Objective: PTEN, a tumor-suppressor gene, located on chromosome 10q23.3, is implicated in various types of cancer including breast cancer. The aim of this study is to investigate the promoter methylation, loss of expression and significance of PTEN gene in breast cancer and to determine the correlation between promoter methylation and gene expression. Methods: Promoter methylation and loss of expression of PTEN gene were analyzed using methylation-specific PCR and immunohistochemical methods respectively. The chi square test is used to correlate the promoter methylation and gene expression with their clincopathologic parameters. Results: We examined 53 breast cancer specimens and 10 normal tissues adjacent to tumor. The results showed a 58.5% promoter methylation in PTEN gene and none in normal tissue. PTEN methylation was observed in advanced stages III-IV (81.8%, 18 of 22, P=0.015) and higher grades G2-G3 (71.4%, 20 of 28, P=0.043) of disease. The correlation of PTEN methylation with clinical stage and tumor grade was found to be statistically significant. Nuclear PTEN expression was detected in 73.6% (39 of 53) cases of breast cancer and in the remaining 26.4% (14 of 53) cases expressional loss was observed. The loss of PTEN expression was observed in all normal tissues (10 of 10). The loss of PTEN expression was significantly correlated with patient’s age (P=0.028) and clinical stage (P = 0.029). The expressional loss was observed in 12 (38.7%) cases among 31 methylation positive cases, whereas among 22 methylation- negative cases, only 2 (9.1%) cases were seen as immunostaining negative with the statistically significant value (P=0.016). Conclusion: Promoter methylation and loss of expression of PTEN gene occur frequently in breast cancer. Our results suggest that PTEN plays an important role in breast carcinogenesis.
Glycation is the result of covalent bonding of a free amino group of biological macromolecules with a reducing sugar, which results in the formation of a Schiff base that undergoes rearrangement, dehydration and cyclization to form a more stable Amadori product. The final products of nonenzymatic glycation of biomacromolecules like DNA, proteins and lipids are known as advanced glycation end products (AGEs). AGEs may be generated rapidly or over long times stimulated by distinct triggering mechanisms, thereby accounting for their roles in multiple settings and disease states. Both Schiff base and Amadori glycation products generate free radicals resulting in decline of antioxidant defense mechanisms and can damage cellular organelles and enzymes. This critical review primarily focuses on the mechanistic insight of glycation and the most probable route for the formation of glycation products and their therapeutic interventions. Furthermore, the prevention of glycation reaction using therapeutic drugs such as metformin, pyridoxamine and aminoguanidine (AG) are discussed with special emphasis on the novel concept of the bioconjugation of these drugs like, AG with gold nanoparticles (GNPs). At or above 10 mM concentration, AG is found to be toxic and therefore has serious health concerns, and the study warrants doing this novel bioconjugation of AG with GNPs. This approach might increase the efficacy of the AG at a reduced concentration with low or no toxicity. Using the concept of synthesis of GNPs with abovementioned drugs, it is assumed that toxicity of various drugs which are used at high doses can be minimized more effectively.
Differentiation of muscle satellite cells (MSCs) involves interaction of the proteins present in the extracellular matrix (ECM) with MSCs to regulate their activity, and therefore phenotype. Herein, we report fibromodulin (FMOD), a member of the proteoglycan family participating in the assembly of ECM, as a novel regulator of myostatin (MSTN) during myoblast differentiation. In addition to having a pronounced effect on the expression of myogenic marker genes [myogenin (MYOG) and myosin light chain 2 (MYL2)], FMOD was found to maintain the transcriptional activity of MSTN. Moreover, coimmunoprecipitation and in silico studies performed to investigate the interaction of FMOD helped confirm that it antagonizes MSTN function by distorting its folding and preventing its binding to activin receptor type IIB. Furthermore, in vivo studies revealed that FMOD plays an active role in healing by increasing satellite cell recruitment to sites of injury. Together, these findings disclose a hitherto unrecognized regulatory role for FMOD in MSCs and highlight new mechanisms whereby FMOD circumvents the inhibitory effects of MSTN and triggers myoblast differentiation. These findings offer a basis for the design of novel MSTN inhibitors that promote muscle regeneration after injury or for the development of pharmaceutical agents for the treatment of different muscle atrophies.—Lee, E. J., Jan, A. T., Baig M. H., Ashraf, J. M., Nahm, S.-S., Kim, Y.-W., Park, S.-Y., Choi, I. Fibromodulin: a master regulator of myostatin controlling progression of satellite cells through a myogenic program. FASEB J. 30, 2708-2719 (2016). www.fasebj.org
Introduction: SARS-CoV2, first reported in December 2019 in Wuhan as COVID-19 causing respiratory illness, rapidly evolved into a pandemic owing to its very high infectivity. There is insufficient evidence about if and how smoking affects the risk of COVID-19 infection, and the reports on whether smoking increases or reduces the risk of respiratory infections, are contradictory. Therefore, the current study was designed to determine the effects of nicotine consumption on the infectivity of COVID-19.
Methods: We performed in silico computer simulation-based study. The structures of SARS-CoV2spike ectodomain, and its receptor ACE2, were obtained from PDB. The structure of nicotine and its metabolites NNK and NNAL were obtained from the PubChem chemical database. After optimization, they were interacted using AutoDock 4.2, to see the effect of nicotine, NNK, or NNAL presence on the docking of viral spike protein to its receptor ACE2.
Results: ACE2 vs spike protein interaction results were used as a control (ZDOCK score 1498.484, with four hydrogen bonds). The NNK+ACE2 vs spike protein docking formed 10 hydrogen bonds with the highest ZDOCK score of 1515.564. NNAL+ ACE2 vs spike protein interaction formed eleven hydrogen bonds with the ZDOCK score of 1499.371. Nicotine+ACE2 vs spike protein docking showed the lowest ZDOCK score of 1496.302 and formed 8 hydrogen bonds. Whereas, NNK+spike vs ACE2 interaction had a ZDOCK score of 1498.490 and formed eight hydrogen bonds. NNAL+spike vs ACE2 docking formed eleven hydrogen bonds with a ZDOCK score of 1498.482. And Nicotine+spike vs ACE2 interaction showed a ZDOCK score of 1498.488 and formed 9 hydrogen bonds.
Conclusions: The binding of nicotine to either spike of virus or its receptor ACE2 is not affecting the viral docking with the receptor. But binding of NNK, a metabolite of nicotine, is facilitating the viral docking with its receptor indicating that smoking may increase the risk of COVID-19 infection.
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