Research into how carvacrol and metformin affect several human proteins in a hyperglycemic condition: A comparative study in silico and in vitro.

Carvacrol (CV) is an organic compound found in the essential oils of many aromatic herbs. It is nearly unfeasible to analyze all the current human proteins for a query ligand using in vitro and in vivo methods. This study aimed to clarify whether CV possesses an anti-diabetic feature via Docking-based inverse docking and molecular dynamic (MD) simulation and in vitro characterization against a set of novel human protein targets. Herein, the best poses of CV docking simulations according to binding energy ranged from -7.9 to -3.5 (kcal/mol). After pathway analysis of the protein list through GeneMANIA and WebGestalt, eight interacting proteins (DPP4, FBP1, GCK, HSD11ß1, INSR, PYGL, PPARA, and PPARG) with CV were determined, and these proteins exhibited stable structures during the MD process with CV. In vitro application, statistically significant results were achieved only in combined doses with CV or metformin. Considering all these findings, PPARG and INSR, among these target proteins of CV, are FDA-approved targets for treating diabetes. Therefore, CV may be on its way to becoming a promising therapeutic compound for treating Diabetes Mellitus (DM). Our outcomes expose formerly unexplored potential target human proteins, whose association with diabetic disorders might guide new potential treatments for DM.

Comparative assessment of different anti-CD147/Basigin 2 antibodies as a potential therapeutic anticancer target by molecular modeling and dynamic simulation.

Cluster of differentiation 147 (CD147) is an attractive target for anticancer therapy since it is pivotal in developing and progressing several of malignant tumors in the context of its high expression levels. Although anti-CD147 antibodies by different laboratories are designed for the Ig-like domains of CD147, there is a demand to provide priority among these anti-CD147 antibodies for developing of therapeutic anti-CD147 antibody before experimental validations. This study uses molecular docking and dynamic simulation techniques to compare the binding modes and affinities of nine antibody models against the Ig-like domains of CD147. After obtaining the model antibodies by homology modeling via Robetta, we predicted the CDRs of nine antibodies and the epitopes of CD147 to reach more accurate results for antigen affinity in molecular docking. Next, from HADDOCK 2.4., we meticulously handpicked the most superior model clusters (Z-Score: - 2.5 to - 1.2) and identified that meplazumab had higher affinities according to the success rate as the percentage of a scoring scale. We achieved stable simulations of CD147-antibody interaction. Our outcomes hold hypothetical importance for further experimental cancer research on the design and development of the relevant model antibodies.

Exosomal Circular Ribonucleic Acid-Microribonucleic Acid Expression Profile from Plasma in Alzheimer's Disease Patients by Bioinformatics and Integrative Analysis.

OBJECTIVE: Alzheimer's disease is a neurodegenerative sickness and increasing with age throughout the world. A substantial body of evidence suggests the role of exosomal noncoding ribonucleic acids in the development of Alzheimer's disease, but the regulatory mechanisms mediated by these noncoding ribonucleic acids remain extensively unknown. Using plasma samples from Alzheimer's disease patients, this study explored the exosomal circular ribonucleic acid-microribonucleic acid profiles. MATERIALS AND METHODS: The ArrayExpress platform was used to convey data from 3 samples from each group (healthy, mild cognitive impairment, and Alzheimer's disease). Using plasma exosomes, differentially expressed microribonucleic acids and differentially expressed circular ribonucleic acids were compared between the Alzheimer's disease and mild cognitive impairment groups. Afterward, to define pathways, gene ontologies, and networks, differentially expressed microribonucleic acids and differentially expressed circular ribonucleic acids common to both mild cognitive impairment and Alzheimer's disease groups were analyzed. Eventually, the selection of hub genes and protein-protein interaction network was analyzed. RESULTS: A total of common 19 (7 upregulated and 12 downregulated) differentially expressed microribonucleic acids and 24 differentially expressed circular ribonucleic acids were recognized. A total of 4559 target genes were predicted for upregulated differentially expressed microribonucleic acids, while 6504 target genes were identified for downregulated differentially expressed microribonucleic acids, and most of the target genes involved in the phosphoinositide 3-kinases-Akt pathway and that were mostly regulated by hsa-mir-374a-3p, mir-196a-5p, let-205-5p, mir-185-3p, mir-374a-5p, mir-615-3p, let-7c-5p, mir-185-5p. Additionally, 9 hub genes (HSP90AA, ACTB, MAPK1, GSK3B, CCNE2, CDK6, AKT1, IGF1R, CCND1) were revealed as the genes considerably related to Alzheimer's disease by a protein-protein interaction network using the cytohubba in Cytoscape software. CONCLUSION: Our findings provide a new perspective on how microribonucleic acids could connect with circular ribonucleic acids in the pathogenesis of Alzheimer's disease.

Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity.

Current evidence strongly suggests that aberrant activation of the nuclear factor kappa B (NF-kB) signaling cascade is connected to carcinogenesis. The matrix metalloproteinases (MMP) which are also the key agents for tumor metastasis may be potent candidates for tumor diagnosis in clinics. In this in vitro study, we hypothesized that metformin with an effective dose can inhibit tumor cell proliferation and metastasis by modulating the expressions of MMP-2 and -9 and interfering with NF-kB signaling in primary breast cancer cells (PBCCs). 300 000 cells per ml were obtained from biopsies of breast tumors from five human donors. The cell viability and proliferation were tested. Immunocytochemistry was performed for MMP-2, MMP-9, and NF-kB, and enzyme-linked immunosorbent assay for NF-kB activity, quantitative real-time PCR for RELA/p65, IkBα, MMP-2, and MMP-9. Three different doses of metformin (5, 10, and 25 mM) (Met) reduced the viability and proliferation of PBCCs in a dose-dependent manner, maximum inhibition was observed at 25 mM Met. The expression of RELA/p65 was not affected by 25 mM Met. Nuclear immunoreactivity and activity of NF-kB reduced while cytoplasmic NF-kB (p65) elevated by 25 mM Met compared to non-treatment (P <  0.05). The expression and immunoreactivity of MMP-9 but not MMP-2 were decreased by 25 mM Met treatment, compared with the non-treatment (P <  0.05). Metformin may have an essential antitumor role in the invasion and metastasis pathways of PBCCs by downregulating the MMP-9 expression blocking both the activity and nuclear translocation of NF-kB.

Metformin promotes apoptosis in primary breast cancer cells by downregulation of cyclin D1 and upregulation of P53 through an AMPK-alpha independent mechanism

Background/aim: In the present study we aimed to figure out the effect of metformin on the expression of AMPK-alpha, cyclin D1, and Tp53, and apoptosis in primary breast cancer cells (PBCCs). Materials and methods: PBCCs were treated with two doses of metformin (0 mM, 25 mM). Proliferation was determined by BrdU as- say. Real-time PCR was used to assess AMPK-alpha, cyclin D1, and Tp53 gene expressions; apoptotic indexes of PBCCs were analyzed using flow-cytometry. Results: Twenty-four­hour incubation with 25 mM metformin reduced the proliferation of PBCCs. AMPK-alpha gene expression in PBCCs was not affected by 25 mM metformin treatment compared with the control group. PBCCs treated with 25 mM metformin had lower cyclin D1 expression compared with nontreated cells; however, the difference was not statistically significant. Twenty-five mil- limolar dose of metformin increased p53 expression significantly compared with the nontreated group. The high concentration of met- formin elevated the number of annexin V-positive apoptotic cells, and the increase in the apoptotic index was statistically significant. Conclusion: Metformin can modulate cyclin D1 and p53 expression through AMPK-alpha-independent mechanism in breast cancer cells, leading to cell proliferation inhibition and apoptosis induction.