Lansoprazole as a potent HDAC2 inhibitor for treatment of colorectal cancer: An in-silico analysis and experimental validation.

BACKGROUND: Histone deacetylase 2 (HDAC2), belonging to the class I HDAC family, holds significant therapeutic potential as a crucial target for diverse cancer types. As key players in the realm of epigenetic regulatory enzymes, histone deacetylases (HDACs) are intricately involved in the onset and progression of cancer. Consequently, pursuing isoform-specific inhibitors targeting histone deacetylases (HDACs) has garnered substantial interest in both biological and medical circles. The objective of the present investigation was to employ a drug repurposing approach to discover novel and potent HDAC2 inhibitors. MATERIALS AND METHODS: In this study, our protocol is presented on virtual screening to identify novel potential HDAC2 inhibitors through 3D-QSAR, molecular docking, pharmacophore modeling, and molecular dynamics (MD) simulation. Afterward, In-vitro assays were employed to evaluate the cytotoxicity, apoptosis, and migration of HCT-116 cell lines under treatment of hit compound and valproic acid as a control inhibitor. The expression levels of HDAC2, TP53, BCL2, and BAX were evaluated by QRT-PCR. RESULTS: RMSD, RMSF, H-bond, and DSSP analysis results confirmed that among bioinformatically selected compounds, lansoprazole exhibited the highest HDAC2 inhibitory potential. Experimental validation revealed that lansoprazole displayed significant antiproliferative activity. The determined IC50 value was 400 ± 2.36 µM. Furthermore, the apoptotic cells ratio concentration-dependently increased under Lansoprazole treatment. Results of the Scratch assay indicated that lansoprazole led to decreasing the migration of CRC cells. Finally, under Lansoprazole treatment the expression level of BCL2 and HDAC2 decreased and BAX and TP53 increased. CONCLUSION: Taking together the results of the current study indicated that Lansoprazole as a novel HDAC2 inhibitor, could be used as a potential therapeutic agent for the treatment of CRC. Although, further experimental studies should be performed before using this compound in the clinic.

Harnessing CRISPR/Cas9 technology in cardiovascular disease.

The CRISPR/Cas9 system is a precisely targeted bacterial defense system, used to control invading viruses. This technology has many potential applications including genetic changes in somatic and germ cells and the creation of knockout animals. Compared to other genome editing techniques such as zinc-finger nucleases and transcription activator-like effector nucleases (TALENS), the CRISPR/Cas9 system is much easier and more efficient. Most importantly, the multifunctional capacity of this technology allows simultaneous editing of several genes. The CRISPR/Cas9 system also potentially has the ability to prevent and treat human diseases. The present article addresses some key points related to the use of the CRISPR/Cas9 system as a powerful tool in cardiovascular research and as a new strategy for the treatment of cardiovascular disease (CVD).

CRISPR-Cas9 in genome editing: Its function and medical applications.

The targeted genome modification using RNA-guided nucleases is associated with several advantages such as a rapid, easy, and efficient method that not only provides the manipulation and alteration of genes and functional studies for researchers, but also increases their awareness of the molecular basis of the disease and development of new and targeted therapeutic approaches. Different techniques have been emerged so far as the molecular scissors mediating targeted genome editing including zinc finger nuclease, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9). CRISPR-Cas9 is a bacterial immune system against viruses in which the single-strand RNA-guided Cas9 nuclease is linked to the targeted complementary sequences to apply changes. The advances made in the transfer, modification, and emergence of specific solutions have led to the creation of different classes of CRISPR-Cas9. Since this robust tool is capable of direct correction of disease-causing mutations, its ability to treat genetic disorders has attracted the tremendous attention of researchers. Considering the reported cases of nonspecific targeting of Cas9 proteins, many studies focused on enhancing the Cas9 features. In this regard, significant advances have been made in choosing guide RNA, new enzymes and methods for identifying misplaced targeting. Here, we highlighted the history and various direct aspects of CRISPR-Cas9, such as precision in genomic targeting, system transfer and its control over correction events with its applications in future biological studies, and modern treatment of diseases.

Cytotoxic T Lymphocyte Antigen-4 Gene Variants in Type 2 Diabetic Patients with or without Neuropathy.

Many studies have shown that cytotoxic T lymphocyte antigen-4 (CTLA-4) gene variants are associated with several autoimmune diseases particularly type 1 diabetes. Due to the lack of consistent data for this association with type 2 diabetes (T2D), this study explored the possible influence of CTLA-4 gene polymorphisms at -1722 (T/C), -318 (C/T), and +49 (G/A) positions for susceptibility to T2D in relation with neuropathy. One hundred and eleven unrelated patients with T2D [49 patients with diabetic peripheral neuropathy (DPN) and 62 patients without PDN] and 100 healthy ethnic- and gender-matched controls were included in this study. The dimorphisms at -1722 (C/T), -318 (C/T) and +49 (A/G) for CTLA-4 gene were determined using ARMS-PCR. The CTLA-4 (+49 G/G) and (+49 A/A) genotypes were found to be positively and negatively associated with T2D, respectively (p=0.03). The -318 C/T and T/T genotypes were more frequent in patients than controls and -318 C/C genotype was shown to be protective for T2D (p=0.003). ACT and GTT Haplotypes were less and more frequent in controls and patients, respectively (p=3.86×10-7 and p=2.29×10-5). Genotypes distribution among T2D patients with and without DPN compared to healthy controls showed significantly lower frequencies for -318 C/C and +49 A/A genotypes and significantly higher frequencies for -318 C/T and T/T genotypes as well. Our findings indicate that CTLA-4 (+49 A/G) and (-318 C/T) genotypes could be considered as genetic risk factors associated with susceptibility or protection for T2D.

Lack of association between rs1800795 (-174 G/C) polymorphism in the promoter region of interleukin-6 gene and susceptibility to type 2 diabetes in Isfahan population.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is an inflammatory autoimmune disease that mostly affects older adults. The etiology of T2DM includes both genetic and environmental factors. rs1800795 (-174 G/C) single nucleotide polymorphism (SNP) linked with autoimmune disorders predispositions, identified by Genome-Wide Association Study among genes, which immunologically related is considerably over signified. The goal of this study was to evaluate the association between rs1800795 (-174 G/C) polymorphisms in the promoter of interleukin-6 (IL-6) gene with susceptibility to T2DM in a subset of the Iranian population. MATERIALS AND METHODS: In this case-control study, 120 healthy subjects and 120 patients with T2DM were included. Genomic DNA obtained from whole blood samples and the polymerase chain reaction was used to amplify the fragment of interest contain rs1800795 SNP, restriction fragment length polymorphism method was applied for genotyping of the DNA samples with NlaIII as a restriction enzyme. SPSS for Windows software (version 18.0, SPSS, Chicago, IL, USA) was performed for statistical analysis. RESULTS: No significant differences were found between healthy controls and T2DM patients with respect to the frequency distribution of the cytokine gene polymorphism investigated. Odds ratio, adjusted for sex, age, and smoking status has displayed similar outcomes. CONCLUSION: These results indicated that the rs1800795 SNP is not a susceptibility gene variant for the development of T2DM in the Isfahan population. Further studies using new data on complex transcriptional interactions between IL-6 polymorphic sites are necessary to determine IL-6 haplotype influence on susceptibility to T2DM.