Faezeh Malakoti

Bio: Faezeh Malakoti is an academic researcher from Tabriz University of Medical Sciences. The author has contributed to research in topics: Medicine & DNA damage. The author has an hindex of 1, co-authored 4 publications receiving 3 citations.

Quercetin: an effective polyphenol in alleviating diabetes and diabetic complications.

Abstract: Various studies, especially in recent years, have shown that quercetin has beneficial therapeutic effects in various human diseases, including diabetes. Quercetin has significant anti-diabetic effects and may be helpful in lowering blood sugar and increasing insulin sensitivity. Quercetin appears to affect many factors and signaling pathways involved in insulin resistance and the pathogenesis of type 2 of diabetes. TNFα, NFKB, AMPK, AKT, and NRF2 are among the factors that are affected by quercetin. In addition, quercetin can be effective in preventing and ameliorating the diabetic complications, including diabetic nephropathy, cardiovascular complications, neuropathy, delayed wound healing, and retinopathy, and affects the key mechanisms involved in the pathogenesis of these complications. These positive effects of quercetin may be related to its anti-inflammatory and anti-oxidant properties. In this article, after a brief review of the pathogenesis of insulin resistance and type 2 diabetes, we will review the latest findings on the anti-diabetic effects of quercetin with a molecular perspective. Then we will review the effects of quercetin on the key mechanisms of pathogenesis of diabetes complications including nephropathy, cardiovascular complications, neuropathy, delayed wound healing, and retinopathy. Finally, clinical trials investigating the effect of quercetin on diabetes and diabetes complications will be reviewed.

Molecular mechanisms involved in DNA repair in human cancers: An overview of PI3k/Akt signaling and PIKKs crosstalk.

Abstract: The cellular genome is frequently subjected to abundant endogenous and exogenous factors that induce DNA damage. Most of the Phosphatidylinositol 3-kinase-related kinases (PIKKs) family members are activated in response to DNA damage and are the most important DNA damage response (DDR) proteins. The DDR system protects the cells against the wrecking effects of these genotoxicants and repairs the DNA damage caused by them. If the DNA damage is severe, such as when DNA is the goal of chemo-radiotherapy, the DDR drives cells toward cell cycle arrest and apoptosis. Some intracellular pathways, such as PI3K/Akt, which is overactivated in most cancers, could stimulate the DDR process and failure of chemo-radiotherapy with the increasing repair of damaged DNA. This signaling pathway induces DNA repair through the regulation of proteins that are involved in DDR like BRCA1, HMGB1, and P53. In this review, we will focus on the crosstalk of the PI3K/Akt and PIKKs involved in DDR and then discuss current achievements in the sensitization of cancer cells to chemo-radiotherapy by PI3K/Akt inhibitors.

CRISPR/Cas9 gene editing: a new approach for overcoming drug resistance in cancer

Abstract: Abstract The CRISPR/Cas9 system is an RNA-based adaptive immune system in bacteria and archaea. Various studies have shown that it is possible to target a wide range of human genes and treat some human diseases, including cancers, by the CRISPR/Cas9 system. In fact, CRISPR/Cas9 gene editing is one of the most efficient genome manipulation techniques. Studies have shown that CRISPR/Cas9 technology, in addition to having the potential to be used as a new therapeutic approach in the treatment of cancers, can also be used to enhance the effectiveness of existing treatments. Undoubtedly, the issue of drug resistance is one of the main obstacles in the treatment of cancers. Cancer cells resist anticancer drugs by a variety of mechanisms, such as enhancing anticancer drugs efflux, enhancing DNA repair, enhancing stemness, and attenuating apoptosis. Mutations in some proteins of different cellular signaling pathways are associated with these events and drug resistance. Recent studies have shown that the CRISPR/Cas9 technique can be used to target important genes involved in these mechanisms, thereby increasing the effectiveness of anticancer drugs. In this review article, studies related to the applications of this technique in overcoming drug resistance in cancer cells will be reviewed. In addition, we will give a brief overview of the limitations of the CRISP/Cas9 gene-editing technique.

miRNAs as potential game-changers in bone diseases: Future medicinal and clinical uses.

Abstract: MicroRNAs (miRNAs), short, highly conserved non-coding RNA, influence gene expression by sequential mechanisms such as mRNA breakdown or translational repression. Many biological processes depend on these regulating substances, thus changes in their expression have an impact on the maintenance of cellular homeostasis and result in the emergence of a variety of diseases. Relevant studies have shown in recent years that miRNAs are involved in many stages of bone development and growth. Additionally, abnormal production of miRNA in bone tissues has been closely associated with the development of numerous bone disorders, such as osteonecrosis, bone cancer, and bone metastases. Many pathological processes, including bone loss, metastasis, the proliferation of osteosarcoma cells, and differentiation of osteoblasts and osteoclasts, are under the control of miRNAs. By bringing together the most up-to-date information on the clinical relevance of miRNAs in such diseases, this study hopes to further the study of the biological features of miRNAs in bone disorders and explore their potential as a therapeutic target.

Molecular mechanisms involved in DNA repair in human cancers: An overview of PI3k/Akt signaling and PIKKs crosstalk.

Abstract: The cellular genome is frequently subjected to abundant endogenous and exogenous factors that induce DNA damage. Most of the Phosphatidylinositol 3-kinase-related kinases (PIKKs) family members are activated in response to DNA damage and are the most important DNA damage response (DDR) proteins. The DDR system protects the cells against the wrecking effects of these genotoxicants and repairs the DNA damage caused by them. If the DNA damage is severe, such as when DNA is the goal of chemo-radiotherapy, the DDR drives cells toward cell cycle arrest and apoptosis. Some intracellular pathways, such as PI3K/Akt, which is overactivated in most cancers, could stimulate the DDR process and failure of chemo-radiotherapy with the increasing repair of damaged DNA. This signaling pathway induces DNA repair through the regulation of proteins that are involved in DDR like BRCA1, HMGB1, and P53. In this review, we will focus on the crosstalk of the PI3K/Akt and PIKKs involved in DDR and then discuss current achievements in the sensitization of cancer cells to chemo-radiotherapy by PI3K/Akt inhibitors.

Redoxisome and Diabetic Retinopathy: Pathophysiology and Therapeutic Interventions.

Abstract: Diabetic retinopathy (DR) is a chronic microvascular complication of diabetes mellitus (DM). It is a worldwide growing epidemic disease considered to be the leading cause of vision-loss and blindness in people with DM. Redox reactions occurring at the extra- and intracellular levels are essential for the maintenance of cellular homeostasis. Dysregulation of redox homeostasis are implicated in the onset and development of DR. Thioredoxin1 (TRX1) and Thioredoxin2 (TRX2) are cytoplasmic and mitochondrially localized antioxidant proteins ubiquitously expressed in various cells and control cellular reactive oxygen species (ROS) by reducing the disulfides into thiol groups. Thioredoxin-interacting protein (TXNIP) binds to TRX system and inhibits the active reduced form of TRX through disulfide exchange reaction. Recent studies indicate the association of TRX/TXNIP with redox signal transduction pathways including activation of Nod-like receptor pyrin domain containing protein-3 (NLRP3) inflammasome, apoptosis, autophagy/mitophagy, epigenetic modifications in a redox-dependent manner. Thus, it is important to gain a more in-depth understanding about the cellular and molecular mechanisms that links redoxisome and ER/Mitochondrial dysfunction to drive the progression of DR. The purpose of this review is to provide a mechanistic understanding of the complex molecular mechanisms and pathophysiological roles associated with redoxisome, the TRX/TXNIP redox signaling complex under oxidative stress in the development of DR. Also, the molecular targets of FDA approved drugs and clinical trials in addition to effective antioxidant strategies for the treatment of diabetic retinopathy are reviewed.

Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy

Abstract: DNA double-strand break (DSB) is considered the most deleterious type of DNA damage, which is generated by ionizing radiation (IR) and a subset of anticancer drugs. DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts as the molecular sensor for DSB and plays a pivotal role in DSB repair through non-homologous end joining (NHEJ). Cells deficient for DNA-PKcs show hypersensitivity to IR and several DNA-damaging agents. Cellular sensitivity to IR and DNA-damaging agents can be augmented by the inhibition of DNA-PK. A number of small molecules that inhibit DNA-PK have been developed. Here, the development and evolution of inhibitors targeting DNA-PK for cancer therapy is reviewed. Significant parts of the inhibitors were developed based on the structural similarity of DNA-PK to phosphatidylinositol 3-kinases (PI3Ks) and PI3K-related kinases (PIKKs), including Ataxia-telangiectasia mutated (ATM). Some of DNA-PK inhibitors, e.g., NU7026 and NU7441, have been used extensively in the studies for cellular function of DNA-PK. Recently developed inhibitors, e.g., M3814 and AZD7648, are in clinical trials and on the way to be utilized in cancer therapy in combination with radiotherapy and chemotherapy.

Metformin Attenuates UVA-Induced Skin Photoaging by Suppressing Mitophagy and the PI3K/AKT/mTOR Pathway

Abstract: Ultraviolet (UV) radiation is a major cause of photoaging that can induce DNA damage, oxidative stress, and cellular aging. Metformin (MF) can repair DNA damage, scavenge reactive oxygen species (ROS), and protect cells. However, the mechanism by which MF inhibits cell senescence in chronic skin damage induced by UVA is unclear. In this study, human foreskin fibroblasts (HFFs) treated with UVA were used as an in vitro model and UVA-induced skin photoaging in Kunming mice was used as an in vivo model to investigate the potential skin protective mechanism of MF. The results revealed that MF treatment attenuated UVA-induced cell viability, skin aging, and activation of the PI3K/AKT/mTOR signaling pathway. Furthermore, MF treatment alleviated the mitochondrial oxidative stress and decreased mitophagy. Knockdown of Parkin by siRNA increased the clearance of MF in senescent cells. The treatment of Kunming mice with MF at a dose of 10 mg/kg/day significantly reduced UVA-induced skin roughness, epidermal thinning, collagen degradation, and skin aging. In conclusion, our experimental results suggest that MF exerts anti-photoaging effects by inhibiting mitophagy and the PI3K/AKT/mTOR signaling pathway. Therefore, our study improves the current understanding of the protective mechanism of MF against photoaging.