverse. In some patients there was a complete loss of tolerance.
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Amara, J. F., and H. F. Lodish. "Specific mRNA destabilization in Dictyostelium discoideum requires RNA synthesis." Molecular and Cellular Biology 7, no. 12 (December 1987): 4585–88. http://dx.doi.org/10.1128/mcb.7.12.4585-4588.1987.
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We tested the effects of inhibitors of protein and RNA synthesis on the disaggregation-mediated destabilization of prespore mRNAs in Dictyostelium discoideum. Incubating disaggregated cells with daunomycin to inhibit RNA synthesis prevented the loss of prespore mRNAs, whereas the inhibitor decreased or did not affect levels of the common mRNAs CZ22 and actin. Protein synthesis inhibitors varied in their effects. Cycloheximide, which inhibited protein synthesis almost completely, prevented the loss of the prespore mRNAs, but puromycin, which inhibited protein synthesis less well, did not. These results indicate that the process of specific mRNA destabilization requires the synthesis of RNA and possibly of protein.
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Amara, J. F., and H. F. Lodish. "Specific mRNA destabilization in Dictyostelium discoideum requires RNA synthesis." Molecular and Cellular Biology 7, no. 12 (December 1987): 4585–88. http://dx.doi.org/10.1128/mcb.7.12.4585.
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We tested the effects of inhibitors of protein and RNA synthesis on the disaggregation-mediated destabilization of prespore mRNAs in Dictyostelium discoideum. Incubating disaggregated cells with daunomycin to inhibit RNA synthesis prevented the loss of prespore mRNAs, whereas the inhibitor decreased or did not affect levels of the common mRNAs CZ22 and actin. Protein synthesis inhibitors varied in their effects. Cycloheximide, which inhibited protein synthesis almost completely, prevented the loss of the prespore mRNAs, but puromycin, which inhibited protein synthesis less well, did not. These results indicate that the process of specific mRNA destabilization requires the synthesis of RNA and possibly of protein.
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Hale, J. P., and M. Burrows. "Innervation patterns of inhibitory motor neurones in the thorax of the locust." Journal of Experimental Biology 117, no. 1 (July 1, 1985): 401–13. http://dx.doi.org/10.1242/jeb.117.1.401.
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The innervation pattern of inhibitory motor neurones of the locust has been revealed by intracellular recording from their cell bodies in the meso- and metathoracic ganglion and simultaneous recording from muscle fibres in a middle, or in a hind leg. Three neurones in each ganglion, the common inhibitor (CI = CI1), the anterior inhibitor (AI = CI2), and the posterior inhibitor (PI = CI3) innervate several muscles in one leg and are thus common inhibitory neurones. Metathoracic CI innervates 13 muscles in one hind leg and mesothoracic CI innervates 12 muscles in one middle leg. The muscles are all in the proximal parts of the legs and move the coxa, the trochanter and the tibia. Metathoracic AI and PI innervate four muscles in the more distal parts of one hind leg that move the tibia, the tarsus and the unguis. None of these muscles is innervated by CI. Each inhibitor innervates muscles that have different and often antagonistic actions during movements of a leg. AI and PI receive many synaptic inputs in common and show similar patterns of spikes during imposed movements of a tibia. Tests fail, however, to reveal evidence for any electrical or synaptic coupling between them. A revised scheme of nomenclature for these inhibitory neurones is proposed.
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Chen, Yun, Yao Guo, Wanting Ho, and Zhizhuang Joe. "Identification and Characterization Of a Potent FLT3 Inhibitor." Blood 122, no. 21 (November 15, 2013): 5027. http://dx.doi.org/10.1182/blood.v122.21.5027.5027.
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Abstract Acute myeloid leukemia (AML) is a malignant myeloid disorder for which there is no effective treatment. Gain-of-function mutations of tyrosine kinase FLT3 are frequently found in AML patients. This makes FLT3 an attractive therapeutic target. Currently, several potent FLT3 inhibitors have been developed. However, their clinical efficacy is limited largely due to their poor effectiveness toward the FLT3-D835 mutants which are often present in AML or acquired after treatment of FLT3-ITD-positive AML with tyrosine kinase inhibitors. Needless to say, more potent FLT3 inhibitors targeting both FLT-ITD and FLT3-D835 mutants are needed. In addition, combinations of tyrosine kinase inhibitors with drugs targeting other signaling pathways represent a new trend in anti-cancer drug development. To establish an effective kinase assay for FLT3 inhibitor screening, we generated a protein substrate designated GST-FLT3S which was expressed in E. coli cells as a glutathione S-transferase fusion protein. The protein substrate together with recombinant proteins containing the catalytic domain of wild type and mutant forms of FLT3 expressed in baculovirus was used in biochemical screening of inhibitors. Several potent inhibitors were obtained. Importantly, one of the inhibitors with an oxindole core structure inhibited FLT3 and D835 FLT3 mutants equally well with nanomolar IC50 values. We further analyzed the potency of the inhibitor by performing cell-based assays. The cells used included FLT3-ITD-positive cell line MV-4-11 and an EPO-dependent erythroleukemia cell line transformed by retrovirus mediated expressions of FLT3-ITD and FLT3-D835 mutants. At nanomolar concentrations, the inhibitor blocked growth factor signaling and effectively caused apoptosis and cell cycle arrest. It showed significant advantage over the current available FLT3 inhibitor, sorafenib. Loss-of-function mutations of tumor suppressor p53 are common in solid tumors but relatively rare in AML although its expression is often suppressed. This makes p53 a potential target for anti-AML drug development. We employed MDM2 inhibitor nutlin-3 which blocks the degradation of p53. Importantly, at sub-nanomolar concentrations, FLT3 inhibitors and nutlin-3 synergistically inhibited growth of cells containing FLT3-ITD or FLT3-D835 mutants. Altogether, we developed an effective substrate for screening of FLT3 inhibitors and identified one compound with high potency toward both FLT3-ITD and FLT3-D835. We further demonstrated that targeting FLT3 and p53 simultaneously greatly increases drug potency. Disclosures: No relevant conflicts of interest to declare.
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Philips, M., Anne-Grethe Juul, S. Thorsen, J. Selmer, and J. Zeuthen. "Immunological Relationship Between the Fast-Acting Plasminogen Activator Inhibitors from Plasma, Blood Platelets and Endothelial Cells Demonstrated with a Monoclonal Antibody Against an Inhibitor from Placenta." Thrombosis and Haemostasis 55, no. 02 (1986): 213–17. http://dx.doi.org/10.1055/s-0038-1661524.
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SummaryTwo plasminogen activator inhibitors (I and II) were demonstrated in human placenta. The complex between inhibitor I and tissue-type plasminogen activator was purified by immunoadsorption to solid-phase anti-activator antibodies. The purified complex (Mr 95.000) was used for immunization of mice and subsequent production of monoclonal antibodies. One antibody (F37), which reacted with both free and complex-bound inhibitor I, was used for further study by a method involving binding of the antibody to protein A-Sepharose, immunoadsorp-tion of antigen and analysis of the resulting supernatant by SDS-polyacrylamide gel electrophoresis and enzymography. The analysis showed that F37 reacted with the fast-acting plasminogen activator inhibitors recently demonstrated in plasma, blood platelets and endothelial cells, indicating that these inhibitors and inhibitor I share a common epitope. Inhibitor II did not react with F37. Inhibitor II is identical to the placenta inhibitor previously described by others. It reacted selectively with polyclonal antibodies against that inhibitor.
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Fields, Gregg B. "The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma." Cells 8, no. 9 (August 27, 2019): 984. http://dx.doi.org/10.3390/cells8090984.
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The pursuit of matrix metalloproteinase (MMP) inhibitors began in earnest over three decades ago. Initial clinical trials were disappointing, resulting in a negative view of MMPs as therapeutic targets. As a better understanding of MMP biology and inhibitor pharmacokinetic properties emerged, it became clear that initial MMP inhibitor clinical trials were held prematurely. Further complicating matters were problematic conclusions drawn from animal model studies. The most recent generation of MMP inhibitors have desirable selectivities and improved pharmacokinetics, resulting in improved toxicity profiles. Application of selective MMP inhibitors led to the conclusion that MMP-2, MMP-9, MMP-13, and MT1-MMP are not involved in musculoskeletal syndrome, a common side effect observed with broad spectrum MMP inhibitors. Specific activities within a single MMP can now be inhibited. Better definition of the roles of MMPs in immunological responses and inflammation will help inform clinic trials, and multiple studies indicate that modulating MMP activity can improve immunotherapy. There is a U.S. Food and Drug Administration (FDA)-approved MMP inhibitor for periodontal disease, and several MMP inhibitors are in clinic trials, targeting a variety of maladies including gastric cancer, diabetic foot ulcers, and multiple sclerosis. It is clearly time to move on from the dogma of viewing MMP inhibition as intractable.
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Cathcart-Rake, Elizabeth Jane, Lindsey R. Sangaralingham, Nilay Shah, and Aaron Scott Mansfield. "Immunotherapy-related toxicities: More common than originally reported?" Journal of Clinical Oncology 36, no. 34_suppl (December 1, 2018): 184. http://dx.doi.org/10.1200/jco.2018.36.34_suppl.184.
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184 Background: Population level data regarding incidence of immune-related adverse events (irAE) is lacking. This study evaluated the frequency of irAEs among a large population of patients with non-small cell lung cancer (NSCLC) who received immune checkpoint inhibitors. Methods: Administrative claims data from a large U.S. commercial insurance database (OptumLabs Data Warehouse) were used to retrospectively identify patients with NSCLC who received PD-1 or PD-L1 inhibitors between January 1, 2015 to December 31, 2017. The frequencies of irAEs were reported, identified by having a new medical claim with a corresponding ICD-9 or ICD-10 code during the time period in which the patient was on immunotherapy. Results: Of 2,798 patients with NSCLC (median age at PD-(L)1 initiation: 69 years, interquartile range: 60-75, 1558 male [55.7%], 1240 [44.3%] female), 1,998 (71.4%) received nivolumab, 699 (25.0%) received pembrolizumab, and 101 (3.6%) received atezolizumab. Most patients (1463, 52.3%) received a PD-(L)1 inhibitor as second line therapy; the majority of patients (744) received alkylating agents and antimetabolites prior to receiving PD-(L)1 therapy. See Table 1 for frequencies of irAEs. Conclusions: The current study suggests that the frequencies of some irAEs related to immune checkpoint inhibitor therapies may be higher than those which were reported in the initial trials that led to the FDA approvals for immunotherapies. For example, hypophysitis was noted to occur in 0.6% of patients in the KEYNOTE-024 trial, but was identified in 2.4% of patients in this large cohort. Real world data may refine provider and patient expectations for outcomes beyond what is observed in clinical trials. [Table: see text]
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Armel, Gregory R., Patrick L. Rardon, Michael C. McComrick, and Nancy M. Ferry. "Differential Response of Several Carotenoid Biosynthesis Inhibitors in Mixtures with Atrazine." Weed Technology 21, no. 4 (December 2007): 947–53. http://dx.doi.org/10.1614/wt-06-133.1.
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Greenhouse studies were conducted in 2003 at the Stine–Haskell Research Center to determine whether herbicide inhibitors of six specific sites in the carotenoid biosynthesis pathway would elicit synergistic responses when applied postemergence (POST) in combination with the photosystem II (PSII) inhibitor atrazine. Based on data analysis with the Isobole method, synergistic responses were observed on red morningglory, common cocklebur, and giant foxtail when atrazine was applied in mixtures with the deoxy-D-xylulose-5-phosphate reductoisomerase (DOXP reductoisomerase) inhibitor fosmidomycin, thep-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor mesotrione, and the DuPont proprietary zeta-carotene desaturase (ZDS) inhibitor DFPC. Clomazone (its metabolite ketoclomazone is the actual enzyme inhibitor), an inhibitor of 1-deoxy-D-xylulose-5-phosphate synthatase (DOXP synthase), provided synergistic responses on red morningglory, but antagonistic responses on both common cocklebur and giant foxtail when applied in mixtures with atrazine. Combinations of the lycopene cyclase (LC) inhibitor, CPTA, with atrazine produced synergistic responses on both common cocklebur and giant foxtail but were antagonistic on red morningglory. Norflurazon, a phytoene desaturase (PDS) inhibitor, applied in mixtures with atrazine provided synergistic responses on red morningglory, antagonistic responses on giant foxtail, and independent responses on common cocklebur. Because carotenoids have been determined to play a key role in quenching singlet oxygen species in the chloroplast and also assist in the maintenance of the D1 protein in PSII, this might help explain the synergistic responses with atrazine observed in our studies.
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Kim, Sue Min, Jung Hee Park, Ky-Youb Nam, June H.-J. Han, Kyu-Tae Kim, Jeong Hyeok Yoon, Sandip Sengupta, Taebo Sim, and Sang Joon Shin. "Abstract 411: PHI-501, a novel pan-RAF/DDRs dual kinase inhibitor, overcomes BRAF or MEK inhibitor resistance in melanoma." Cancer Research 83, no. 7_Supplement (April 4, 2023): 411. http://dx.doi.org/10.1158/1538-7445.am2023-411.
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Abstract Background: PHI-501 is a newly developed, highly effective, and orally accessible dual inhibitor for pan-RAF and discoidin domain receptor (DDR) that is a collagen-activated receptor tyrosine kinase. Mutations of the BRAF and NRAS are the most common genetic alterations in melanoma and consequently lead to activation of mitogen activated protein kinase (MAPK) signaling. The major drawback of melanoma treatment is the innate and acquired drug resistance to MAPK inhibitors. In this study, we investigated the inhibitory effects of a novel compound, PHI-501 on resistance to known BRAF and MEK inhibitors in melanoma. Methods: After compounds treatment, the growth-inhibiting activity was assessed using the CCK test. Inhibition of RAF/DDR1 pathway signaling was evaluated by western blotting. Using annexin-V/propidium iodide-stained cells and flow cytometry, apoptosis induction was assessed. To quantify cell mobility, monolayer cells were subjected to a wound-healing assay. Long-term therapy with dabrafenib (BRAF inhibitor), cobimetinib or trametinib (MEK inhibitor) led to the establishment of the drug-resistant SK-MEL-3 (BRAF V600E) and SK-MEL-30 (NRAS Q61K) melanoma cell line. Results: PHI-501 demonstrated potent growth inhibition (GI50 <1 µM) in seven melanoma cell lines harboring BRAF V600E or NRAS mutations. Western blot revealed that PHI-501 inhibited the phosphorylation of MEK, ERK, and AKT proteins in the downstream signaling of RAF/DDRs and decreased the levels of cyclin D1 and survivin. In SK-MEL-3, PHI-501 was 47-fold more effective than the class I BRAF inhibitor, dabrafenib (GI50: 0.08 µM vs 3.73 µM). Established dabrafenib- or trametinib-resistant SK-MEL-3 cells were extremely sensitive to PHI-501 (GI50: 0.20 µM and 0.13 µM), whereas their sensitivity to dabrafenib or trametinib was diminished (GI50: NA and 39.61 µM). PHI-501 triggered apoptosis more effectively than these inhibitors, as revealed by a larger proportion of annexin staining and extensive PARP1 cleavage. Comparing the potency of PHI-501 to cobimetinib in acquired resistant SK-MEL-30 cells showed that PHI-501 had 74-fold more inhibitory effect on cell proliferation (GI50: 0.55 µM to 40 µM). Moreover, treatment with PHI-501 strongly suppressed cell migration of cobimetinib-resistant SK-MEL-30 cells. PHI-501 inhibited the growth of drug-resistant melanoma cells as effectively as the original drug-naïve cells, and western blot analysis revealed considerable suppression of DDR1/2, ERK, and AKT phosphorylation in MAPK inhibitor-resistant cells. Conclusion: Melanoma cells resistant to RAF or MEK-targeted treatments or harboring NRAS mutation exhibited strong antiproliferative activity when treated with PHI-501, a highly potent pan-RAF/DDR dual inhibitor. The results of this study suggest that PHI-501, as a single agent, has the potential to overcome the restricted response in the treatment of melanoma. Citation Format: Sue Min Kim, Jung Hee Park, Ky-Youb Nam, June H-J Han, Kyu-Tae Kim, Jeong Hyeok Yoon, Sandip Sengupta, Taebo Sim, Sang Joon Shin. PHI-501, a novel pan-RAF/DDRs dual kinase inhibitor, overcomes BRAF or MEK inhibitor resistance in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 411.
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Carlson, Robert H. "TKI Inhibitor Active in Common and Rare Tumors." Oncology Times 38, no. 11 (June 2016): 23–25. http://dx.doi.org/10.1097/01.cot.0000484649.13722.19.
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Schlomann, Uwe, Kristina Dorzweiler, Elisa Nuti, Tiziano Tuccinardi, Armando Rossello, and Jörg W. Bartsch. "Metalloprotease inhibitor profiles of human ADAM8 in vitro and in cell-based assays." Biological Chemistry 400, no. 6 (June 26, 2019): 801–10. http://dx.doi.org/10.1515/hsz-2018-0396.
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AbstractADAM8 as a membrane-anchored metalloproteinase-disintegrin is upregulated under pathological conditions such as inflammation and cancer. As active sheddase, ADAM8 can cleave several membrane proteins, among them the low-affinity receptor FcεRII CD23. Hydroxamate-based inhibitors are routinely used to define relevant proteinases involved in ectodomain shedding of membrane proteins. However, for ADAM proteinases, common hydroxamates have variable profiles in their inhibition properties, commonly known for ADAM proteinases 9, 10 and 17. Here, we determined the inhibitor profile of human ADAM8 for eight ADAM/MMP inhibitors byin vitroassays using recombinant ADAM8 as well as thein vivoinhibition in cell-based assays using HEK293 cells to monitor the release of soluble CD23 by ADAM8. ADAM8 activity is inhibited by BB94 (Batimastat), GW280264, FC387 and FC143 (two ADAM17 inhibitors), made weaker by GM6001, TAPI2 and BB2516 (Marimastat), while no inhibition was observed for GI254023, an ADAM10 specific inhibitor. Modeling of inhibitor FC143 bound to the catalytic sites of ADAM8 and ADAM17 reveals similar geometries in the pharmacophoric regions of both proteinases, which is different in ADAM10 due to replacement in the S1 position of T300 (ADAM8) and T347 (ADAM17) by V327 (ADAM10). We conclude that ADAM8 inhibitors require maximum selectivity over ADAM17 to achieve specific ADAM8 inhibition.
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Kang, Joyeon, Doyeon Lee, Kyoung Jin Lee, Jaepil Eric Yoon, Ji-Hee Kwon, Yoojeong Seo, Janghyun Kim, et al. "Tumor-Suppressive Effect of Metformin via the Regulation of M2 Macrophages and Myeloid-Derived Suppressor Cells in the Tumor Microenvironment of Colorectal Cancer." Cancers 14, no. 12 (June 10, 2022): 2881. http://dx.doi.org/10.3390/cancers14122881.
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Myeloid-derived suppressor cells (MDSCs) and M2 macrophages in the tumor microenvironment contribute to tumor progression by inducing immune tolerance to tumor antigens and cancer cells. Metformin, one of the most common diabetes drugs, has shown anti-inflammatory and anti-tumor effects. However, the effects of metformin on inflammatory cells of the tumor microenvironment and its underlying mechanisms remain unclarified. In this study, we investigated the effect of metformin on M2 macrophages and MDSCs using monocyte THP-1 cells and a dextran sodium sulfate (DSS)-treated ApcMin/+ mouse model of colon cancer. Metformin decreased the fractions of MDSCs expressing CD33 and arginase, as well as M2 macrophages expressing CD206 and CD163. The inhibitory effect of metformin and rapamycin on MDSCs and M2 macrophages was reversed by the co-treatment of Compound C (an AMP-activated protein kinase (AMPK) inhibitor) or mevalonate. To examine the effect of protein prenylation and cholesterol synthesis (the final steps of the mevalonate pathway) on the MDSC and M2 macrophage populations, we used respective inhibitors (YM53601; SQLE inhibitor, FTI-277; farnesyl transferase inhibitor, GGTI-298; geranylgeranyl transferase inhibitor) and found that the MDSC and M2 populations were suppressed by the protein prenylation inhibitors. In the DSS-treated ApcMin/+ mouse colon cancer model, metformin reduced the number and volume of colorectal tumors with decreased populations of MDSCs and M2 macrophages in the tumor microenvironment. In conclusion, the inhibitory effect of metformin on MDSCs and M2 macrophages in the tumor microenvironment of colon cancers is mediated by AMPK activation and subsequent mTOR inhibition, leading to the downregulation of the mevalonate pathway.
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Kim, Byung-Su, Chansu Lee, Juwon Park, Kwang-Sung Ahn, Byoung Kook Kim, Seonyang Park, Young-Yiul Lee, and Sung-Soo Yoon. "Inactivation of JAK/STAT Cell Signaling by SK-7041, a Novel HDAC Inhibitor, Effectively Inhibits Growth of Acute Myeloid Leukemia Cells." Blood 112, no. 11 (November 16, 2008): 4005. http://dx.doi.org/10.1182/blood.v112.11.4005.4005.
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Abstract Activation of the JAK/STAT pathway appears common in AML, occurring in up to 70% of AML patients. Therefore, JAK/STAT signal inhibitors are promising as candidate anti-cancer agents in AML. Recently, we reported that SK-7041, an HDAC inhibitor, inhibited the growth of AML cells via activation of caspase-3 and down-regulation of cyclin D1. These findings lead us to further examine whether SK-7041 inhibits the growth of KG1 AML cells via inactivation of JAK/STAT signals. Multi-immunoblotting technique (Kinetworks™ analysis) showed that expression of p-STAT-3, p-STAT-5, and p-Erk was down-regulated in KG1 cells treated with SK-7041. These results were confirmed by individual western blot analysis. In addition, IL-6-induced activation of STAT-3 and Erk was inhibited by treatment of SK-7041. Combined treatment of SK-7041 and JAK inhibitor (AG490) showed additive anti-leukemic effect as evidenced by caspase-3 activation, down-regulation of cyclin D1 (cMYC), and inhibition of phosphorylation of STATs (−1, −3). These results suggest that HDAC inhibitor, SK-7041, inhibited AML cell growth via inactivation of JAK/STATs pathway.
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Sedov, Igor, and Diliara Khaibrakhmanova. "Molecular Mechanisms of Inhibition of Protein Amyloid Fibril Formation: Evidence and Perspectives Based on Kinetic Models." International Journal of Molecular Sciences 23, no. 21 (November 3, 2022): 13428. http://dx.doi.org/10.3390/ijms232113428.
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Inhibition of fibril formation is considered a possible treatment strategy for amyloid-related diseases. Understanding the molecular nature of inhibitor action is crucial for the design of drug candidates. In the present review, we describe the common kinetic models of fibril formation and classify known inhibitors by the mechanism of their interactions with the aggregating protein and its oligomers. This mechanism determines the step or steps of the aggregation process that become inhibited and the observed changes in kinetics and equilibrium of fibril formation. The results of numerous studies indicate that possible approaches to antiamyloid inhibitor discovery include the search for the strong binders of protein monomers, cappers blocking the ends of the growing fibril, or the species absorbing on the surface of oligomers preventing nucleation. Strongly binding inhibitors stabilizing the native state can be promising for the structured proteins while designing the drug candidates targeting disordered proteins is challenging.
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Yoshihara, S., K. Kondo, K. Kanaya, K. Suzukawa, S. Baba, M. Toma-Hirano, S. Kikuta, Y. Iwasaki, K. Fujio, and T. Yamasoba. "Tumour necrosis factor inhibitor-associated sinusitis." Rhinology journal 52, no. 3 (September 1, 2014): 246–51. http://dx.doi.org/10.4193/rhino13.074.
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Aim: To describe the features of chronic sinusitis associated with the use of tumour necrosis factor (TNF) inhibitors. Methodology: A retrospective review of the medical records between 2003 and 2011 revealed that five patients had developed chronic sinusitis after the start of TNF inhibitor administration and required rhinological evaluation and treatment. Results: The incidence of refractory sinusitis associated with TNF inhibitors was approximately 2%. Of the five patients identified, four patients were medicated with etanercept and one with infliximab. The maxillary sinus was most commonly involved and cultures of the sinus discharge revealed Pseudomonas aeruginosa in three cases. Two patients showed improvement of sinusitis with antibiotic medication, despite the continuous use of TNF inhibitor, while in two other patients, sinusitis was resistant to antibiotic medication. Another patient who had developed recurrence of sinusitis after complete remission of previous chronic sinusitis by endoscopic sinus surgery showed remission only after cessation of TNF inhibitor. Conclusion: Chronic sinusitis associated with TNF inhibitors is considered to be a new disease entity, and it will become more common due to the increasing use of TNF inhibitors.
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Burger, Dylan, Timothy L. Reudelhuber, Aman Mahajan, Kelly Chibale, Edward D. Sturrock, and Rhian M. Touyz. "Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension." Clinical Science 127, no. 1 (March 10, 2014): 57–63. http://dx.doi.org/10.1042/cs20130808.
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The C-domain selective ACE inhibitor lisW-S reduced blood pressure and AngII levels in hypertensive TtRhRen mice similarly to classical ACE inhibitors and has the potential to avoid undesirable effects on the bradykinin system common to classic ACE inhibitors.
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Fakhoury, A. M., and C. P. Woloshuk. "Inhibition of Growth of Aspergillus flavus and Fungal α-Amylases by a Lectin-Like Protein from Lablab purpureus." Molecular Plant-Microbe Interactions® 14, no. 8 (August 2001): 955–61. http://dx.doi.org/10.1094/mpmi.2001.14.8.955.
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Aspergillus flavus is a fungal pathogen of maize causing an important ear rot disease when plants are exposed to drought and heat stress. Associated with the disease is the production of aflatoxins, which are a series of structurally related mycotoxins known to be carcinogenic. Previous research has suggested that the α-amylase of A. flavus promotes aflatoxin production in the endosperm of infected maize kernels. We report here the isolation and characterization of a 36-kDa α-amylase inhibitor from Lablab purpureus (AILP). AILP inhibited the α-amylases from several fungi but had little effect on those from animal and plant sources. The protein inhibited conidial germination and hyphal growth of A. flavus. The amino acid sequence indicated that AILP is similar to lectin members of a lectin-arcelin-α-amylase inhibitor family described in common bean and shown to be a component of plant resistance to insect pests. AILP also agglutinated papain-treated red blood cells from human and rabbit. These data indicate that AILP represents a novel variant in the lectin-arcelin-α-amylase inhibitor family of proteins having lectin-like and α-amylase inhibitory activity.
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Tanaka, Masakazu, Masatoshi Mushiake, Jun Takahashi, Yuka Sasaki, Sachiko Yamashita, Chieri Ida, Mitsuko Masutani, and Masanao Miwa. "PARP Inhibitor Decreases Akt Phosphorylation and Induces Centrosome Amplification and Chromosomal Aneuploidy in CHO-K1 Cells." International Journal of Molecular Sciences 23, no. 7 (March 23, 2022): 3484. http://dx.doi.org/10.3390/ijms23073484.
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Cancer cells are known to have chromosomal number abnormalities (aneuploidy), a hallmark of malignant tumors. Cancer cells also have an increased number of centrosomes (centrosome amplification). Paradoxically, cancer therapies, including γ-irradiation and some anticancer drugs, are carcinogenic and can induce centrosome amplification and chromosomal aneuploidy. Thus, the processes of carcinogenesis and killing cancer cells might have some mechanisms in common. Previously, we found that the inhibitors of polyADP-ribosylation, a post-translational modification of proteins, caused centrosome amplification. However, the mechanism of action of the inhibitors of polyADP-ribosylation is not fully understood. In this study, we found that an inhibitor of polyADP-ribosylation, 3-aminobenzamide, caused centrosome amplification, as well as aneuploidy of chromosomes in CHO-K1 cells. Moreover, inhibitors of polyADP-ribosylation inhibited AKT phosphorylation, and inhibitors of AKT phosphorylation inhibited polyADP-ribosylation, suggesting the involvement of polyADP-ribosylation in the PI3K/Akt/mTOR signaling pathway for controlling cell proliferation. Our data suggest a possibility for developing drugs that induce centrosome amplification and aneuploidy for therapeutic applications to clinical cancer.
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&NA;. "ACE inhibitor-induced cough more common in Black patients." Reactions Weekly &NA;, no. 636 (February 1997): 5. http://dx.doi.org/10.2165/00128415-199706360-00013.
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Vagnerova, Kamila, R. Noppens, P. D. Hurn, J. R. Kirsch, and A. Bhardwaj. "COMMON NEUROPROTECTIVE MECHANISM 1 RECEPTOR AGONIST AND INOS INHIBITOR." Critical Care Medicine 32, Supplement (December 2004): A98. http://dx.doi.org/10.1097/00003246-200412001-00353.
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Nguyen, Cuong, and Seung Kee Han. "Synchronization of toggle switches coupled through a common inhibitor." EPL (Europhysics Letters) 90, no. 1 (April 1, 2010): 10010. http://dx.doi.org/10.1209/0295-5075/90/10010.
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Lee, Seung-Hwa, Jungchan Park, Rae Woong Park, Seo Jeong Shin, Jinseob Kim, Ji Dong Sung, Dae Jung Kim, and Kwangmo Yang. "Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Cancer: A Population-Based Cohort Study Using a Common Data Model." Diagnostics 12, no. 2 (January 21, 2022): 263. http://dx.doi.org/10.3390/diagnostics12020263.
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Studies have reported conflicting results on the association between the use of renin-angiotensin-aldosterone system (RAAS) inhibitors and cancer development. We compared the incidence of cancer between patients using RAAS inhibitors and other antihypertensive drugs. This retrospective observational cohort study used data from seven hospitals in Korea that were converted for use in the Observational Medical Outcomes Partnership Common Data Model. A total of 166,071 patients on antihypertensive therapy across the databases of the seven hospitals were divided into two groups according to the use of RAAS inhibitors. The primary outcome was the occurrence of cancer. A total of 166,071 patients across the databases of the seven hospitals was included in the final analysis; 26,650 (16%) were in the RAAS inhibitors group and 139,421 (84%) in the other antihypertensive drugs group. The meta-analysis of the whole cohort showed a lower incidence of cancer occurrence in the RAAS inhibitor group (9.90 vs. 13.28 per 1000 person years; HR, 0.81; 95% confidence interval [CI], 0.75–0.88). After propensity-score matching, the RAAS inhibitor group consistently showed a lower incidence of cancer (9.90 vs. 13.28 per 1000 person years; HR, 0.86; 95% CI, 0.81–0.91). The patients using RAAS inhibitors showed a lower incidence of cancer compared with those using other antihypertensive drugs. These findings support the association between the use of RAAS inhibitors and cancer occurrence.
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Klei, Herbert E., Kevin Kish, Pin-Fang M. Lin, Qi Guo, Jacques Friborg, Ronald E. Rose, Yaqun Zhang, et al. "X-Ray Crystal Structures of Human Immunodeficiency Virus Type 1 Protease Mutants Complexed with Atazanavir." Journal of Virology 81, no. 17 (May 30, 2007): 9525–35. http://dx.doi.org/10.1128/jvi.02503-05.
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ABSTRACT Atazanavir, which is marketed as REYATAZ, is the first human immunodeficiency virus type 1 (HIV-1) protease inhibitor approved for once-daily administration. As previously reported, atazanavir offers improved inhibitory profiles against several common variants of HIV-1 protease over those of the other peptidomimetic inhibitors currently on the market. This work describes the X-ray crystal structures of complexes of atazanavir with two HIV-1 protease variants, namely, (i) an enzyme optimized for resistance to autolysis and oxidation, referred to as the cleavage-resistant mutant (CRM); and (ii) the M46I/V82F/I84V/L90M mutant of the CRM enzyme, which is resistant to all approved HIV-1 protease inhibitors, referred to as the inhibitor-resistant mutant. In these two complexes, atazanavir adopts distinct bound conformations in response to the V82F substitution, which may explain why this substitution, at least in isolation, has yet to be selected in vitro or in the clinic. Because of its nearly symmetrical chemical structure, atazanavir is able to make several analogous contacts with each monomer of the biological dimer.
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Valencia-Jiménez, A., J. W. Arboleda V, A. López Ávila, and M. F. Grossi-de-Sá. "Digestive α-amylases from Tecia solanivora larvae (Lepidoptera: Gelechiidae): response to pH, temperature and plant amylase inhibitors." Bulletin of Entomological Research 98, no. 6 (July 1, 2008): 575–79. http://dx.doi.org/10.1017/s0007485308005944.
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AbstractThe biochemical properties of the digestive alpha-amylase from Tecia solanivora larvae, an important and invasive insect pest of potato (Solanum tuberosum), were studied. This insect has three major digestive α-amylases with isoelectric points 5.30, 5.70 and 5.98, respectively, which were separated using native and isoelectric focusing gels. The alpha-amylase activity has an optimum pH between 7.0 and 10.0 with a peak at pH 9.0. The enzymes are stable when heated to 50°C and were inhibited by proteinaceous inhibitors from Phaseolus coccineus (70% inhibition) and P. vulgaris cv. Radical (87% inhibition) at pH 6.0. The inhibitors present in an amaranth hybrid inhibited 80% of the activity at pH 9.0. The results show that the alpha-amylase inhibitor from amaranth seeds may be a better candidate to make genetically-modified potatoes resistant to this insect than inhibitors from common bean seeds.
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Rozpędek, Wioletta, Dariusz Pytel, Adam Wawrzynkiewicz, Natalia Siwecka, Adam Dziki, Łukasz Dziki, J. Alan Diehl, and Ireneusz Majsterek. "Use of Small-molecule Inhibitory Compound of PERK-dependent Signaling Pathway as a Promising Target-based Therapy for Colorectal Cancer." Current Cancer Drug Targets 20, no. 3 (March 19, 2020): 223–38. http://dx.doi.org/10.2174/1568009620666200106114826.
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Background: Colorectal cancer constitutes one of the most common cancer with a high mortality rate. The newest data has reported that activation of the pro-apoptotic PERK-dependent unfolded protein response signaling pathway by small-molecule inhibitors may constitute an innovative anti-cancer treatment strategy. Objective: In the presented study, we evaluated the effectiveness of the PERK-dependent unfolded protein response signaling pathway small-molecule inhibitor 42215 both on HT-29 human colon adenocarcinoma and CCD 841 CoN normal human colon epithelial cell lines. Methods: Cytotoxicity of the PERK inhibitor was evaluated by the resazurin-based and lactate dehydrogenase (LDH) tests. Apoptotic cell death was measured by flow cytometry using the FITCconjugated Annexin V to indicate apoptosis and propidium iodide to indicate necrosis as well as by colorimetric caspase-3 assay. The effect of tested PERK inhibitor on cell cycle progression was measured by flow cytometry using the propidium iodide staining. The level of the phosphorylated form of the eukaryotic initiation factor 2 alpha was detected by the Western blot technique. Results: Obtained results showed that investigated PERK inhibitor is selective only toward cancer cells, since inhibited their viability in a dose- and time-dependent manner and induced their apoptosis and G2/M cell cycle arrest. Furthermore, 42215 PERK inhibitor evoked significant inhibition of eIF2α phosphorylation within HT-29 cancer cells. Conclusion: Highly-selective PERK inhibitors may provide a ground-breaking, anti-cancer treatment strategy via activation of the pro-apoptotic branch of the PERK-dependent unfolded protein response signaling pathway.
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Zhang, Na, Mengjie Shang, Hongxin Li, Lan Wu, Meichen Dong, Baiqu Huang, Jun Lu, and Yu Zhang. "Dual Inhibition of H3K9me2 and H3K27me3 Promotes Tumor Cell Senescence without Triggering the Secretion of SASP." International Journal of Molecular Sciences 23, no. 7 (April 1, 2022): 3911. http://dx.doi.org/10.3390/ijms23073911.
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Chemotherapy remains the most common cancer treatment. Although chemotherapeutic drugs induce tumor cell senescence, they are often associated with post-therapy tumor recurrence by inducing the senescence-associated secretory phenotype (SASP). Therefore, it is important to identify effective strategies to induce tumor cell senescence without triggering SASP. In this study, we used the small molecule inhibitors, UNC0642 (G9a inhibitor) and UNC1999 (EZH2 inhibitor) alone or in combination, to inhibit H3K9 and H3K27 methylation in different cancer cells. Dual inhibition of H3K9me2 and H3K27me3 in highly metastatic tumor cells had a stronger pro-senescence effect than either inhibitor alone and did not trigger SASP in tumor cells. Dual inhibition of H3K9me2 and H3K27me3 suppressed the formation of cytosolic chromatin fragments, which inhibited the cGAS-STING-SASP pathway. Collectively, these data suggested that dual inhibition of H3K9 and H3K27 methylation induced senescence of highly metastatic tumor cells without triggering SASP by inhibiting the cGAS-STING-SASP pathway, providing a new mechanism for the epigenetics-based therapy targeting H3K9 and H3K27 methylation.
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Popovici, Despina Calamar, Ioana Ionita, Mirela Nedelcu, Claudiu Ionita, Hortensia Ionita, Radu Dumitru Moleriu, Calin Ovidiu Ilie, et al. "Complications of Tyrosine Kinase Inhibitors Therapy in Chronic Myeloid Leukemia - Chronic Phase." Revista de Chimie 70, no. 8 (September 15, 2019): 3017–20. http://dx.doi.org/10.37358/rc.19.8.7477.
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Chronic myeloid leukaemia is a malignant tumor of pluripotent haemopoetic stem cell, characterized by increase granulocytes with left shift and the presence of the Ph chromosome.Treatment of chronic phase is made with tyrosine kinase inhibitors administered orally and can have secondary effects: haematological and non-haematological. The purpose of this paper is to assess complications of tyrosine kinase inhibitor therapy in chronic phase of chronic myeloid leukemia and establishing correlations with the type of inhibitor used. The study was performed on a total of 140 patients diagnosed with chronic phase CML in the Hematology Department of the City Clinical Emergency Hospital Timisoara between January 2006 - January 2016. The lot proposed has been studied in terms of anthropometric parameters and also the haematological and biochemical. It showed complications after initiation of therapy with tyrosine kinase inhibitors and also the correlations statistically significant between complications and type of inhibitor used. The study reveals that regardless the type of inhibitor used both haematological complications arise and non haematological. The most common are: neutropenia, thrombocytopenia, anemia, fluid retention, muscle and joint pain. Less common are nausea, diarrhea, abdominal pain, increased liver enzymes. Despite complications of occurring, these modern therapies significantly improve both survival and quality of life of patients.
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Dong, Jingwen, Tingting Zhong, Zhijian Xu, Haiyi Chen, Xianjun Wang, Lili Yang, Zhiyuan Lou, et al. "Identification of Monobenzone as a Novel Potential Anti-Acute Myeloid Leukaemia Agent That Inhibits RNR and Suppresses Tumour Growth in Mouse Xenograft Model." Cancers 14, no. 19 (September 27, 2022): 4710. http://dx.doi.org/10.3390/cancers14194710.
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Acute myeloid leukaemia (AML) is one of the most common types of haematopoietic malignancy. Ribonucleotide reductase (RNR) is a key enzyme required for DNA synthesis and cell proliferation, and its small subunit RRM2 plays a key role for the enzymatic activity. We predicted monobenzone (MB) as a potential RRM2 target compound based on the crystal structure of RRM2. In vitro, MB inhibited recombinant RNR activity (IC50 = 0.25 μM). Microscale thermophoresis indicated that MB inhibited RNR activity by binding to RRM2. MB inhibited cell proliferation (MTT IC50 = 6–18 μM) and caused dose-dependent DNA synthesis inhibition, cell cycle arrest, and apoptosis in AML cells. The cell cycle arrest was reversed by the addition of deoxyribonucleoside triphosphates precursors, suggesting that RNR was the intracellular target of the compound. Moreover, MB overcame drug resistance to the common AML drugs cytarabine and doxorubicin, and treatment with the combination of MB and the Bcl-2 inhibitor ABT-737 exerted a synergistic inhibitory effect. Finally, the nude mice xenografts study indicated that MB administration produced a significant inhibitory effect on AML growth with relatively weak toxicity. Thus, we propose that MB has the potential as a novel anti-AML therapeutic agent in the future.
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SNIPAS, Scott J., Henning R. STENNICKE, Stefan RIEDL, Jan POTEMPA, James TRAVIS, Alan J. BARRETT, and Guy S. SALVESEN. "Inhibition of distant caspase homologues by natural caspase inhibitors." Biochemical Journal 357, no. 2 (July 9, 2001): 575–80. http://dx.doi.org/10.1042/bj3570575.
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Caspases play an important role in the ability of animal cells to kill themselves by apoptosis. Caspase activity is regulated in vivo by members of three distinct protease inhibitor families, two of which, baculovirus p35 and members of the inhibitor of apoptosis (IAP) family, are thought to be caspase specific. However, caspases are members of the clan of cysteine proteases designated CD, which also includes animal and plant legumains, and the bacterial proteases clostripain, gingipain-R and gingipain-K. Since these proteases have been proposed to have a common mechanism and evolutionary origin, we hypothesized that the caspase inhibitors may also regulate these other proteases. We tested this hypothesis by examining the effect of the natural caspase inhibitors on other members of protease clan CD. The IAP family proteins were found to have only a slight inhibitory effect on gingipain-R. The cowpox viral cytokine-response modifier A (CrmA) serpin had no effect on any of the proteases tested but a single point mutation of CrmA (Asp → Lys) resulted in strong inhibition of gingipain-K. More substantial, with respect to the hypothesis, was the strong inhibition of gingipain-K by wild-type p35. The site in p35, required for inhibition of gingipain-K, was mapped to Lys94, seven residues C-terminal to the caspase inhibitory site. Our data indicate that the virally encoded caspase inhibitors have adopted a mechanism that allows them to regulate disparate members of clan CD proteases.
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Ke, Qiang, and Fa Shu Liang. "Investigation of Application Conditions of Barium/Strontium Scale Inhibitor in Oilfields." Advanced Materials Research 311-313 (August 2011): 1097–101. http://dx.doi.org/10.4028/www.scientific.net/amr.311-313.1097.
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In response to the serious barium / strontium – scale in oilfields, we simulated oilfield conditions and investigated the scale inhibition performance of several common scale inhibitors to barium and strontium, by following the protocol from Evaluation Methods of Anti-Scale Agent for Oilfield Use, Petroleum Gas Standards of People’s Republic of China SY/T 5673. The most effective scale inhibitor CD-1 was screened out. With CD-1 as barium / strontium scale inhibitor in the static anti-scale analytical experiments, the dependence of scale inhibition performance on scale inhibitor concentration, saltiness, temperature, time and the system pH was investigated. The application conditions of barium / strontium scale inhibitor in real petroleum and gas field was obtained. Under the optimized application conditions, the mixture scale inhibitor had better scale inhibition efficiency than CD-1 alone.