Apple Flavonoids Suppress Carcinogen-Induced DNA Damage in Normal Human Bronchial Epithelial Cells

Scope. Human neoplastic transformation due to DNA damage poses an increasing global healthcare concern. Maintaining genomic integrity is crucial for avoiding tumor initiation and progression. The present study aimed to investigate the efficacy of an apple flavonoid fraction (AF4) against various carcinogen-induced toxicity in normal human bronchial epithelial cells and its mechanism of DNA damage response and repair processes. Methods and Results. AF4-pretreated cells were exposed to nicotine-derived nitrosamine ketones (NNK), NNK acetate (NNK-Ae), methotrexate (MTX), and cisplatin to validate cytotoxicity, total reactive oxygen species, intracellular antioxidants, DNA fragmentation, and DNA tail damage. Furthermore, phosphorylated histone (γ-H2AX) and proteins involved in DNA damage (ATM/ATR, Chk1, Chk2, and p53) and repair (DNA-PKcs and Ku80) mechanisms were evaluated by immunofluorescence and western blotting, respectively. The results revealed that AF4-pretreated cells showed lower cytotoxicity, total ROS generation, and DNA fragmentation along with consequent inhibition of DNA tail moment. An increased level of γ-H2AX and DNA damage proteins was observed in carcinogen-treated cells and that was significantly (p≤0.05) inhibited in AF4-pretreated cells, in an ATR-dependent manner. AF4 pretreatment also facilitated the phosphorylation of DNA-PKcs and thus initiation of repair mechanisms. Conclusion. Apple flavonoids can protect in vitro oxidative DNA damage and facilitate repair mechanisms

Mitochondrial DNA, a Powerful Tool to Decipher Ancient Human Civilization from Domestication to Music, and to Uncover Historical Murder Cases

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Mitochondria are unique organelles carrying their own genetic material, independent from that in the nucleus. This review will discuss the nature of mitochondrial DNA (mtDNA) and its levels in the cell, which are the key elements to consider when trying to achieve molecular identification in ancient and degraded samples. mtDNA sequence analysis has been appropriately validated and is a consistent molecular target for the examination of biological evidence encountered in forensic cases-and profiling, in certain conditions-especially for burnt bodies and degraded samples of all types. Exceptional cases and samples will be discussed in this review, such as mtDNA from leather in Beethoven's grand piano, mtDNA in mummies, and solving famous historical criminal cases. In addition, this review will be discussing the use of ancient mtDNA to understand past human diet, to trace historical civilizations and ancient trade routes, and to uncover geographical domestication origins and lineage relationships. In each topic, we will present the power of mtDNA and how, in many cases, no nuclear DNA was left, leaving mitochondrial DNA analysis as a powerful alternative. Exploring this powerful tool further will be extremely useful to modern science and researchers, due to its capabilities in providing us with previously unattainable knowledge.Peer reviewedFinal Published versio

Plant Flavonoids on Oxidative Stress-Mediated Kidney Inflammation

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Simple Summary: Increased stress is often observed in patients with kidney diseases, contributing to renal injury progression. Flavonoids are naturally occurring plant compounds with known health benefits, including antiapoptotic, anti-inflammatory, and antioxidant properties. Flavonoids can protect the kidney by improving antioxidant status, ameliorating excess reactive oxygen species levels, and acting as Nrf2-mediators in generating antioxidant responses in the body. Flavonoids also modulate inflammatory markers, exert anti-inflammatory effects, and protect the cells from apoptotic cell death in the kidney. Interestingly, few clinical trials have reported a direct correlation between a flavonoid-rich diet and better kidney disease prognosis. However, flavonoids have a low bioavailability in the body, making it essential to understand better their molecular mechanism of action. We suggest that a flavonoid-rich diet could have promising nephroprotective effects and beneficial outcomes in treating patients with kidney diseases. Abstract: The kidney is susceptible to reactive oxygen species-mediated cellular injury resulting in glomerulosclerosis, tubulointerstitial fibrosis, tubular cell apoptosis, and senescence, leading to renal failure, and is a significant cause of death worldwide. Oxidative stress-mediated inflammation is a key player in the pathophysiology of various renal injuries and diseases. Recently, flavonoids’ role in alleviating kidney diseases has been reported with an inverse correlation between dietary flavonoids and kidney injuries. Flavonoids are plant polyphenols possessing several health benefits and are distributed in plants from roots to leaves, flowers, and fruits. Dietary flavonoids have potent antioxidant and free-radical scavenging properties and play essential roles in disease prevention. Flavonoids exert a nephroprotective effect by improving antioxidant status, ameliorating excessive reactive oxygen species (ROS) levels, and reducing oxidative stress, by acting as Nrf2 antioxidant response mediators. Moreover, flavonoids play essential roles in reducing chemical toxicity. Several studies have demonstrated the effects of flavonoids in reducing oxidative stress, preventing DNA damage, reducing inflammatory cytokines, and inhibiting apoptosis-mediated cell death, thereby preventing or improving kidney injuries/diseases. This review covers the recent nephroprotective effects of flavonoids against oxidative stress-mediated inflammation in the kidney and their clinical advancements in renal therapy.Peer reviewe

DNA-dependent protein kinase: Epigenetic alterations and the role in genomic stability of cancer

DNA-dependent protein kinase (DNA-PK), a member of phosphatidylinositol-kinase family, is a key protein in mammalian DNA double-strand break (DSB) repair that helps to maintain genomic integrity. DNA-PK also plays a central role in immune cell development and protects telomerase during cellular aging. Epigenetic deregulation due to endogenous and exogenous factors may affect the normal function of DNA-PK, which in turn could impair DNA repair and contribute to genomic instability. Recent studies implicate a role for epigenetics in the regulation of DNA-PK expression in normal and cancer cells, which may impact cancer progression and metastasis as well as provide opportunities for treatment and use of DNA-PK as a novel cancer biomarker. In addition, several small molecules and biological agents have been recently identified that can inhibit DNA-PK function or expression, and thus hold promise for cancer treatments. This review discusses the impact of epigenetic alterations and the expression of DNA-PK in relation to the DNA repair mechanisms with a focus on its differential levels in normal and cancer cells

Editorial: The use of plant metabolites to ameliorate sequelae of chemotherapy

© 2023 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Peer reviewe

Siglecs in Brain Function and Neurological Disorders

Siglecs (Sialic acid-binding immunoglobulin-type lectins) are a I-type lectin that typically binds sialic acid. Siglecs are predominantly expressed in immune cells and generate activating or inhibitory signals. They are also shown to be expressed on the surface of cells in the nervous system and have been shown to play central roles in neuroinflammation. There has been a plethora of reviews outlining the studies pertaining to Siglecs in immune cells. However, this review aims to compile the articles on the role of Siglecs in brain function and neurological disorders. In humans, the most abundant Siglecs are CD33 (Siglec-3), Siglec-4 (myelin-associated glycoprotein/MAG), and Siglec-11, Whereas in mice the most abundant are Siglec-1 (sialoadhesin), Siglec-2 (CD22), Siglec-E, Siglec-F, and Siglec-H. This review is divided into three parts. Firstly, we discuss the general biological aspects of Siglecs that are expressed in nervous tissue. Secondly, we discuss about the role of Siglecs in brain function and molecular mechanism for their function. Finally, we collate the available information on Siglecs and neurological disorders. It is intriguing to study this family of proteins in neurological disorders because they carry immunoinhibitory and immunoactivating motifs that can be vital in neuroinflammation

Interplay between Epigenetics, Expression of Estrogen Receptor- α, HER2/ERBB2 and Sensitivity of Triple Negative Breast Cancer Cells to Hormonal Therapy

Triple negative breast cancer (TNBC) cells are resistant to hormonal/targeted therapies. This study aims to investigate epigenetic differences between TNBC and other types of breast cancer and the effect of epigenetic modulation on the response of TNBC cells to hormonal therapy. Thus, we investigated (i) the expression of different epigenetic markers, (ii) the effect of epigenetic modifying agents on the expression of ERα and HER2/ERBB2 and (iii) the effect on the response to tamoxifen in four breast cancer cell lines with different hormonal receptor status. Our results revealed a differential expression patterns of epigenetic markers in the four breast cancer cells. In TNBC cells, histone deacetylases (HDAC) 1 and 2 were less expressed, whereas HDACs 4 and 6 were overexpressed. Interestingly, treatment with epigenetic modifiers resulted in (i) a pronounced increase in the expression of ERα and HER2/ERBB2 along with (ii) an increase in the sensitivity of TNBC cells to tamoxifen. Collectively, this study indicates a different epigenetic background for TNBC cells, which represses the expression of ERα and HER2/ERBB2. Furthermore, we provide here the rationale for the use of epigenetic modifiers to enhance the response of TNBC to hormonal therapy through upregulation of ERα

Differential dose–response effect of cyclosporine A in regulating apoptosis and autophagy markers in MCF-7 cells

© 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1007/s10787-023-01247-4Cyclosporine A (CsA) is an immunosuppressant primarily used at a higher dosage in transplant medicine and autoimmune diseases with a higher success rate. At lower doses, CsA exhibits immunomodulatory properties. CsA has also been reported to inhibit breast cancer cell growth by downregulating the expression of pyruvate kinase. However, differential dose–response effects of CsA in cell growth, colonization, apoptosis, and autophagy remain largely unidentified in breast cancer cells. Herein, we showed the cell growth-inhibiting effects of CsA by preventing cell colonization and enhancing DNA damage and apoptotic index at a relatively lower concentration of 2 µM in MCF-7 breast cancer cells. However, at a higher concentration of 20 µM, CsA leads to differential expression of autophagy-related genes ATG1, ATG8, and ATG9 and apoptosis-associated markers, such as Bcl-2, Bcl-XL, Bad, and Bax, indicating a dose–response effect on differential cell death mechanisms in MCF-7 cells. This was confirmed in the protein–protein interaction network of COX-2 (PTGS2), a prime target of CsA, which had close interactions with Bcl-2, p53, EGFR, and STAT3. Furthermore, we investigated the combined effect of CsA with SHP2/PI3K-AKT inhibitors showing significant MCF-7 cell growth reduction, suggesting its potential to use as an adjuvant during breast cancer therapy.Peer reviewe