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Bioorganic Chemistry Feb 2024Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a...
Overexpression of transglutaminase 2 (TGase 2; TG2) has been implicated in the progression of renal cell carcinoma (RCC) through the inactivation of p53 by forming a protein complex. Because most p53 in RCC has no mutations, apoptosis can be increased by inhibiting the binding between TG2 and p53 to increase the stability of p53. In the present study, a novel TG2 inhibitor was discovered by investigating the structure of 1H-benzo[d]imidazole-4,7-dione as a simpler chemotype based on the amino-1,4-benzoquinone moiety of streptonigrin, a previously reported inhibitor. Through structure-activity relationship (SAR) studies, compound 8j (MD102) was discovered as a potent TG2 inhibitor with an IC value of 0.35 µM, p53 stabilization effect and anticancer effects in the ACHN and Caki-1 RCC cell lines with sulforhodamine B (SRB) GI values of 2.15 µM and 1.98 µM, respectively. The binding property of compound 8j (MD102) with TG2 was confirmed to be reversible in a competitive enzyme assay, and the binding interaction was expected to be formed at the β-sandwich domain, a p53 binding site, in the SPR binding assay with mutant proteins. The mode of binding of compound 8j (MD102) to the β-sandwich domain of TG2 was analyzed by molecular docking using the crystal structure of the active conformation of human TG2. Compound 8j (MD102) induced a decrease in the downstream signaling of p-AKT and p-mTOR through the stabilization of p53 by TG2 inhibition, resulting in tumor cell apoptosis. In a xenograft animal model using ACHN cancer cells, oral administration and intraperitoneal injection of compound 8j (MD102) showed an inhibitory effect on tumor growth, confirming increased levels of p53 and decreased levels of Ki-67 in tumor tissues through immunohistochemical (IHC) tissue staining. These results indicated that the inhibition of TG2 by compound 8j (MD102) could enhance p53 stabilization, thereby ultimately showing anticancer effects in RCC. Compound 8j (MD102), a novel TG2 inhibitor, can be further applied for the development of an anticancer candidate drug targeting RCC.
Topics: Animals; Humans; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Line, Tumor; Imidazoles; Kidney Neoplasms; Molecular Docking Simulation; Protein Glutamine gamma Glutamyltransferase 2; Transglutaminases; Tumor Suppressor Protein p53
PubMed: 38154386
DOI: 10.1016/j.bioorg.2023.107061 -
The Journal of Antibiotics Jan 2017Xantholipin is a polycyclic xanthone antibiotic that exhibits potent cytotoxic and antibacterial activity. In this study, a new xanthone-type antibiotic, xantholipin B... (Comparative Study)
Comparative Study
Xantholipin is a polycyclic xanthone antibiotic that exhibits potent cytotoxic and antibacterial activity. In this study, a new xanthone-type antibiotic, xantholipin B (1), was isolated for the first time along with its known derivative, xantholipin (2), from strain WJN-1, an aminotransferase inactivation mutant of the streptonigrin-producer Streptomyces flocculus CGMCC 4.1223. The structure of 1 was established based on spectroscopic analysis and supports the previously proposed biosynthetic pathway as a key intermediate of 2. Moreover, 1 showed 3- to 10-fold greater cytotoxicity than 2 against a select panel of human cancer cell lines. In addition, 1 demonstrated powerful antimicrobial activity against both Gram-positive bacteria and fungi. Importantly, both 1 and 2 inhibited the methicillin-resistant strain Staphylococcus aureus Mu50, with the MIC value of 0.025 μg ml. The new structural features of 1 enrich the structural diversity of xantholipin family compounds and shed new light on the structure-activity relationship of 1 as a promising antitumor drug candidate.
Topics: Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Cell Line, Tumor; Fungi; Gram-Positive Bacteria; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Neoplasms; Polyketides; Spectrum Analysis; Streptomyces; Structure-Activity Relationship
PubMed: 27328868
DOI: 10.1038/ja.2016.60 -
PloS One 2016An mbfA mutant of Bradyrhizobium japonicum defective in iron export is sensitive to short term exposure to high levels iron or H2O2. Here, we found that the mbfA strain...
Synthetic Lethality of the bfr and mbfA Genes Reveals a Functional Relationship between Iron Storage and Iron Export in Managing Stress Responses in Bradyrhizobium japonicum.
An mbfA mutant of Bradyrhizobium japonicum defective in iron export is sensitive to short term exposure to high levels iron or H2O2. Here, we found that the mbfA strain grown in elevated iron media (100 μM) became resistant to those treatments, suggesting a stress response adaptation. The bfr gene encodes the iron storage protein bacterioferritin, and its expression is derepressed by iron. An mbfA bfr double mutant showed a loss of stress adaptation, and had a severe growth phenotype in high iron media. Moreover, a bfrup allele in which bfr is constitutively derepressed conferred stress tolerance on an mbfA mutant without elevating the iron content in the growth media. The intracellular iron content of the mbfA bfr double mutant was substantially higher than that found in the wild type, even when grown in relatively low iron media (5 μM). Under that condition, iron-responsive gene expression was aberrant in the mbfA bfr strain. Moreover, the double mutant was sensitive to the iron-activated antibiotic streptonigrin. We conclude that MbfA and Bfr work in concert to manage iron and oxidative stresses. In addition, the need for iron detoxification is not limited to extreme environments, but is also required for normal cellular function.
Topics: Bacterial Proteins; Bradyrhizobium; Cytochrome b Group; Ferritins; Gene Expression Regulation, Bacterial; Hydrogen Peroxide; Iron; Membrane Transport Proteins; Oxidative Stress; Synthetic Lethal Mutations
PubMed: 27285822
DOI: 10.1371/journal.pone.0157250 -
Infection Control and Hospital... Oct 2016OBJECTIVE To evaluate the new adult Centers for Disease Control and Prevention (CDC) ventilator-associated event (VAE) module in critically ill children and compare with...
OBJECTIVE To evaluate the new adult Centers for Disease Control and Prevention (CDC) ventilator-associated event (VAE) module in critically ill children and compare with the traditionally used CDC definition for ventilator-associated pneumonia (VAP). DESIGN Retrospective observational study of mechanically ventilated children in a pediatric intensive care unit in Greece January 1-December 31, 2011. METHODS Assessment of new adult CDC VAE module including 3 definition tiers: ventilator-associated condition (VAC), infection-related VAC, and possible/probable ventilator-associated pneumonia (VAE-VAP); comparison with traditional CDC criteria for clinically defined pneumonia in mechanically ventilated children (PNEU-VAP). We recorded Pediatric Risk of Mortality score at admission (PRISM III), number of ventilator-days, and outcome. RESULTS Among 119 patients with mechanical ventilation (median [range] number of ventilator-days, 7 [1-183]), 19 patients experienced VAC. Criteria for VAE-VAP were fulfilled in 12 of 19 patients with VAC (63%). Children with either VAC or VAE-VAP were on ventilation more days than patients without these conditions (16.5 vs 5 d, P=.0006 and 18 vs 5 d, P<.001, respectively), whereas PRISM-III score was similar between them. Mortality was significant higher in patients with new VAE-VAP definition (50%), but not in patients with VAC (31.6%), than the patients without new VAE-VAP (14%, P=.007) or VAC (15%, P=.1), respectively. No significant association was found between PNEU-VAP and death. Incidences of PNEU-VAP and VAE-VAP were similar, but the agreement was poor. CONCLUSIONS VAE-VAP and PNEU-VAP found similar prevalence in critically ill children but with poor agreement. However, excess of death was significantly associated only with VAE-VAP. Infect Control Hosp Epidemiol 2016:1-5.
Topics: Adolescent; Algorithms; Centers for Disease Control and Prevention, U.S.; Child; Child, Preschool; Critical Illness; Female; Greece; Humans; Infant; Intensive Care Units, Pediatric; Male; Pneumonia, Ventilator-Associated; Respiration, Artificial; Severity of Illness Index; Streptonigrin; United States; Ventilator-Induced Lung Injury; Ventilators, Mechanical
PubMed: 27396590
DOI: 10.1017/ice.2016.135 -
PloS One 2014Enteric pathogens, such as enterohemorrhagic E. coli (EHEC) O157:H7, encounter varying concentrations of iron during their life cycle. In the gastrointestinal tract, the...
Antisense transcription regulates the expression of the enterohemorrhagic Escherichia coli virulence regulatory gene ler in response to the intracellular iron concentration.
Enteric pathogens, such as enterohemorrhagic E. coli (EHEC) O157:H7, encounter varying concentrations of iron during their life cycle. In the gastrointestinal tract, the amount of available free iron is limited because of absorption by host factors. EHEC and other enteric pathogens have developed sophisticated iron-responsive systems to utilize limited iron resources, and these systems are primarily regulated by the Fur repressor protein. The iron concentration could be a signal that controls gene expression in the intestines. In this study, we explored the role of iron in LEE (locus for enterocyte effacement) virulence gene expression in EHEC. In contrast to the expression of Fur-regulated genes, the expression of LEE genes was greatly reduced in fur mutants irrespective of the iron concentration. The expression of the ler gene, the LEE-encoded master regulator, was affected at a post-transcription step by fur mutation. Further analysis showed that the loss of Fur affected the translation of the ler gene by increasing the intracellular concentration of free iron, and the transcription of the antisense strand was necessary for regulation. The results indicate that LEE gene expression is closely linked to the control of intracellular free iron homeostasis.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Escherichia coli O157; Escherichia coli Proteins; Ferritins; Gene Expression; Gene Expression Regulation, Bacterial; Iron; Oligoribonucleotides, Antisense; Phosphoproteins; RNA Interference; Regulon; Repressor Proteins; Streptonigrin; Trans-Activators; Transcription, Genetic; Virulence
PubMed: 25006810
DOI: 10.1371/journal.pone.0101582