Publications by authors named "Elena Kazakova"

16 Publications

  • Page 1 of 1

New Angiogenic Regulators Produced by TAMs: Perspective for Targeting Tumor Angiogenesis.

Cancers (Basel) 2021 Jun 29;13(13). Epub 2021 Jun 29.

Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia.

Angiogenesis is crucial to the supply of a growing tumor with nutrition and oxygen. Inhibition of angiogenesis is one of the main treatment strategies for colorectal, lung, breast, renal, and other solid cancers. However, currently applied drugs that target VEGF or receptor tyrosine kinases have limited efficiency, which raises a question concerning the mechanism of patient resistance to the already developed drugs. Tumor-associated macrophages (TAMs) were identified in the animal tumor models as a key inducer of the angiogenic switch. TAMs represent a potent source not only for VEGF, but also for a number of other pro-angiogenic factors. Our review provides information about the activity of secreted regulators of angiogenesis produced by TAMs. They include members of SEMA and S100A families, chitinase-like proteins, osteopontin, and SPARC. The COX-2, Tie2, and other factors that control the pro-angiogenic activity of TAMs are also discussed. We highlight how these recent findings explain the limitations in the efficiency of current anti-angiogenic therapy. Additionally, we describe genetic and posttranscriptional mechanisms that control the expression of factors regulating angiogenesis. Finally, we present prospects for the complex targeting of the pro-angiogenic activity of TAMs.
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http://dx.doi.org/10.3390/cancers13133253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268686PMC
June 2021

Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages.

Cancers (Basel) 2020 May 29;12(6). Epub 2020 May 29.

Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, 634050 Tomsk, Russia.

Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.
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http://dx.doi.org/10.3390/cancers12061411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352439PMC
May 2020

Anomalous current-voltage characteristics of SFIFS Josephson junctions with weak ferromagnetic interlayers.

Beilstein J Nanotechnol 2020 23;11:252-262. Epub 2020 Jan 23.

National Research University Higher School of Economics, 101000 Moscow, Russia.

We present a quantitative study of the current-voltage characteristics (CVC) of SFIFS Josephson junctions (S = bulk superconductor, F = metallic ferromagnet, I = insulating barrier) with weak ferromagnetic interlayers in the diffusive limit. The problem is solved in the framework of the nonlinear Usadel equations. We consider the case of a strong tunnel barrier such that the left SF and the right FS bilayers are decoupled. We calculate the density of states (DOS) in SF bilayers using a self-consistent numerical method. Then we obtain the CVC of corresponding SFIFS junctions, and discuss their properties for different set of parameters including the thicknesses of ferromagnetic layers, the exchange field, and the magnetic scattering time. We observe an anomalous nonmonotonic CVC in case of weak ferromagnetic interlayers, which we attribute to DOS energy dependencies in the case of small exchange fields in the F layers.
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http://dx.doi.org/10.3762/bjnano.11.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006479PMC
January 2020

Novel pleconaril derivatives: Influence of substituents in the isoxazole and phenyl rings on the antiviral activity against enteroviruses.

Eur J Med Chem 2020 Feb 23;188:112007. Epub 2019 Dec 23.

Jena University Hospital, Department of Medical Microbiology, Section Experimental Virology, Hans-Knöll-Strasse 2, Jena, 07745, Germany. Electronic address:

Today, there are no medicines to treat enterovirus and rhinovirus infections. In the present study, a series of novel pleconaril derivatives with substitutions in the isoxazole and phenyl rings was synthesized and evaluated for their antiviral activity against a panel of pleconaril-sensitive and -resistant enteroviruses. Studies of the structure-activity relationship demonstrate the crucial role of the N,N-dimethylcarbamoyl group in the isoxazole ring for antiviral activity against pleconaril-resistant viruses. In addition, one or two substituents in the phenyl ring directly impact on the spectrum of antienteroviral activity. The 3-(3-methyl-4-(3-(3-N,N-dimethylcarbamoyl-isoxazol-5-yl)propoxy)phenyl)-5-trifluoromethyl-1,2,4-oxadiazole 10g was among the compounds exhibiting the strongest activity against pleconaril-resistant as well as pleconaril-susceptible enteroviruses with IC values from 0.02 to 5.25 μM in this series. Compound 10g demonstrated markedly less CYP3A4 induction than pleconaril, was non-mutagenic, and was bioavailable after intragastric administration in mice. These results highlight compound 10g as a promising potential candidate as a broad spectrum enterovirus and rhinovirus inhibitor for further preclinical investigations.
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http://dx.doi.org/10.1016/j.ejmech.2019.112007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002245PMC
February 2020

East Asian Genome-wide association study derived loci in relation to type 2 diabetes in the Han Chinese population.

Acta Biochim Pol 2019 May;66(2):159-165

Department of Endocrinology and Metabolism, The Second Affiliated Hospital, Harbin Medical University, Nangang District, Harbin, Heilongjiang, China.

Meta-analysis of GWAS in East Asian populations had established 10 loci that were associated with type 2 diabetes. Eight of them were with genome-wide significance and two with a border line association. Since these data have not been studied in an independent Han Chinese population, we aimed to investigate the association of these susceptibility loci with type 2 diabetes in an independent Han Chinese population. We executed a case-control study in 2 000 Chinese by the SNPscan method. Firstly, the repetitive sequences of 10 loci were assessed. Next, we investigated the association of 8 SNPs out of 10 with type 2 diabetes and constructed the GRS of those 8 SNPs. Finally, the relationship of the 8 loci and diabetes-related traits was analyzed. Based on the fact, that highly repetitive sequences were detected in 2 SNPs, we investigated the remaining 8 SNPs. With the exception of four SNPs (CMIP rs16955379, PEPD rs3786897, PSMD6 rs831571, ZFAND3 rs9470794), the other SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports, especially GLIS3 rs7041847 and KCNK16 rs1535500 were significantly associated with type 2 diabetes (rs1535500: p=0.005, OR=1.224, 95% CI 1.062-1.409; rs7041847: p=0.035, OR=1.118, 95% CI 1.070-1.388). The GRS constructed from the 8 SNPs was significantly associated with type 2 diabetes in the Chinese population (p=0.004, OR=1.065, 95% CI: 1.021-1.111). Among the participants with 24≤BMI<28 kg/m2 the 8 SNPs were significantly associated with type 2 diabetes (p=0.040, OR=1.079, 95% CI: 1.003-1.160). In quantitative trait analyses, WWOX rs17797882 was associated with decreased HOMA-β and increased level of TG and HDL-Ch, while PEPD rs3786897 and MAEA rs6815464 were associated with decreased fasting plasma glucose, and KCNK16 rs1535500 has shown a significant association with increased T-Ch and PSMD6 rs831571 had a significant association with decreased HDL-Ch. In Conclusion, with high probability the 8 loci identified in the East Asian GWAS meta-analysis are associated with type 2 diabetes in the Han Chinese population.
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http://dx.doi.org/10.18388/abp.2018_2632DOI Listing
May 2019

Association between RBMS1 gene rs7593730 and BCAR1 gene rs7202877 and Type 2 diabetes mellitus in the Chinese Han population.

Acta Biochim Pol 2018 8;65(3):377-382. Epub 2018 Sep 8.

Department of Endocrinology and Metabolism, the Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China.

Two recent studies found that RBMS1 gene rs7593730 and BCAR1 gene rs7202877 are related to type 2 diabetes. However, the association of these loci with type 2 diabetes mellitus (T2DM) has not been examined in Chinese. We performed a replication study to investigate the association of the 2 susceptibility loci with T2DM in the Chinese population. We genotyped 1961 Chinese participants (991 with T2DM and 970 controls) for each of the 2 single nucleotide polymorphisms (SNPs) rs7593730 in RBMS1 and rs7202877 near BCAR1 using SNPscan and examined their association with T2DM using logistic regression analysis. We also analyzed the correlation of the SNP alleles and clinical phenotypes. In additive model, genotype association analysis of BCAR1 rs7202877 loci revealed that the homozygous of rs7202877 GG carriers had significantly decreased T2DM risk compared to homozygous carriers of TT (P=0.038, OR 0.44, 95% CI 0.20-0.96). In the recessive model, the GG genotype GG had significantly decreased T2DM risk compared to GT+TT (P=0.043, OR 0.67, 95% CI 0.46-0.99). Allele G was statistically significantly correlated with TC (mmol/L) (P=0.036) and LDL-C (mmol/L) (P=0.007). As for rs7593730, the carriers of CT and TT genotype had significantly decreased T2DM risk compared to the carriers of CC genotype (CT: CC P=0.038, OR 0.71, 95% CI 0.51-0.98; TT: CC P=0.010, OR 0.32, 95% CI 0.13-0.76). In a dominant model, TT+CT: CC (P=0.013, OR 0.673, 95% CI 0.49-0.92) and in a recessive model, TT: CT+CC (P=0.019, OR 0.59, 95% CI 0.39-0.92). The T allele carriers had significantly decreased T2DM risk compared to the carriers of C (P=0.002, OR 0.65, 95% CI 0.50-0.86). Allele T was statistically correlated with FINS (P=0.010). In conclusion, our study showed that RBMS1 gene rs7593730 and BCAR1 gene rs7202877 were significantly associated with type 2 diabetes in the Chinese population.
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http://dx.doi.org/10.18388/abp.2017_1451DOI Listing
December 2018

Copper-related toxicity in replicating and dormant Mycobacterium tuberculosis caused by 1-hydroxy-5-R-pyridine-2(1H)-thiones.

Metallomics 2018 07;10(7):992-1002

Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Leninsky Prospekt 33-2, Moscow, 119071, Russia.

With the emerging primary resistance of Mycobacterium tuberculosis to current drugs and wide distribution of latent tuberculosis infection, the need for new compounds with a novel mode of action is growing. Copper-mediated innate immunity and its antibacterial toxicity pose novel strategies for tuberculosis drug discovery and development. Transcriptome response to 1-hydroxy-5-R-pyridine-2(1H)-thiones, which were found to be highly active in vitro against actively growing and dormant nonculturable M. tuberculosis, revealed signs of copper toxicity. 1-Hydroxy-5-R-pyridine-2(1H)-thiones were found to form stable charged lipophilic complexes with Cu2+ ions that could transport into mycobacterial cells. Copper accumulated inside treated bacilli as subsequent metabolic destruction of the complex led to chemical transformation of 1-hydroxy-5-R-pyridine-2(1H)-thiones and release of free Cu2+ into the cytoplasm. 1-Hydroxy-5-R-pyridine-2(1H)-thiones are a potent class of Cu-dependent inhibitors of M. tuberculosis, and may control infection by impairment of copper homeostasis.
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http://dx.doi.org/10.1039/c8mt00067kDOI Listing
July 2018

A multitarget approach to drug discovery inhibiting Mycobacterium tuberculosis PyrG and PanK.

Sci Rep 2018 02 16;8(1):3187. Epub 2018 Feb 16.

Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia, Italy.

Mycobacterium tuberculosis, the etiological agent of the infectious disease tuberculosis, kills approximately 1.5 million people annually, while the spread of multidrug-resistant strains is of great global concern. Thus, continuous efforts to identify new antitubercular drugs as well as novel targets are crucial. Recently, two prodrugs activated by the monooxygenase EthA, 7947882 and 7904688, which target the CTP synthetase PyrG, were identified and characterized. In this work, microbiological, biochemical, and in silico methodologies were used to demonstrate that both prodrugs possess a second target, the pantothenate kinase PanK. This enzyme is involved in coenzyme A biosynthesis, an essential pathway for M. tuberculosis growth. Moreover, compound 11426026, the active metabolite of 7947882, was demonstrated to directly inhibit PanK, as well. In an independent screen of a compound library against PyrG, two additional inhibitors were also found to be active against PanK. In conclusion, these direct PyrG and PanK inhibitors can be considered as leads for multitarget antitubercular drugs and these two enzymes could be employed as a "double-tool" in order to find additional hit compounds.
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http://dx.doi.org/10.1038/s41598-018-21614-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816626PMC
February 2018

Relationship between Modulator Recognition Factor 2/AT-rich Interaction Domain 5B Gene Variations and Type 2 Diabetes Mellitus or Lipid Metabolism in a Northern Chinese Population.

Chin Med J (Engl) 2017 May;130(9):1055-1061

Department of Endocrinology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, China.

Background: Four single nucleotide polymorphisms (SNPs) in the modulator recognition factor 2/AT-rich interaction domain 5B (MRF2/ARID5B) gene located at chromosome 10q21.2 have been shown to be associated with both type 2 diabetes mellitus (T2DM) and coronary artery disease in a Japanese cohort. This study aimed to investigate the relationship between these SNPs (rs2893880, rs10740055, rs7087507, rs10761600) and new-onset T2DM and lipid metabolism in a Northern Chinese population.

Methods: This was a case-control study. The rs2893880, rs10740055, rs7087507, and rs10761600 genetic variants were genotyped by SNPscan and analyzed in relation to T2DM susceptibility in 2000 individuals (999 with newly diagnosed T2DM and 1001 controls without diabetes mellitus). Associations between the MRF2/ARID5B genetic models and T2DM were determined by multivariate logistic regression.

Results: Regarding the rs10740055 SNP, AA was associated with a higher risk of T2DM compared with codominant-type CC (adjusted by sex, age, and body mass index [BMI], P= 0.041, odds ratio [OR] = 1.421, 95% confidence interval [CI] 1.014-1.991). Meanwhile, AA individuals were at increased risk of presenting with T2DM compared with individuals with CC or a single C (adjusted by sex, age, and BMI, P= 0.034, OR = 1.366, 95% CI 1.023-1.824). With respect to rs10761600, AT contributed to a higher risk of T2DM compared with AA (adjusted by sex, age, and BMI, P= 0.013, OR = 1.585, 95% CI 1.101-2.282), while TT also increased the risk of presenting with T2DM compared with AA or A (adjusted by sex, age, and BMI, P= 0.004, OR = 1.632, 95% CI 1.166-2.284). High-density lipoprotein cholesterol (HDL-C) levels were significantly different among the three genotypes of rs7087507 in the controls (P = 0.048) (GG>GA).

Conclusions: The present results identified MRF2/ARID5B as a potential susceptibility gene for new-onset T2DM in a Northern Chinese population, while the rs7087507 SNP was associated with HDL-C levels. Further larger studies are required to validate these findings.
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http://dx.doi.org/10.4103/0366-6999.204926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421175PMC
May 2017

The Gas6 gene rs8191974 and Ap3s2 gene rs2028299 are associated with type 2 diabetes in the northern Chinese Han population.

Acta Biochim Pol 2017 11;64(2):227-231. Epub 2017 Apr 11.

The Fifth Endocrine Department, the Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China.

Previous studies in other countries have shown that single nucleotide polymorphisms (SNPs) in the growth arrest-specific gene 6 (Gas6; rs8191974) and adapter-related protein complex 3 subunit sigma-2 (Ap3s2; rs2028299) were associated with an increasedrisk for type 2 diabetes mellitus (T2DM). However, the association of these loci with T2DM has not been examined in Chinese populations. We performed a replication study to investigate the association of these susceptibility loci with T2DM in the Chinese population.We genotyped 1968 Chinese participants (996 with T2DM and 972controls) for rs8191974 in Gas6 and rs2028299 near Ap3s2, and examined their association with T2DM using a logistic regression analysis. We also analyzed the correlation of genotypes and clinical phenotypes. The distribution of the T allele of SNP rs8191974 in the Gas6 gene was significantly different between T2DM cases and controls when compared with the C allele (P<0.05, OR: 0.80, 95% CI: 0.69-0.94). The occurrence of the CT genotype and the dominant model was also significantly less frequent in the T2DM cases vs. controls when compared with the CC genotype (CT vs. CC: P<0.05, OR: 0.75, 95% CI:0.62-0.90; TT+CT vs. CC: P<0.05, OR:0.75, 95% CI:0.63-0.90). In SNP rs2028299, the allele C showed no statistically significant differencein distribution between the control and T2DM groups when compared with allele A. However, in male populations, the dominant model was statistically more frequent when compared with genotype AA (CC+CA vs. AA: P<0.05, OR:1.29, 95% CI:1.02-1.64), and in obesity-stratified analysis, we also observed a significant difference in the distribution of the dominant model between the T2DM cases and controls in subjects with BMI≥24 kg/m and BMI<28kg/m (CC+CA vs. AA: P<0.05, OR: 6.33, 95% CI:4.17-9.61). In conclusion, our study shows that SNPsrs8191974 and rs2028299 are significantly associated with T2DM in the Chinese population.
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http://dx.doi.org/10.18388/abp.2016_1299DOI Listing
August 2017

CXCL12 methylation-mediated epigenetic regulation of gene expression in papillary thyroid carcinoma.

Sci Rep 2017 03 8;7:44033. Epub 2017 Mar 8.

Department of Endoerinology and Metabolism, The Second Affiliated Hospital, Harbin Medical University, Harbin 150001, China.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, and its incidence rate is rapidly growing. It is necessary to understand the pathogenesis of PTC to develop effective diagnosis methods. Promoter methylation has been recognized to contribute to the alterations in gene expression observed in tumorigenesis. Our RNA-seq data identified 1191 differentially expressed mRNAs and 147 differentially expressed lncRNAs in PTC. Next, promoter methylation of these genes was detected by reduced representation bisulfite sequencing (RRBS) technology and comprehensively analyzed to identify differential methylation. In total, 14 genes (13 mRNAs and 1 lncRNA), in which methylation was intimately involved in regulating gene expression, were proposed as novel diagnostic biomarkers. To gain insights into the relationships among these 14 genes, a core co-function network was constructed based on co-expression, co-function and co-methylation data. Notably, CXCL12 was identified as an essential gene in the network that was closely connected with the other genes. These data suggested that CXCL12 down-regulation in PTC may be caused by promoter hypermethylation. Our study was the first to perform an RRBS analysis for PTC and suggested that CXCL12 may contribute to PTC development by methylation-mediated epigenetic regulation of gene expression.
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http://dx.doi.org/10.1038/srep44033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356381PMC
March 2017

Pyrazolopyrimidines: Potent Inhibitors Targeting the Capsid of Rhino- and Enteroviruses.

ChemMedChem 2015 Oct 10;10(10):1629-34. Epub 2015 Aug 10.

Virology & Antiviral Therapy, Jena University Hospital, Hans-Knöll-Str. 2, 07745 Jena (Germany).

There are currently no drugs available for the treatment of enterovirus (EV)-induced acute and chronic diseases such as the common cold, meningitis, encephalitis, pneumonia, and myocarditis with or without consecutive dilated cardiomyopathy. Here, we report the discovery and characterization of pyrazolopyrimidines, a well-tolerated and potent class of novel EV inhibitors. The compounds inhibit the replication of a broad spectrum of EV in vitro with IC50 values between 0.04 and 0.64 μM for viruses resistant to pleconaril, a known capsid-binding inhibitor, without affecting cytochrome P450 enzyme activity. Using virological and genetics methods, the viral capsid was identified as the target of the most promising, orally bioavailable compound 3-(4-trifluoromethylphenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine (OBR-5-340). Its prophylactic as well as therapeutic application was proved for coxsackievirus B3-induced chronic myocarditis in mice. The favorable pharmacokinetic, toxicological, and pharmacodynamics profile in mice renders OBR-5-340 a highly promising drug candidate, and the regulatory nonclinical program is ongoing.
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http://dx.doi.org/10.1002/cmdc.201500304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600222PMC
October 2015

Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG.

Chem Biol 2015 Jul 18;22(7):917-27. Epub 2015 Jun 18.

Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, 27100 Pavia, Italy. Electronic address:

To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target.
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http://dx.doi.org/10.1016/j.chembiol.2015.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521081PMC
July 2015

Association between UBE2E2 variant rs7612463 and type 2 diabetes mellitus in a Chinese Han population.

Acta Biochim Pol 2015 28;62(2):241-5. Epub 2015 May 28.

Department of Endemic Disease, the Second Affiliated Hospital, Harbin Medical University, Harbin, Heilongjiang, China.

UBE2E2 encodes ubiquitin-conjugating enzyme E2E2, which plays an important role in the synthesis and secretion of insulin. Two previous studies indicated that SNPs in UBE2E2 were associated with risk for type 2 diabetes mellitus (T2DM) in the Japanese and Korean populations, respectively. We examined the association of one SNP in this gene, rs7612463, with the risk of T2DM in 1957 Han participants in northeastern China, using an SNPscan(TM) Kit. rs7612463 genotype was significantly associated with risk for T2DM under various genetic models, including an additive model (P = 0.004), a dominant model (P = 0.024), and a recessive model (P = 0.008). The AA genotype was associated with a significantly decreased risk for T2DM (P = 0.004, OR = 0.513, 95% CI = 0.325-0.810) after adjustment for age, gender, and BMI. The heterozygous genotype, AC, was associated with increased risk for total cholesterol (mmol l-1; P = 0.031) and triglycerides (mmol l-1; P = 0.039) in control individuals. Our results show that rs7612463 is associated with T2DM, with homozygotes of the AA genotype at decreased risk for T2DM in the Chinese population. Additionally, heterozygotes may have decreased risk of T2DM due to insulin resistance.
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http://dx.doi.org/10.18388/abp.2014_936DOI Listing
April 2016

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis.

Antimicrob Agents Chemother 2015 Aug 18;59(8):4446-52. Epub 2015 May 18.

More Medicines for Tuberculosis Consortium‡ Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1) and display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity. Here, we report the synthesis and characterization of the pyrrole-benzothiazinones PyrBTZ01 and PyrBTZ02, non-nitro-benzothiazinones that retain significant antimycobacterial activity, with MICs of 0.16 μg/ml against M. tuberculosis. These compounds inhibit DprE1 with 50% inhibitory concentration (IC50) values of <8 μM and present favorable in vitro absorption-distribution-metabolism-excretion/toxicity (ADME/T) and in vivo pharmacokinetic profiles. The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency.
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http://dx.doi.org/10.1128/AAC.00778-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505264PMC
August 2015

Comparison of biphasic insulin aspart 30 given three times daily or twice daily in combination with metformin versus oral antidiabetic drugs alone in patients with poorly controlled type 2 diabetes: a 16-week, randomized, open-label, parallel-group trial conducted in russia.

Clin Ther 2007 Nov;29(11):2374-84

Department of Prophylactic Medicine, Post-graduate Medical Education Institute, Khabarovsk, Russia.

Background: Modern premixed insulins offer a flexible approach to the initiation of insulin therapy in patients with poorly controlled type 2 diabetes. A disadvantage of twice-daily regimens of biphasic insulin aspart 30 (BIAsp 30) is that lunchtime control (when no insulin is administered) can be suboptimal. Therefore, it is possible that administering BIAsp 30 thrice daily might further optimize glycemic control and offer an option for patients in whom metformin (MET) is contraindicated.

Objective: This study evaluated the efficacy and safety profiles of 2 different regimens of BIAsp 30 compared with a regimen consisting of oral antidiabetic drugs (OADs) alone.

Methods: In this multicenter, randomized, open-label, parallel-group trial, insulin-naive patients with poorly controlled type 2 diabetes (baseline glycosylated hemoglobin [HbA(1c) > or =8.0%) who were taking OADs (a sulfonylurea or meglitinide with/without MET or MET only) were randomized to receive BIAsp 30 TID, BIAsp 30 BID + MET, or continuation of their current OAD therapy for 16 weeks. The primary end point was HbA(1c) at the end of the study. Secondary end points included reductions in HbA(1c), mean blood glucose (BG), prandial increment, mean 7-point self-monitored BG profile, weight changes, tolerability (hypoglycemia, adverse events), and satisfaction/quality of life (derived from 2 questionnaires completed at weeks 0, 8, and 16).

Results: The study enrolled 308 insulin-naive patients with type 2 diabetes (78.9% female; mean age, 58.3 years; body mass index, 29.4 kg/m(2); HbA(1c), 10.3%). Both BIAsp 30 TID and BIAsp 30 BID + MET were associated with significantly greater mean (SD) reductions in HbA(1c) relative to OADs alone (absolute percent reduction: 2.9% [1.5%], 3.0% [1.6%], and 2.1% [1.4%], respectively; P < 0.001, both insulin groups vs OAD group) and improved post-prandial glucose control (reduction in mean post-prandial glucose:-6.32 [4.07], -6.44 [4.70], and -3.59 [4.22] mmol/L; P < 0.001, both insulin groups vs OAD group). The mean decrease in the prandial increment was -1.26 mmol/L for BIAsp 30 TID, -2.15 mmol/L for BIAsp 30 BID + MET, and -0.44 mmol/L for OAD. The differences in reduction in the prandial increment were statistically significant for BIAsp 30 TID versus OAD (P = 0.047), BIAsp 30 BID + MET versus OAD (P < 0.001), and BIAsp 30 TID versus BIAsp 30 BID + MET (P = 0.042). Mean body weight increased significantly from baseline with both BIAsp 30 TID and BIAsp 30 BID + MET (+1.71 and +1.50 kg, respectively; both, P < 0.001), and decreased significantly in the OAD group (-0.75 kg; P = 0.003). There were no major hypoglycemic events, and most hypoglycemic events were recorded as symptoms only (144/158 [91.1%]). There were no significant differences in the mean frequency of overall hypoglycemic episodes between BIAsp 30 TID and BIAsp 30 BID + MET (0.73 and 0.69 episodes per patient-year, respectively).

Conclusions: In these patients with type 2 diabetes that was poorly controlled by OADs, BIAsp 30 TID and BIAsp 30 BID plus MET were associated with significantly greater reductions in HbA(1c) and postprandial BG compared with OADs alone. The insulin regimens were associated with significantly more weight gain than OADs alone. There were no differences in rates of hypoglycemia between the insulin regimens.
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http://dx.doi.org/10.1016/j.clinthera.2007.11.017DOI Listing
November 2007
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